Comparative clinical trial of bemetizide/triamterene and cyclopenthiazide/potassium chloride combinations in patients with mild to moderate hypertension.

A double-blind trial was carried out to compare the combination of 25 mg bemetizide plus 50 mg triamterene ('Hypertane') and 0.25 mg cyclopenthiazide plus 600 mg potassium chloride ('Navidrex' K) in the treatment of mild to moderate essential hypertension. Two well matched groups of patients were treated for periods of 6 weeks with one or other of the drugs under test. There were 2-week placebo run-in and run-out periods. Blood pressure and laboratory investigations were performed every 2 weeks during the trial period. Both treatments resulted in similar overall statistically significant reductions in blood pressure during the trial. With bemetizide/triamterene, mean lying blood pressure decreased by 11.1/11.2 mmHg and mean standing blood pressure by 15.9/10.3 mmHg; with cyclopenthiazide/potassium chloride the corresponding reductions were 14.9/12.1 mmHg and 9.1/11.7 mmHg. The fact that some of the observed overall reduction seen with both drugs was due to 'placebo effect' is discussed but the clinical importance of overall changes is stressed. There were no significant differences between changes in blood pressure with the two treatments. Biochemical changes were those expected with thiazide diuretics. However, the decrease in potassium and increases in urea and uric acid levels were less with bemetizide/triamterene than with cyclopenthiazide/potassium chloride. Clinical tolerance of both treatments was good.

Factors affecting men's liking of condoms they have used.

The objective of this study was to assess the impact on men's liking for the condoms they use of a range of factors including demographic variables and variables that describe men's experience of using particular condoms. One hundred and ninety-four men used 3765 condoms for which they provided a liking rating. The condoms were manufactured to one of 2 published standards and the study employed a double-blind crossover design. Sixty-one per cent of condoms were rated favourably, 31% were rated neutrally and the remainder (8%) unfavourably. Men rated condoms less favourably if they were experienced as too loose, too tight, too short, if difficulty was experienced applying the condom, if the condom slipped partially or completely down the penis or if the condom broke. Men rated more highly condoms which were experienced as well lubricated throughout use. Men with larger penises rated condoms less favourably and, of all the variables considered, ejaculating in the condom was the variable which had the largest positive impact. Men's liking for the condoms they use is influenced by a range of factors. However, given that most of the factors associated with men liking condoms less are those that can be addressed through better condom design and manufacture, the opportunity exists to enhance men's experience of condom use and hence help reduce resistance to the adoption of consistent condom use.

Does penis size influence condom slippage and breakage?

This study examined the effect of penis dimensions on the probability of complete condom slippage and condom breakage in actual use. Men were recruited through advertising, used the condoms supplied and completed a diary sheet for each condom used. A total of 3658 condoms were used by 184 men of which 1.34% broke and 2.05% slipped off. No significant effect was demonstrated for penile dimensions on the probability of complete condom slippage. However, condom breakage was strongly associated with penile circumference. These findings suggest that condom manufacturers may need to increase the range of condom sizes available, or some aspects of their performance, in order to ensure that condoms meet the needs of all men without unduly exposing them to risk.

PIP: Anecdotal reports suggest large penis size may be associated with condom breakage, while small penis size increases the risk of condom slippage. The effect of penis dimensions on the likelihood of both these events was investigated in 184 male volunteers recruited through advertisements and posters in Victoria, Australia. Each participant was provided with 12 condoms at a time and instructed to complete a diary sheet for each condom. According to self-measurements, men had a mean total penis length of 15.71 cm and a mean basal circumference of 13.19 cm. Of the 3658 condoms used by these men, 49 (1.34%) broke and 73 (2.05%) slipped. 30 men (16.3%) experienced at least one instance of breakage and 35 (19.0%) experienced complete slippage. There was no evidence for an effect of penis length or circumference on condom slippage. Condom breakage, on the other hand, was strongly associated with penis circumference. Each additional centimeter of penile circumference increased the risk of condom breakage by 50-100%. This finding suggests a need to increase either the range of condom sizes available or the lateral extension of currently available condoms.

