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PubMed1993

Finasteride. A review of its potential in the treatment of benign prostatic hyperplasia.

Finasteride is a novel therapeutic agent that selectively inhibits the enzyme 5 alpha-reductase, thereby reducing prostatic dihydrotestosterone (DHT) levels and prostate size. In men with symptomatic benign prostatic hyperplasia (BPH), these effects have been associated with improvements in peak urinary flow rate and urological symptoms; withdrawal from therapy, however, results in regrowth of the adenoma and long term therapy is therefore necessary. Although the magnitude of clinical improvement seen with finasteride has been perceived to be modest [especially when compared with that associated with transurethral resection of the prostate (TURP)], it has been maintained in the medium term (up to 2 years) and thus may represent significant reversal of disease progression. Such beneficial effects, however, may not become apparent until completion of at least 6 months of therapy. Furthermore, since clinical studies have been unable to proactively identify a responsive subgroup, a trial period of 6 or possibly 12 months is necessary to assess patient responsiveness. Despite these potential shortcomings, the benefits of therapy appear to outweigh the risks. Indeed, finasteride is well tolerated; most adverse events have been related to sexual dysfunction (decreased libido, ejaculation disorders and impotence) and occurred in only a small proportion (about 2 to 3%) of patients. Moreover, although there has been concern that finasteride might mask the detection of prostate cancer through its decremental effects on serum prostate specific antigen (PSA) levels, careful monitoring in clinical trials appears to have avoided this problem. Thorough pretreatment assessment and periodic follow-up examinations for malignancy are therefore required in clinical practice. The role of finasteride in the treatment of patients with BPH is still emerging and will no doubt gain in clarity with further planned investigations. TURP (or other invasive procedures such as the insertion of prostatic stents in patients unsuitable for resection), continues to be the mainstay of therapy for those patients with severe symptomatic BPH. However, available data support a first line role for finasteride in the treatment of patients with uncomplicated symptomatic BPH. Within this setting, finasteride appears to offer a needed additional treatment option for those patients in whom surgery is not indicated, and may be of special benefit to the considerable proportion of patients who opt not to undergo prostatectomy.

Animals↗
PubMed2004

"Opening a can of worms": GP and practice nurse barriers to talking about sexual health in primary care.

BACKGROUND: There is evidence that health professionals do not discuss sexually related issues in consultations as often as patients would like. Although primary care has been identified as the preferred place to seek treatment for sexual health concerns, little is known either of the factors that prevent GPs and practice nurses initiating such discussions or of how they feel communication in this area could be improved. OBJECTIVE: The purpose of the present study was to identify barriers perceived by GPs and practice nurses to inhibit discussion of sexual health issues in primary care and explore strategies to improve communication in this area. METHODS: Semi-structured interviews were conducted with 22 GPs and 35 practice nurses recruited from diverse practices throughout Sheffield. RESULTS: The term 'can of worms' summarized participants' beliefs that sexually related issues are highly problematic within primary care because of their sensitivity, complexity and constraints of time and expertise. Particular barriers were identified to discussing sexual health with patients of the opposite gender, patients from Black and ethnic minority groups, middle-aged and older patients, and non-heterosexual patients. Potential strategies to improve communication about sexual health within primary care included training, providing patient information and expanding the role of the practice nurse; however, several limitations to these approaches were identified. CONCLUSION: GPs and practice nurses do not address sexual health issues proactively with patients, and this area warrants further attention if policy recommendations to expand the role of primary care within sexual health management are to be met.

Age Factors↗
PubMed1973

Pathogenetic mechanisms in dengue haemorrhagic fever: report of an international collaborative study.

