bluuebunny/crossref_metadata_2025 huggingface dataset:
Proteomic analysis of supernatants of stored red blood cell products
Authors: Anniss Angela M. , Glenister Kristen M. , Killian Jessica J. , Sparrow Rosemary L.
Published: August 2006

BACKGROUND: The development of the red blood cell (RBC) storage lesion remains incompletely understood. To gain a greater insight into the mechanisms involved, a proteomics analysis was used to identify proteins that accumulate in supernatants of standard nonleukoreduced RBC products (S‐RBCs) and prestorage leukofiltered RBC products (LF‐RBCs) during storage.

STUDY DESIGN AND METHODS: S‐RBCs and LF‐RBCs were collected and stored in accordance with standard blood bank procedures. Supernatant samples were collected at fortnightly intervals until product expiry (at Day 42). Maps of supernatant proteins were generated by two‐dimensional (2D)‐gel electrophoresis and selected proteins were identified by mass spectrometry.

RESULTS: 2D‐gel mapping revealed that greater numbers of proteins accumulated in supernatants of S‐RBCs compared to LF‐RBCs. Abundant plasma proteins were strongly represented in both products. Several potentially bioactive proteins were found to predominantly accumulate in supernatant of S‐RBCs. Among these, a promoter of neutrophil adhesion and an acute‐phase scavenger protein were identified. In contrast, proteins found to accumulate predominantly in supernatant of LF‐RBCs were RBC‐regulatory proteins.

CONCLUSION: Proteomics provides a valuable approach to examine storage‐related effects on RBCs. Such analytical approaches may help to elucidate the mechanisms involved in the RBC storage lesion and provide insights into the biologic consequences of transfusion of stored RBC products.
A multicenter assessment of recombinant factor VIIa off‐label usage: clinical experiences and associated outcomes
Authors: MacLaren Robert , Weber Laura A. , Brake Helga , Gardner Melinda A. , Tanzi Mario
Published: August 2006

BACKGROUND: Off‐label use of recombinant factor VIIa (rFVIIa) occurs despite minimal data. The purpose of this study was to describe prescribing practices and clinical outcomes for off‐label rFVIIa use.

STUDY DESIGN AND METHODS: A retrospective, multicenter chart audit of 315 nonhemophiliac patients was performed.

RESULTS: Off‐label indications included prevention of bleeding primarily related to procedural manipulation in 37.8 percent of patients and treatment of bleeding in 62.2 percent of patients. Baseline coagulopathy was present in 79.7 percent of patients. Prescriber specialty varied. The median doses for prevention and treatment were 75.6 and 89.4 µg per kg, respectively (p = 0.0006). The international normalized ratio (INR) decreased (p < 0.0001) from baseline in both groups. Transfusions of blood products were provided to 85.1 percent of patients before rFVIIa administration with considerable practice variation. Few patients received other procoagulant agents. In the prevention group, 14.3 percent of patients bled within 6 hours of their procedure. No variable was independently associated with bleeding prevention. In the treatment group, 52.6 percent of patients stopped bleeding within 6 hours of rFVIIa administration. The only independent variable associated with bleeding cessation was an arterial pH value of less than 7.20, which was a negative predictor (odds ratio, 0.207; 95% confidence interval, 0.084‐0.507). Possible rFVIIa‐associated adverse events occurred in 9.8 percent of patients and primarily involved undesirable clotting. No variable was independently associated with adverse events.

CONCLUSIONS: Off‐label use of rFVIIa includes prevention and treatment of bleeding. rFVIIa is associated with INR reduction. Bleeding is rare with prophylactic rFVIIa but the cessation of bleeding is less than reported in the literature and may be related to pH. Possible adverse events are related to undesirable clotting.
Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S‐59) and ultraviolet A light
Authors: Yarranton Helen , Lawrie Andrew S. , Mackie Ian J. , Pinkoski Linda , Corash Laurence , Machin Samuel J.
Published: August 2006

BACKGROUND: The standard treatment for thrombotic thrombocytopenic purpura (TTP) is plasma exchange with fresh‐frozen plasma (FFP). Exposure to large volumes of FFP increases the risk of transfusion‐transmitted infections. Cryosupernatant (CSP) offers a theoretical advantage over FFP, because it lacks the large von Willebrand factor (VWF) forms implicated in the pathogenesis of TTP. This study compared the hemostatic variables of CSP prepared from FFP treated with a photochemical pathogen inactivation process to CSP prepared from conventional FFP.

STUDY DESIGN AND METHODS: Forty CSP units were prepared from North American blood group A donor FFP. Twenty‐one of the FFP units were individually treated with amotosalen hydrochloride (S‐59) and ultraviolet A light (test, photochemically treated FFP), and 19 units were not treated (control, FFP).

RESULTS: Hemostatic variables of test and control CSP were similar and within reported ranges for conventional FFP with the exception of those properties depleted in CSP. VWF‐cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP. There were statistical differences between test and control CSP for α2‐antiplasmin, antithrombin, protein C, and VWF:CP on a per‐volume basis, but all levels were within the reference range for FFP, and the differences were not significant when expressed per gram of CSP protein.