Does additional lubrication affect condom slippage and breakage?

The risk of condom slippage (1.94%) and breakage (0.89%) among 3607 condoms was analysed with respect to the use of additional lubricant. Whether or not lubricant was used, the site at which it was applied and the type of lubricant used were all found to vary significantly with the type of sexual act(s) for which the condoms were used. Little evidence was found for differing effects of type of additional lubricant (water-based, saliva or other) or site of lubricant use (on penis/inside condom, on condom, in vagina/anus). The use of lubricant more than doubles the risk of slippage for vaginal sex. While anal sex is associated with much higher risks of slippage the use of lubricant for this practice actually reduces the risk of slippage to that similar for vaginal sex where lubricant is used. No significant effect of additional lubricant on condom breakage was observed. It is recommended that education messages concerning the use of additional lubricant may need to change to take into account the varied nature of lubricant use practices and the differential effects of lubricant with respect to sexual practices. Specifically, if the use of additional lubricant has little or no impact on condom breakage but increases condom slippage then encouraging its use may be counterproductive if condom users consider slippage to be a reason not to use condoms.

PIP: Findings are reported from a study involving 194 men aged 19-54 years of mean age 30.7 years, and their sex partners, conducted to assess the effect of using supplemental lubricant upon condom slippage and breakage during a range of sex practices. A total 3607 condoms were used by the study participants. 59.8% of the men described themselves as heterosexual, 8.2% as bisexual, and 32% as homosexual. 32 (0.89%) condoms broke either during penetration or were found to have broken once the penis was withdrawn, while 70 (1.94%) slipped completely off of the penis. 5.7% of condoms were used only for oral sex, 58.0% only for vaginal sex, 25.4% only for anal sex, and 10.9% for more than one form of sexual practice. The use of additional lubricant was the norm for anal sex, but it was rarely used for vaginal and oral sex. The site at which additional lubricant was applied and the type of lubricant used varied significantly with the type of sexual acts for which the condoms were used. The use of lubricant was found to increase slippage for oral sex and more than double the risk of slippage during vaginal sex. However, lubricant use for anal sex and multiple practices reduces the risk of condom slippage to a level comparable to that observed for vaginal sex when lubricant is used. No significant effect of additional lubricant on condom breakage was observed. Education messages on the use of additional lubricant should take into account the range of different sex and lubricant use practices.

An actual use comparison of condoms meeting Australian and Swiss standards: results of a double-blind crossover trial.

The performance of condoms in actual use has been poorly researched in the past, especially in comparing condoms that met different quality control standards as indicated by laboratory testing. The present study used a double-blind crossover design to compare the performance of 2 types of condoms in actual use; one that met the Australian and International Organization for Standardization (ISO) standards for condom quality and one that met the more stringent Swiss Quality Seal requirements. Ninety-two men recruited from Metropolitan Melbourne completed a self-report diary sheet after each condom was used which assessed the performance of the condom and the conditions under which it was used. From a total of 1917 condom uses, there was an overall breakage risk of 2.7%. The breakage risk ratio (Australian/ISO:Swiss) for all types of use was 1.16 (95% confidence interval 0.68-1.99). When subanalyses by method of entry were performed, the condoms meeting the Swiss standard appeared to fare better than the Australian/ ISO standards for anal sex (RR = 4.84, 95% CI 1.07-21.8, P = 0.022), while the opposite was the case for vaginal sex (RR = 0.74, 95% CI 0.35-1.53, P = 0.41). The result for anal use was statistically significant at the 5% level, despite being based on fewer condom trials than that for vaginal use, but this result needs to be replicated. Although the participants appeared representative of the general male population in Melbourne in the age bracket 18-46 years, there was a significant history of condom usage reported. This may have influenced the risk of breakage.

Tuberculosis testing in correctional officers: a national random survey of jails in the United States.