In a study of 55 persons with dengue haemorrhagic fever-36 of whom showed the dengue shock syndrome-clinical, haematological, virological, and serological changes were correlated with serial measurements of complement components and immunopathological studies. Viruses dengue-1 or dengue-2 were isolated from the sera of 9 patients. Serological responses indicative of secondary dengue virus infections were observed in 53 patients; 2 (infants) had primary infections. During the acute phase of the disease, dengue antibody titres rose logarithmically. Marked depression of complement components, especially C3, was observed. Activation of both the classical and alternative complement pathways was demonstrated, with depression of both C4 and C3 proactivator levels in most instances, although in some cases it appeared that one mechanism was involved to a greater extent than the other. The level of depression of C3 was correlated with the severity of the disease. Relatively stable transferrin levels indicated that depletion of complement proteins was not primarily due to extravasation. Fibrinogen levels were depressed and fibrinogen split products were found in the plasma. The accumulated data provide further evidence of the central role that activated complement components play in the pathogenesis of dengue haemorrhagic fever.

Blood Coagulation Tests↗
PubMed1999

MK-801-induced disruptions of one-trial inhibitory avoidance are potentiated by stress and reversed by naltrexone.

Five experiments were carried out to investigate opioid and NMDA receptor-mediated responses to one-trial inhibitory avoidance training in CD1 mice. In the first experiment immediate posttraining intraperitoneal administration of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 impaired the performance of mice. The effects of MK-801 were time-dependent (they were absent in mice injected with the drug starting 120 min after training). No effect was evident in no-foot-shock groups, showing lack of proactive influence of the treatment on performance. In the second experiment preexposure of the mice to the testing apparatus decreased the effects of MK-801. In the the third experiment naltrexone antagonized the effects of MK-801, suggesting an involvement of opioid neurons. In the fourth experiment immediate posttraining immobilization stress exerted a potentiating effect on the performance of MK-801-injected animals. In the fifth experiment the potentiation of the impairing effect of MK-801 induced by immobilization stress was antagonized by naltrexone.

Animals↗
PubMed1998

Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor.

Filarial nematode parasites establish long-term chronic infections in the context of an antiparasite immunity that is strongly biased toward a Th2 response. The mechanisms that lead to this Th2 bias toward filarial antigens are not clear, but one possibility is that the parasites produce molecules that have the capacity to proactively modify their immunological environment. Here we report that filarial parasites of humans secrete a homologue of the human proinflammatory cytokine macrophage migration inhibitory factor (MIF) that has the capability of modifying the activity of human monocytes/macrophages. A cDNA clone isolated from a Brugia malayi infective-stage larva expression library encoded a 12.5-kDa protein product (Bm-MIF) with 42% identity to human and murine MIF. MIF homologues were also found to be expressed in the related filarial species Wuchereria bancrofti and Onchocerca volvulus. Bm-mif was transcribed by adult and larval parasites, and the protein product was found in somatic extracts and in the parasite's excretory-secretory products. Immunohistocytochemistry revealed that Bm-MIF was localized to cells of the hypodermis/lateral chord, the uterine wall, and larvae developing in utero. Unexpectedly, the activities of recombinant Bm-MIF and human MIF on human monocytes/macrophages were found to be similar. When placed with monocytes/macrophages in a cell migration assay, Bm-MIF inhibited random migration. When placed away from cells, Bm-MIF induced an increase in monocyte/macrophage migration that was specifically inhibited by neutralizing anti-Bm-MIF antibodies. Bm-MIF is the first demonstration that helminth parasites produce cytokine homologues that have the potential to modify host immune responses to promote parasite survival.

Amino Acid Sequence↗
PubMed2002

Supervisor tolerance-responsiveness to substance abuse and workplace prevention training: use of a cognitive mapping tool.

Supervisor tolerance-responsiveness, referring to the attitudes and behaviors associated with either ignoring or taking proactive steps with troubled employees, was investigated in two studies. The studies were conducted to help examine, understand and improve supervisor responsiveness to employee substance abuse. Study 1 examined supervisor response to and tolerance of coworker substance use and ways of interfacing with the Employee Assistance Program (EAP) in two workplaces (n = 244 and 107). These surveys suggested that engaging supervisors in a dialogue about tolerance might improve their willingness to use the EAP. Study 2 was a randomized control field experiment that assessed a team-oriented training. This training adopted a cognitive mapping technique to help improve supervisor responsiveness. Supervisors receiving this training (n = 29) were more likely to improve on several dimensions of responsiveness (e.g. likely to contact the EAP) than were supervisors who received a more didactic, informational training (n = 23) or a no-training control group (n = 17). Trained supervisors also showed increases in their own help-seeking behavior. Procedures and maps from the mapping activity (two-stage conversational mapping) are described. Overall, results indicate that while supervisor tolerance of coworker substance use inhibits EAP utilization, it may be possible to address this tolerance using team-oriented prevention training in the work-site.