CONCLUSION: S‐59–treated CSP retained adequate levels of critical plasma proteins for plasma exchange therapy in acute TTP. The data indicate good preservation of hemostasis control proteins such as PS, α2‐antiplasmin, and VWF:CP activity (ADAMTS13).
Leishmania inactivation in human pheresis platelets by a psoralen (amotosalen HCl) and long‐wavelength ultraviolet irradiation
Authors: Eastman Richard T. , Barrett Lynn K. , Dupuis Kent , Buckner Frederick S. , Van Voorhis Wesley C.
Published: August 2006

BACKGROUND: Leishmania spp. are protozoans that cause skin and visceral diseases. Leishmania are obligate intracellular parasites of mononuclear phagocytes and have been documented to be transmitted by blood transfusion.

STUDY DESIGN AND METHODS: This study examines whether Leishmania can be inactivated in human platelet (PLT) concentrates by a photochemical treatment process that is applicable to blood bank use. Human PLT concentrates were contaminated with Leishmania mexicana metacyclic promastigotes or mouse‐derived Leishmania major amastigotes and were exposed to long‐wavelength ultraviolet (UV) A light (320‐400 nm) plus the psoralen amotosalen HCl.

RESULTS: Neither treatment with amotosalen nor UVA alone had an effect on Leishmania viability; however, treatment with 150 µmol per L amotosalen plus 3 J per cm2 UVA inactivated both metacyclic promastigotes and amastigotes to undetectable levels, more than a 10,000‐fold reduction in viability.

CONCLUSIONS: This study demonstrates the effectiveness of photochemical treatment to inactivate Leishmania in PLT concentrates intended for transfusion. Both metacylic promastigotes, which represent the infectious form from the sand fly vector, and amastigotes, which represent the form that grows in mononuclear phagocytes, were extremely susceptible to photochemical inactivation by this process. Thus, the photochemical treatment of PLT concentrates inactivates both forms of Leishmania that would be expected to circulate in blood products collected from infected donors.
Cardiogenic shock complicates successful treatment of refractory thrombotic thrombocytopenia purpura with rituximab
Authors: Millward P.M. , Bandarenko N. , Chang P.P. , Stagg K.F. , Afenyi‐Annan A. , Hay S.N. , Brecher M.E.
Published: August 2006

BACKGROUND: Treatment of thrombotic thrombo‐cytopenia purpura (TTP) with daily therapeutic plasma exchange (TPE) may be accompanied by a variety of adjunctive interventions including most recently rituximab. Rituximab, a murine and human monoclonal antibody directed against CD20 antigen on B lymphocytes, is primarily used for treatment of non‐Hodgkin's lymphomas. Because of severe and fatal infusion reactions including heart failure, rituximab carries a boxed warning.

CASE REPORT: A 20‐year‐old female presented with TTP. She underwent 17 daily (1 day skipped) TPE. Her platelet (PLT) count reached 150 × 109 per L and then gradually declined to 36 × 109 per L despite continuing TPE. Because of the refractory behavior of her disease, rituximab was administered. After the rituximab infusion, she developed a nonproductive cough which progressed to a productive cough, acute respiratory failure, chest pain, and hypotension and was moved to intensive care for management of biventricular cardiogenic shock (ejection fraction was 5%‐10%). Once stable in the intensive care unit, TPE was resumed. Her PLT count reached 241 × 109 per L, and her lactate dehydrogenase decreased to normal after four TPEs. Her heart failure completely resolved and she was discharged. Rituximab was added to her medical record as a drug allergy.

CONCLUSION: Refractory TTP has been reported to respond favorably to rituximab when used as an adjunct. Interventions, however, can also carry significant risk as illustrated by the cardiogenic shock in our patient. Use of rituximab for refractory TTP should follow a careful assessment of benefits.
High‐Resolution Mapping Around the Eustachian Ridge During Typical Atrial Flutter
Authors: HUANG JIN‐LONG , TAI CHING‐TAI , LIU TU‐YING , LIN YENN‐JIANG , LEE PI‐CHANG , TING CHIH‐TAI , CHEN SHIH‐ANN
Published: August 2006

Background: Although the reentrant circuit of typical atrial flutter (AFL) has been well recognized, the activation around the Eustachian ridge (ER) has not been fully characterized. The aim of this study was to delineate the activation patterns around the ER during typical AFL using high‐resolution noncontact mapping.

Methods: Fifty‐three patients (M/F = 43/10, 62 ± 14 years) with typical AFL were included. The high‐resolution mapping of the right atrium using a noncontact mapping system during AFL and pacing from the coronary sinus (CS) was performed to evaluate the conduction through the ER.

Results: Three types of activation patterns around the ER could be classified according to the ER conduction during AFL and CS pacing. Type I (n = 21, M/F = 16/5, 61 ± 13 years) exhibited conduction block at the ER during AFL and CS pacing. The local unipolar electrograms at the ER exhibited long double potentials (DPs) (109 ± 12 ms, range 77–153 ms) during AFL and CS pacing (84 ± 18 ms, range 48–129 ms). Type II (n = 8, M/F = 7/1, 61 ± 15 years) exhibited conduction block at the ER during AFL, but conduction through the ER during CS pacing. The unipolar electrograms exhibited long DPs (119 ± 12 ms, range 97–141 ms) at the ER during the tachycardia and an rS pattern during CS pacing. Type III (n = 24, M/F = 20/4, 61 ± 16 years) exhibited an activation wavefront that passed along the ER, with the sinus venosa as the posterior barrier during AFL. During CS pacing, all cases exhibited conduction through the ER with an rS pattern.

Conclusions: This study is the first to demonstrate the three patterns of activation along the ER during AFL and CS pacing. This finding suggested that the ER is an anatomic and functional barrier during typical AFL.
The Impact of CT Image Integration into an Electroanatomic Mapping System on Clinical Outcomes of Catheter Ablation of Atrial Fibrillation
Authors: KISTLER PETER M. , RAJAPPAN KIM , JAHNGIR MOHAMMED , EARLEY MARK J. , HARRIS STUART , ABRAMS DOMINIC , GUPTA DHIRAJ , LIEW REGINALD , ELLIS STEPHEN , SPORTON SIMON C. , SCHILLING RICHARD J.
Published: August 2006

Background: A detailed appreciation of left atrial/pulmonary vein (LA/PV) anatomy may be important in improving the safety and success of catheter ablation (CA) for atrial fibrillation (AF).

Objectives: The aim of this nonrandomized study was to determine the impact of computerized tomography (CT) image integration into a 3‐dimensional (3D) mapping system on the clinical outcome of patients undergoing CA for AF.

Methods: Ninety‐four patients (age: 56 ± 10 years) with AF (paroxysmal 46, persistent 48) underwent wide encirclement of ipsilateral PV pairs using irrigated radiofrequency ablation with the endpoint of electrical isolation. Ablation was guided by 3D mapping alone (electroanatomic 24, noncontact 23) in 47 (3DM group) patients and by CT image integration (Cartomerge®) in 47 (CT group). In persistent AF, a combination of linear ablation and targeted ablation of complex fractionated electrograms was also performed.

Results: Successful PV electrical isolation did not differ between the two groups. A significant reduction in fluoroscopy times was demonstrated in the CT group (49 ± 27 minutes vs 3DM group 62 ± 26 minutes, P = 0.03). Arrhythmia recurrence was reduced in the CT group (32% vs 51% in the 3DM group, P < 0.01). In 30 symptomatic patients (12 CT and 18 3DM), repeat procedures for AF (13 in 3DM and 5 CT, P ≤ 0.10) and AT (5 in 3DM and 7 CT, P = NS) were performed. Overall success on 7‐day monitor off antiarrhythmic drugs was achieved in 60% in the 3DM group when compared with 83% in the CT group (P < 0.05) at a follow‐up of 25 ± 5 weeks.

Conclusion: CA for AF guided by CT integration was associated with reduced fluoroscopy times, arrhythmia recurrence, and increased restoration of sinus rhythm. Improved visualization of complex LA geometries might improve the safety and success of CA for AF.
Thermal Stability of (1−x)BiScO3−xPbTiO3 Piezoelectric Ceramics for High‐Temperature Sensor Applications
Authors: Chen Si , Dong Xianlin , Mao Chaoliang , Cao Fei
Published: August 2006

High‐temperature piezoelectric (1−x)BiScO3−xPbTiO3 ceramics with composition (x=0.62, 0.63, 0.64, and 0.65) near the morphotropic phase boundary were fabricated. A thermal depoling experiment was used to investigate the stability of polarization at the temperature range from 200° to 460°C. The results indicated that samples with rhombohedral phase began to depole when the temperature was higher than 300°C, while samples with a tetragonal phase showed good resistance to thermal depoling up to 440°C, close to their Curie temperature.
Degradation Mechanism of Dielectric Loss in Barium Niobate Under a Reducing Atmosphere
Authors: Kim Dong‐Wan , Kim Byung‐Kook , Je Hae‐June , Park Jae‐Gwan , Kim Jeong‐Ryeol , Hong Kug Sun
Published: August 2006

We developed multilayer ceramic capacitors (MLCCs) of the type negative–positive zero (NP0) cofired with Cu inner electrodes using novel low‐loss barium niobates. The excellent dielectric properties of ceramics and compatibility between electrodes and dielectrics under a reducing atmosphere led to low loss character in the Cu‐MLCCs, even in the high‐frequency single‐layer capacitors. We also examine the atmospheric dependence on dielectric loss of barium niobates. The origin of degradation in dielectric loss under a highly reducing atmosphere is explained by the association of two loss mechanisms: the oxygen vacancies in NbO6 octahedra and the subsequent formation of a reduced second phase: Ba3Nb4+Nb5+4O15.
Rapid Formation of Active Mesoporous TiO2 Photocatalysts via Micelle in a Microwave Hydrothermal Process
Authors: Wang Hong‐Wen , Kuo Chien‐Hung , Lin Hsiu‐Chu , Kuo I.‐Ting , Cheng Chi‐Feng
Published: August 2006

Rapid formation of active, mesoporous, and crystalline TiO2 photocatalysts via a novel microwave hydrothermal process is presented. Crystalline anatase mesoporous nanopowders 100–300 nm in size with worm hole‐like pore sizes of 3–5 nm were prepared by a modified sol–gel of titanium tetra‐isopropoxide, accelerated by a microwave hydrothermal process. The organic surfactant, tetradecylamine, which is used as a self‐assembly micelle in the sol–gel and microwave hydrothermal process, enables to harvest crystallized mesoporous anatase nanoparticles with a high‐surface area. Mesoporous worm hole‐like and crystalline powders with surface areas of 243–622 m2/g are obtained. X‐ray diffraction, N2‐adsorption isotherms (Barrett–Joyner–Halenda and Brunauer–Emmet–Teller method), scanning electron microscope, and transmission electron microscope are used to identify the characteristics and morphologies of the powders. It is shown that crystallization by calcination at 400°C/3 h inevitably reduced the surface area, while the microwave hydrothermal process demonstrated a rapid formation of crystalline mesoporous TiO2 nanopowders with a high‐surface area and excellent photocatalytic effects.
Generation and distribution of reactive oxygen species in the skin of hairless mice under UVA: studies on in vivo chemiluminescent detection and tape stripping methods
Authors: Nishimura Hitoshi , Yasui Hiroyuki , Sakurai Hiromu
Published: August 2006