Adult↗
PubMed2004

Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia.

Mutations in the receptor tyrosine kinase FLT3 occur frequently in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Small molecules that selectively inhibit FLT3 kinase activity induce apoptosis in blasts from AML patients with FLT3 mutations and prolong survival in animal models of FLT3-induced myeloproliferative disease. A spectrum of structurally different small molecules with activity against FLT3 have been described, and their efficacy for treatment of AML and ALL is now being investigated in clinical trials. Here, we describe the results of an in vitro screen designed to identify mutations in the ATP-binding pocket of FLT3 that confer resistance to tyrosine kinase inhibitors. Mutations at four different positions (Ala-627, Asn-676, Phe-691, and Gly-697) were identified that confer varying degrees of resistance to PKC412, SU5614, or K-252a. FLT3 proteins mutated at Ala-627, Asn-676, or Phe-691 remained sensitive to higher concentrations of the inhibitors, but the G697R mutation conferred high-level resistance to each of these inhibitors as well as to six additional experimental inhibitors. These data provide insights into potential mechanisms of acquired resistance of FLT3 to small molecule inhibitors and indicate that the G697R mutation may be a clinically problematic resistance mutation that warrants proactive screening for additional inhibitors.

Acute Disease↗
PubMed2001

Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck.

This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m(2)administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9-20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7-28.1 months; 95% CI: 3.9-7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B(12)supplementation.

Adult↗
PubMed1999

The role of interference in memory span.

In two experiments, we investigated the possibility that susceptibility to proactive interference (PI) affects performance on memory span measures. We tested both younger and older adults (older adults were tested because of the suggestion that they are differentially susceptible to PI). We used two different span measures and manipulated testing procedures to reduce PI for these tasks. For older adults, span estimates increased with each PI-reducing manipulation; for younger adults, scores increased when multiple PI manipulations were combined or when PI-reducing manipulations were used in paradigms in which within-task PI was especially high. The findings suggest that PI critically influences span performance. We consider the possibility that interference-proneness may influence cognitive behaviors previously thought to be governed by capacity.

Adult↗
PubMed2004

Different latex aeroallergen size distributions between powdered surgical and examination gloves: significance for environmental avoidance.

BACKGROUND: Proactive medical institutions implement latex allergen avoidance to protect workers and patients with latex allergy and to prevent latex sensitization in these groups by creating latex-safe environments that include replacement of natural rubber latex examination and surgical gloves, especially those that are powdered, with synthetic alternatives. We have hypothesized that an apparent decreasing trend in new latex allergy cases in hospitals using only synthetic examination gloves but the occasional powdered latex surgical glove might result from constitutive differences in allergen content (particle size distribution and quantity) between powdered surgical gloves and examination gloves. OBJECTIVE: Because aerodynamic particle size determines where inhaled airborne allergen deposits in the airway, the aim of this study was to investigate the differential particle size distribution of latex allergen released from powdered latex examination and surgical gloves. METHODS: Powdered and nonpowdered latex examination and surgical gloves were processed to create an aerosol in a glove box equipped with air sampling equipment capable of total particle number and mass measurements. Air particulate generated in the glove box was collected on impactors with less than 2.5-microm, 2.5- to 10-microm, and greater than 10-microm particle size limits (4 L/min for 4 hours). All filters were extracted, and latex allergen was quantified by using a latex-CAP inhibition assay with a human IgE anti-latex serum pool. RESULTS: Latex aeroallergen on powdered sterile surgical gloves resided primarily on particles greater than 10 microm in size (P <.006). In contrast, powdered examination gloves released the highest total latex aeroallergen content, with 68% of the particles sized in the respirable 2.5- to 10-microm range and carrying 56% of the airborne latex allergen. CONCLUSIONS: Significantly lower quantities and larger sizes of latex allergen-containing particles released from surgical gloves provides one potential explanation as to why an apparent decrease in new cases of latex allergy can occur in hospitals that successfully replace latex examination gloves with synthetic gloves but continue occasional use of powdered surgical gloves.