Abstract:  Although the formation of reactive oxygen species (ROS) in the skin induced by the ultraviolet (UV) light has been shown to lead to many cutaneous disorders, skin cancer and photoageing, the mechanism and distribution of ROS generation has not yet been definitively determined. In the present study, we examined the distribution of UVA‐induced ROS in the skin of live hairless mice, using our proposed in vivo imaging chemiluminescent (CL) method to detect ROS combined with a CL probe (cypridina hilgendorfii luciferin analogue; CLA) and tape stripping (TS) technique. The CL intensities in the skin of live hairless mice were confirmed to significantly increase by UVA exposure. When TS was conducted five times in a maximum level after CL measurement following UVA exposure and subsequent CLA application, CL intensities due to UVA‐induced ROS generation in the residual skin decreased to 10% of the original levels; and those in the stripped skin on each tape decreased in the stripped order such as 52%, 16%, 11%, 6% and 5%. Next, CLA was applied and then CL intensities were measured in the residual skin after advance 1, 3 and 5 tape strippings, and CL intensities due to ROS were detected primarily in the outer layer of the skin. On the basis of these results, we concluded that ROS induced by UVA exposure occurs and distributes in the outermost layer of the stratum corneum.
Glutathione S‐transferase and CYP1A1 gene polymorphisms and non‐melanoma skin cancer risk in Italian transplanted patients
Authors: Lira Macarena Gomez , Provezza Lisa , Malerba Giovanni , Naldi Luigi , Remuzzi Giuseppe , Boschiero Luigino , Forni Alberto , Rugiu Carlo , Piaserico Stefano , Alaibac Mauro , Turco Alberto , Girolomoni Giampiero , Tessari Gianpaolo
Published: August 2006

Abstract:  Solid organ transplant recipients are at higher risk of non‐melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S‐transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1–2.5); P = 0.017]. Homozygosity for allele GSTP1 Val105 was lower in cases [OR 0.3 (0.1–0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0–0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4–6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val462 genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val462, show a higher risk of developing NMSC [OR 4.5 (1.1–21.4); P = 0.03], especially SCC [OR 6.5 (1.4–34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val462 are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.
Non‐steroidal anti‐inflammatory drugs selectively inhibit cytokine production by NK cells andγδT cells
Authors: Inaoka Miyuki , Kimishima Momoko , Takahashi Ryo , Shiohara Tetsuo
Published: August 2006

Abstract: Non‐steroidal anti‐inflammatory drugs (NSAIDs) are known to be risk factors for a systemic inflammatory syndrome in viral infections. Innate immune cells are likely to represent the preferential targets for the deleterious effects of NSAIDs in patients with viral infections. We therefore examined whether various classes of NSAIDs could selectively inhibit cytokine production by innate immune cells. NSAIDs selectively inhibited interferon (IFN)‐γand tumor necrosis factor (TNF)‐αproduction by natural killer (NK) andγδT cells with each NSAID displaying its own unique pattern of inhibition, while sparing that by acquired immune cells. These inhibitions were independent on cyclooxygenase inhibition. These NSAIDs directly inhibited the cytokine production by the purifiedγδT‐cell population without involving other cell populations. The selective inhibition of the early generation of IFN‐γand TNF‐αfrom NK andγδT cells by NSAIDs may serve to drive the subsequent acquired immune responses towards a Th2 phenotype, leading to the aggravation of allergic symptoms. Our results provide a mechanism to explain the deleterious effects of NSAIDs on clinical symptoms of viral infections and allergic diseases and suggest more targeted use depending on the type of disease.
Modulation of melatonin receptors and G‐protein function by microtubules
Authors: Jarzynka Michael J. , Passey Deepshikha K. , Ignatius Paul F. , Melan Melissa A. , Radio Nicholas M. , Jockers Ralf , Rasenick Mark M. , Brydon Lena , Witt‐Enderby Paula A.
Published: August 2006

Abstract:  Chronic melatonin exposure produces microtubule rearrangements in Chinese hamster ovary (CHO) cells expressing the human MT1 melatonin receptor while at the same time desensitizing MT1 receptors. Because microtubule rearrangements parallel MT1 receptor desensitization, we tested whether microtubules modulate receptor responsiveness. We determined whether depolymerization of microtubules by Colcemid, which prevents melatonin‐induced outgrowths in MT1‐expressing CHO cells, also prevents MT1 receptor desensitization by affecting G‐GTP exchange on G‐proteins. In this study, we found that depolymerization of microtubules in MT1 receptor expressing cells, prevented melatonin‐induced receptor desensitization reflected by an increase in the number of high potency sites when compared with melatonin‐treated cells. Further examination of the mechanism(s) underlying this desensitization suggested that these effects occurred at the level of G‐proteins. Depolymerization of microtubules during melatonin‐induced desensitization, attenuated forskolin‐induced cAMP accumulation, the opposite of which usually occurs following melatonin exposure alone. Concomitant to this attenuation in the forskolin response was a reduction in the amount of Giα protein coupled to MT1 receptors and an increase in [32P] azidoanilido GTP incorporation into Gi proteins. These data are consistent with the findings that microtubule depolymerization did not affect MT1/Gq coupling nor did it affect melatonin‐induced phosphoinositide hydrolysis following melatonin exposure. However, interestingly, microtubule depolymerization enhanced melatonin‐induced protein kinase C activation that was blocked in the presence of pertussis toxin. These data demonstrate that microtubule dynamics can modulate melatonin receptor function through their actions on Gi proteins and impact on downstream signaling cascades.
Female Sexual Satisfaction and Pharmaceutical Intervention: A Critical Review of the Drug Intervention Studies in Female Sexual Dysfunction
Authors: Nijland Esmé , Davis Susan , Laan Ellen , Schultz Willibrord Weijmar
Published: August 2006

Introduction

A considerable number of double-blind randomized controlled studies investigating the effects of pharmaceutical intervention on female sexual functioning have been published in recent years. However, a comparison between outcomes of various studies is difficult as no generally accepted/correct approach to research has been established yet. To be able to translate trial results to daily clinical practice, current limitations and issues in drug intervention studies in female sexual dysfunction (FSD) need to be clarified.

Aim

To evaluate the needs in research into intervention in FSD by reviewing published studies.

Methods

A systematic review of double-blind randomized controlled intervention trials on FSD.

Main Outcome Measures

Definitions of study populations, inclusion and exclusion criteria, use of power calculations, outcome measures and treatment duration.

Results

A total of 25 double-blind randomized controlled trials investigating the effects of pharmaceutical intervention on female sexual functioning have been published. Of these, 11 studies required the diagnosis of FSD as an inclusion criterion. A standard methodology for research in this field is lacking. Significant differences in population inclusion requirements and tools for the measurement of change in sexual functioning were identified as major limiting factors.

Conclusions

The investigation of FSD is an evolving area in that new definitions and a new model for female sexual functioning have been recently proposed. There is a need for experts in the field and regulating authorities to reach a consensus regarding appropriate inclusion and exclusion criteria for FSD trials and main outcome measures appropriate for the evaluation of drug interventions. This consensus should also determine which treatment effect is considered to be clinically relevant. Treatment efficacy and clinical relevance should be related to outcomes which are meaningful for affected women.
Obesity, Dyslipidemias and Erectile Dysfunction: A Report of a Subcommittee of the Sexual Medicine Society of North America
Authors: Mulhall John , Teloken Patrick , Brock Gerald , Kim Edward
Published: August 2006

Because of increasingly sedentary lifestyles and diets higher in saturated fats, obesity and dyslipidemias are common and increasing in prevalence in Westernized countries. Longitudinal population-based studies clearly demonstrate that dyslipidemias and obesity, as well as factors such as hypertension, diabetes, and smoking, are major risk factors for atherosclerosis. Both clinical and animal models of endothelial dysfunction confirm that atherosclerosis leads to increased cerebrovascular and cardiovascular morbidity. Clinical studies with hypolipidemic agents demonstrate that hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can decrease the risk of vascular morbidity. An increasing body of evidence from animal models demonstrates that hypercholesterolemia and atherosclerosis are risk factors for the development of erectile dysfunction (ED). This causal relationship between obesity and dyslipidemias with the development of ED in humans still needs further definition with convincing peer-reviewed scientific studies. The challenge for the future will be to define the benefit of controlling obesity and dyslipidemias on the development of ED and improvement of erectile function.
Subclinical Erectile Dysfunction: Proposal for a Novel Taxonomic Category in Sexual Medicine
Authors: Jannini Emmanuele A. , Lenzi Andrea , Isidori Andrea , Fabbri Andrea
Published: August 2006

The definition of erectile dysfunction currently used and accepted worldwide does not encompass all possible changes to male erection. Partial, temporary, or episodic absence of erection is not considered as true erectile dysfunction. This leads to a lack of diagnosis and therapy and perhaps even the risk of the subsequent development of overt impotence. The lack of an evidence-based diagnosis of such a condition may be due to the widespread, pernicious self-prescription of erection drugs, obtained from the illegal market. To define the pathological condition of men experiencing a lack of erection who are unaffected by erectile dysfunction, we propose herein a new taxonomic category, based on new sexological criteria. In addition, we suggest research into biochemical markers to define this condition, which we have named subclinical erectile dysfunction.
Sexual Problems Among a Specific Population of Minority Women Aged 40–80 Years Attending a Primary Care Practice
Authors: Sadovsky Richard , Alam Wahila , Enecilla Mignon , Cosiquien Reginald , Tipu Omar , Etheridge-Otey Jennifer
Published: August 2006

Introduction

Clinicians are embarrassed about discussing sex with patients and do not know how to ask about sexual problems in a way that will optimize honest and open responses. Learning about inquiry responses and the prevalence of sexual problems among specific groups of women, including minority women, can help identify appropriate inquiry and management pathways.

Aim

To better understand useful inquiry techniques as well as to describe the prevalence of sexual problems among a specific group of minority women aged 40–80 years.