Allergens↗
PubMed2002

Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and gamma-aminobutyric acid systems.

BACKGROUND AND RATIONALE: Aggressive outbursts that result in harm and injury present a major problem for the public health and criminal justice systems, but there are no adequate treatment options. Obstacles at the level of social policy, institutional regulation, and scientific strategy in developing animal models continue to impede the development of specific anti-aggressive agents for emergency and long-term treatments. OBJECTIVE: To be more relevant to the clinical situation, preclinical aggression research has begun to focus on the neurobiological determinants of escalated aggressive behavior that exceeds species-typical patterns. It is the goal of this review to examine novel pharmacological and molecular tools that target the neural mechanisms for different kinds of aggressive behavior more selectively than previously possible and to outline potential pharmacotherapeutic options. RESULTS AND CONCLUSIONS: (1) The preclinical focus on the behavioral characteristics and determinants of intense aggression promises to be most relevant to the clinical distinction between the proposed impulsive-reactive-hostile-affective subtypes of human aggression and the controlled-proactive-instrumental-predatory subtypes of aggression. The neural circuits for many types of human and animal aggression critically involve serotonin, dopamine and gamma-aminobutyric acid (GABA) and specific receptor subtypes. (2) The dynamic changes in frontal cortical serotonin that are triggered by engaging in aggressive behavior imply that serotonergic drug effects are largely determined by the functional state of the receptors at the time of drug treatment. Of the numerous 5-HT receptors currently identified, the 5-HT(1B) receptors offer a promising target for reducing impulsive aggressive behavior, particularly if the action can be limited to sites in the central nervous system. (3) Aggressive confrontations are salient stressors, both for the aggressor as well as the victim of aggression, that are accompanied by activation of the mesocorticolimbic but not the striatal dopamine system. Dopaminergic manipulations, particularly targeting the D(2) receptor family, can influence aggressive behavior in animals and human patients, suggesting that mesocorticolimbic dopamine may have important enabling or permissive functions. (4) GABA is critical in the neurochemical control of aggressive behavior as evidenced by studies that directly modify GABAergic neurotransmission and neurochemical studies that correlate GABA measurements with aggressive behavioral responses in several animal species. The GABA(A) receptor complex is a mechanism through which certain benzodiazepines and alcohol enhance and inhibit aggressive behaviors. Social and pharmacological experiences decisively determine the effects of GABAergic positive modulators on aggression.

Adaptation, Psychological↗
PubMed2005

Inhibitory processes in young children and individual variation in short-term memory.

A precise definition of executive control remains elusive, related in part to the variations among executive tasks in the nature of the task demands, which complicate the identification of test-specific versus construct-specific performance. In this study, tasks were chosen that varied in the nature of the stimulus (verbal, nonverbal), response (naming, somatic motor), conflict type (proactive interference, distraction), and inhibitory process (attention control, response suppression) required. Then performance differences were examined in 184 young children (age range = 3 years 6 months to 6 years 1 month), comparing those with high (5 or more digits) and low (3 or fewer digits) spans to determine the dependence on short-term memory. Results indicated that there was communality in inhibitory task demands across instruments, although the specific pattern of task intercorrelations varied in children with high and low spans. Furthermore, only performance on attention control tasks-that is, that require cognitive engagement/disengagement among an internally represented rule or response set that was previously active versus those currently active-differed between children of high and low spans. In contrast, there were differences neither between children with high and low spans on response suppression tasks nor on tasks when considered by type of stimulus, response, or conflict. Individual differences in well-regulated thought may rest in variations in the ability to maintain information in an active, quickly retrievable state that subserve controlling attention in a goal-relevant fashion.

Child↗