Main Outcome Measures

Responses to two styles of sexual problem inquiry, direct vs. ubiquity, were compared among sexually active subjects. Prevalence of sexual problems and interest in discussing problems with personal clinician were determined.

Methods

Minority women aged 40–80 years receiving care at one of two Family Health Centers in Brooklyn, New York who could speak English met inclusion criteria. A cross-sectional survey of 212 subjects, the majority being Afro-Caribbean, identified those who were sexually active and then randomly asked about sexual problems using one of two inquiry types: (i) a direct question, such as “Do you have a problem during sex,” or (ii) a ubiquity-style question, such as “Many women with diabetes have sexual problems, how about you?” Sexual problems were characterized by recognized phases of female sexual activity. Interest in discussing sexual problems with a personal clinician was determined.

Results

Of the 212 women surveyed, 108 (50.9%) were sexually active with 37 (34.3%) of these women responding “yes” when asked about sexual problems using one of the two inquiry techniques. Stratified analysis by age group showed significantly higher reporting of sexual problems when a ubiquity-style inquiry was used among older women aged 61–80 years (P = 0.028) but not among younger ones. The prevalence of sexual problems was 14.8% reporting pain, 12.0% lack of interest, 9.2% lack of excitation, 5.5% lack of orgasm, and 6.5%“other.” Forty-three percent of women with problems said they would like to discuss their problem(s) with their clinician.

Conclusions

In a specific minority group of women aged 40 years and older, especially those over age 60 years, ubiquity-style inquiries may encourage more open and honest responses about sexual problems. The most common sexual problem among this group of women was pain. There is willingness and even interest in talking with clinicians about sexual issues. Recognition of sexual problem prevalences helps clarify the high number of women who could be potentially helped with current and future pharmacologic and psychosocial treatments.
Differential Regulation of the Expression of Estrogen, Progesterone, and Androgen Receptors by Sex Steroid Hormones in the Vagina: Immunohistochemical Studies
Authors: Pessina Monica A. , Hoyt Richard F. , Goldstein Irwin , Traish Abdulmaged M.
Published: August 2006

Objective

Significant structural changes occur in the rat vagina in response to sex steroid hormone deprivation and replacement. However, the mechanism by which these changes occur is not clearly understood and our current hypothesis is that these effects are mediated, at least in part, by the expression of sex steroid hormone receptors. The goal of this study was to assess changes in steroid hormone receptor expression and distribution in response to sex steroid hormone deprivation and administration.

Methods

Female rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or hormone combinations. Using immunohistochemistry, hormone receptor distribution was assessed in all layers of the vaginal wall.

Results

After ovariectomy, estrogen receptor alpha (ERα) was up-regulated and progesterone receptor (PR) was down-regulated. Estradiol replacement restored these ovariectomy-induced changes, and this effect was dose-dependent. Androgen receptor (AR) expression was unaffected by ovariectomy or estradiol replacement. However, testosterone treatment resulted in increased AR density in the muscularis. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone.

Conclusion

Estradiol down-regulated ERα and up-regulated PR expression in the vagina, suggesting this may be a mechanism to prevent continued proliferation of the epithelium by surges of estradiol during the estrous cycle.
Brain-Derived Neurotrophic Factor (BDNF) Acts Primarily via the JAK/STAT Pathway to Promote Neurite Growth in the Major Pelvic Ganglion of the Rat: Part I
Authors: Bella Anthony J. , Lin Guiting , Tantiwongse Kavirach , Garcia Maurice , Lin Ching-Schwun , Brant William , Lue Tom F.
Published: August 2006

Introduction

Identification of the molecular mechanism of cavernous nerve regeneration is essential for future development of neuroprotective and regenerative strategies.

Aim

To identify specific signal transduction pathway(s) associated with brain-derived neurotrophic factor (BDNF) enhanced cavernous nerve regeneration in an in vitro model.

Materials and Methods

Using 6-month-old male Fisher rats, inhibitors of four candidate signaling pathways were added to BDNF-treated explant cultures of major pelvic ganglia with attached cavernous nerve fragments. Study groups comprised of controls, BDNF alone at 50 ng/mL, or BDNF 50 ng/mL and inhibitors against MEK, PI3-K, PKA, and JAK/STAT pathways at increasing concentrations.

Main Outcome Measure

The maximal neurite length for each tissue culture was measured and the mean maximal length ± standard deviation was determined for all groups at 24, 36, and 48 hours.

Results

The JAK/STAT specific inhibitor AG490 significantly reduced BDNF-enhanced neurite growth. Maximum neurite lengths at 24, 36, and 48 hours for BDNF 50 ng/mL treated groups were 182.3, 348.1, and 528.1 µm, compared with AG490 at 25 µM (86.4, 165.1, 278.3 µm), 50 µM (78.8, 151.7, 235.3 µm), and 100 µM (71.83, 107.0, 219.6 µm) (P < 0.05). Neurite measures for BDNF with 25 and 50 µM U0126 (MEK pathway) were reduced to 402.0 and 424.3 µm at 48 hours, respectively (P < 0.05), likely reflecting an accessory molecular pathway. A similar observation was made for 100 uM LY294002 (PI3-K). No difference was observed for PKA inhibition.

Conclusion

The JAK/STAT pathway is the major signal-transduction pathway of BDNF-enhanced cavernous nerve growth in an in vitro rat model.
Brain-Derived Neurotrophic Factor (BDNF) Acts Primarily via the JAK/STAT Pathway to Promote Neurite Growth in the Major Pelvic Ganglion of the Rat: Part 2
Authors: Lin Guiting , Bella Anthony J. , Lue Tom F. , Lin Ching-Shwun
Published: August 2006

Introduction

Surgical and radiation therapies of bladder and prostate cancers may damage cavernous nerves and cause erectile dysfunction (ED). We previously showed that brain-derived neurotrophic factor (BDNF) could restore erectile function in a neurogenic ED rat model. We now investigated the signaling mechanism of BDNF in major pelvic ganglia (MPG) explants.

Aim

To identify the signaling mechanism that mediates the neurotrophic effect of BDNF in cultured MPG.

Methods

Major pelvic ganglia was isolated from male rats for immunohistochemistry and immunofluorescence staining to locate BDNF receptors, pan-neurotrophin 75 (p75), tropomyosin-related kinase B (TrkB), and tropomyosin-related kinase C (TrkC). The dorso-caudal region of MPG was treated with BDNF to determine the optimal dosage for promoting neurite growth. Specific kinase inhibitors AG490, KT5720, LY294002, and U0126 were then used to treat MPG either alone or prior to BDNF treatment. The treated MPG was examined for neurite growth and for expression and phosphorylation of JAK2, STAT1, and STAT3 by Western blot analysis.

Main Outcome Measures

Lengths of neurite growth from MPG were measured to quantify the effects of BDNF and to identify specific signaling pathways. Ratios of phosphorylated vs. unphosphoryated proteins of JAK2, STAT1, and STAT2 in control and treated MPG were determined to confirm JAK/STAT as the principal signaling pathway.

Results

Tropomyosin-related kinase B and TrkC were localized to neurons whereas p75 to perineuronal satellite glial cells (SGC). The optimal dosage of BDNF for promoting MPG neurite growth was between 25 and 50 ng/mL. Among the four specific kinase inhibitors, AG490 was the strongest in suppressing MPG neurite growth as well as BDNF-induced phosphorylation of JAK2, STAT1, and STAT3.

Conclusions

In rat MPG, TrkB and TrkC were expressed in neurons, whereas p75 in SGC. Optimal BDNF dosage for promoting MPG neurite growth was between 25 and 50 ng/mL. BDNF promotes MPG neurite growth primarily by activating the JAK/STAT pathway.
Efficacy and Safety of Flexible-Dose Vardenafil in Men with Type 1 Diabetes and Erectile Dysfunction
Authors: Ziegler Dan , Merfort Frank , Van Ahlen Hermann , Yassin Aksam , Reblin Tjark , Neureither Marcus
Published: August 2006

Introduction

Erectile dysfunction (ED) affects up to 70% of men with diabetes, occurring with a higher prevalence in those with type 1 diabetes than with type 2 diabetes. Studies investigating treatment of ED in men with diabetes have largely been conducted in a total male population with diabetes. Limited data are available on the efficacy and safety of the potent oral phosphodiesterase-5 inhibitor vardenafil in men with ED and type 1 diabetes.

Aims

To evaluate the safety and efficacy of flexible-dose vardenafil therapy in a prospective randomized study in phosphodiesterase 5 inhibitor-naïve subjects with type 1 diabetes and ED.

Methods

In this multicenter, double-blind, placebo-controlled clinical trial, phosphodiesterase-5 inhibitor-naïve patients were randomized to receive placebo (N = 149) or flexible-dose (5–20 mg) (N = 153) vardenafil.

Main Outcome Measure

Sexual Encounter Profile diary questions 2 and 3, concerning success rates of vaginal insertion and maintenance of erection to allow successful intercourse, respectively.

Results

Vardenafil significantly improved mean success rates for Sexual Encounter Profile 2 and 3 compared with baseline and placebo at 4, 8, and 12 weeks (P < 0.0001, intention to treat and last observation carried forward). These rates were unaffected by stratification into distinct subsets according to the level of HbA1c (HbA1c < 7%, good glycemic control; HbA1c >7–≤8%, moderate glycemic control; and HbA1c > 8%, poor glycemic control). Vardenafil treatment also significantly improved the Erectile Function domain score (P < 0.0001) of the International Index of Erectile Function compared with placebo, in addition to scores for the other individual domains of the International Index of Erectile Function. The most commonly reported treatment-emergent adverse events were headache (3.1%) and flushing (2.5%), which were mild to moderate and transient in nature.

Conclusion

These data suggest that vardenafil significantly improves erectile function in men with type 1 diabetes and is well tolerated, regardless of the level of glycemic control.
Vardenafil Improved Erectile Function in a “Real-Life” Broad Population Study of Men with Moderate to Severe Erectile Dysfunction in Australia and New Zealand
Authors: McMahon Chris , Lording Douglas , Stuckey Bronwyn , Tan Ven , Gillman Michael , White Warwick , Di Natale Sebastian , Bramwell Pauline
Published: August 2006

Introduction

Phosphodiesterase type 5 inhibitor drugs produce vasodilatation by inhibiting the breakdown of cyclic guanosine monophosphate and have proven efficacy in treating erectile dysfunction (ED).

Aim

To evaluate the efficacy, safety, and tolerability of vardenafil in men with moderate to severe ED of broad etiology.

Main Outcome Measures

The erectile function (EF) domain score, the response to Questions 13 and 14 of the International Index of Erectile Function (IIEF) questionnaire, and the proportion of “yes” responses to questions 2 and 3 of the Sexual Encounter Profile (SEP), a Global Assessment (GAQ), and Global Satisfaction Questions (GSQ) were compared at baseline and at 12 weeks of treatment with as-needed vardenafil.

Methods

A total of 326 subjects with a mean age of 57.6 years and moderate to severe erectile dysfunction of various etiologies received vardenafil (5–20 mg) for 12 weeks in a prospective multicenter, open-label flexible-dose study.

Results

Compared with baseline, vardenafil was superior in all efficacy outcomes. A significant mean improvement of 13.4 (P < 0.001) in the EF domain from baseline was obtained at week 12. Subjects who received 5, 10, and 20 mg vardenafil at week 12 experienced improvements of 11.9, 15.1, and 12.9 respectively in the EF domain score. Sexual intercourse was successfully completed (SEP3) in 76.3%, 80.1%, and 74.3% of subjects receiving 5, 10, and 20 mg vardenafil compared with 25.9%, 17.9%, and 19.2% at baseline, respectively. For all doses combined at week 12, the change in SEP3 from baseline was 56.7% (P < 0.001). Treatment with vardenafil was well tolerated, and headaches, flushing, nasal congestion, and dyspepsia were the most frequently observed adverse events.

Conclusions

Vardenafil was effective and well tolerated in men with moderate to severe erectile dysfunction. Treatment with vardenafil was associated with a significantly higher IIEF erectile function domain score and completion of successful intercourse rate compared with baseline.
Prospective, Randomized, Open-Label, Fixed-Dose, Crossover Study to Establish Preference of Patients with Erectile Dysfunction After Taking the Three PDE-5 Inhibitors
Authors: Tolrà Josep Rodríguez , Campaña José María Cuadrado , Ciutat Lluis Fumadó , Miranda Eladio Franco
Published: August 2006

Introduction

We conducted a prospective, randomized, open-label, fixed-dose preference study, with a crossover design, using sildenafil, vardenafil, and tadalafil.

Aim

To assess patient preference for sildenafil (100 mg), vardenafil (20 mg), and tadalafil (20 mg) for the treatment of erectile dysfunction. Secondary objectives included finding out whether patients would follow treatment with a second or third option, in the event that the preferred drug was not available, and to assess side effects.

Main Outcome Measures

Patient preference for any treatment, and evaluation of the elements that patients would assess when choosing one of these drugs.

Material and Methods

Sildenafil (100 mg), vardenafil (20 mg), and tadalafil (20 mg) were taken at least six times over a period of 45–60 days with a washout period of 7 days. A total of 132 patients were enrolled to achieve a valid sample of 90 cases (15 per randomized group, total of six groups). Enrolled patients had mild to moderate erectile function.

Results

The International Index of Erectile Function (IIEF) score improved from baseline and was statistically significant in all cases (P < 0.0001). When we compared the IIEF scores, we found a statistically significant difference between tadalafil and vardenafil (P = 0.0002) favoring the former; similar results were obtained with the Erectile Dysfunction Inventory for Treatment Satisfaction (EDITS) Questionnaire (P = 0.000075). We also found a significant difference (P = 0.012) between tadalafil and sildenafil, again in favor of the former. In assessing drug preference, 25 patients (27.77%) chose sildenafil, 18 (20%) vardenafil, and 47 (52.22%) tadalafil. A total of 94% of patients would be willing to take another drug if the preferred choice was not available. All drugs were well tolerated.

Conclusions

Although this is a preference study based on subjective elements, statistically significant differences comparing the IIEF score and the EDITS Questionnaire lead us to believe that beyond patients’ subjective preference per se, said preference is probably also based on a genuinely superior response to one drug over another.
Cues Resulting in Desire for Sexual Activity in Women
Authors: McCall Katie , Meston Cindy
Published: August 2006

Introduction

A number of questionnaires have been created to assess levels of sexual desire in women, but to our knowledge, there are currently no validated measures for assessing cues that result in sexual desire. A questionnaire of this nature could be useful for both clinicians and researchers, because it considers the contextual nature of sexual desire and it draws attention to individual differences in factors that can contribute to sexual desire.

Aim

The aim of the present study was to create a multidimensional assessment tool of cues for sexual desire in women that is validated in women with and without hypoactive sexual desire disorder (HSDD).

Methods

Factor analyses conducted on both an initial sample (N = 874) and a community sample (N = 138) resulted in the Cues for Sexual Desire Scale (CSDS) which included four factors: (i) Emotional Bonding Cues; (ii) Erotic/Explicit Cues; (iii) Visual/Proximity Cues; and (iv) Implicit/Romantic Cues.

Main Outcome Measures

Scale construction of cues associated with sexual desire and differences between women with and without sexual dysfunction.

Results

The CSDS demonstrated good reliability and validity and was able to detect significant differences between women with and without HSDD. Results from regression analyses indicated that both marital status and level of sexual functioning predicted scores on the CSDS. The CSDS provided predictive validity for the Female Sexual Function Index desire and arousal domain scores, and increased cues were related to a higher reported frequency of sexual activity in women.

Conclusions

The findings from the present study provide valuable information regarding both internal and external triggers that can result in sexual desire for women. We believe that the CSDS could be beneficial in therapeutic settings to help identify cues that do and do not facilitate sexual desire in women with clinically diagnosed desire difficulties.