SETTING: The correctional system in the United States is large and growing. The Centers for Disease Control and Prevention recommend baseline and annual testing of employees in correctional facilities for latent tuberculosis infection (LTBI). OBJECTIVE: To describe the extent of and factors associated with LTBI testing practices for jail correctional officers. DESIGN: A national survey of 1760 randomly selected jails was conducted. We used multivariable logistic regression models to examine factors associated with testing officers in a guideline-concordant manner and having a written policy. RESULTS: A total of 1174 (67%) surveys were returned. Only 52% of jails had a written policy on LTBI testing of officers, and 51% screened officers at least annually (guideline concordance). Large jails (OR 2.41, 95%CI 1.67-3.49) and jails in states with a high tuberculosis incidence (OR 1.67, 95%CI 1.17-2.38) and in the Midwest (OR 1.58, 95%CI 1.07-2.33) were more likely to screen in a guideline-concordant manner. CONCLUSION: Screening for LTBI among correctional officers in the United States was inconsistent. Strategies to improve LTBI testing among correctional officers are needed.

A transcriptionally permissive epigenetic landscape at the vasoactive intestinal peptide receptor-1 promoter suggests a euchromatin nuclear position in murine CD4 T cells.

T cells express receptors for neuropeptides that mediate immunological activities. Vasoactive intestinal peptide receptor-1 (VPAC1), the prototypical group II G protein coupled receptor, binds two neuropeptides with high-affinity, called vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide. During T cell signaling, VPAC1 mRNA expression levels are significantly downregulated through a Src kinase dependent mechanism, thus altering the sensitivity for these neuropeptides during an immune reaction. Presently, it is unknown whether the mechanism that regulates VPAC1 during T cell signaling involves epigenetic changes. Therefore, we hypothesized that the epigenetic landscape consisting of diacetylation at H3K9/14 and trimethylation at H3K4, two transcriptionally permissive histone modifications, would parallel VPAC1 expression showing high enrichment in untreated T cells, but lower enrichment in alpha-CD3 treated T cells. To this end, quantitative chromatin immunoprecipitation (ChIP) analysis of H3K9/14ac and H3K4me3 was conducted using purified CD4(+) T cells, with CD45R(+) B cells as a negative control. Our data revealed that these histone modifications at the VPAC1 promoter did indeed parallel its mRNA levels between T and B lymphocytes, but did not decrease during T cell signaling. Collectively, these data strongly imply a euchromatin nuclear position for the VPAC1 locus irrespective of the activation status of T cells.

MBC / UNAIDS / SPC Pacific Islands AIDS / STD strategic planning. Project update.

PIP: This article presents an update of the Pacific Islands AIDS/sexually transmitted disease (STD) Strategic Planning Project. It also provides specific stories on the strategic planning experiences and achievements of four countries namely New Caledonia, Kiribati, Solomon Islands, and Nauru. The project began in 1998 when 17 Pacific Island countries participated in a workshop where each country developed an action plan which contained the following common elements: 1) a plan on how to integrate the strategic planning process into existing structures for HIV/AIDS activities; 2) strategies to gain political and other organizational support into HIV/AIDS and STD planning; 3) a summary of the factors contributing to HIV and STD risk; and 4) a review of what has been done to address these problems. In 1999, these plans were put into action. Each country was challenged at the planning and execution of situational analysis and response review. A project review conducted in June 1999 resulted in a decision to hold individual country workshops in the future which will allow more participants and facilitators to concentrate their efforts on developing an individual strategic plan for each country.^ieng

A pneumolysin-negative mutant of Streptococcus pneumoniae causes chronic bacteremia rather than acute sepsis in mice.

Pneumolysin is a cytoplasmic virulence factor of Streptococcus pneumoniae that can interfere with phagocyte function in vitro. We have examined the effects of pneumolysin in vitro and in vivo and have found that it protects intravenously injected pneumococci against infection-induced host resistance. We employed a virulent capsular type 2 pneumococcal strain, D39, and its isogenic pneumolysin-negative mutant, PLN. Strain D39 exhibited exponential net growth in mice (doubling time, 1.4 h); 24 to 28 h after infection with 10(4) CFU, the numbers of pneumococci reached 10(9) to 10(10) CFU/ml and the mice died. Strain PLN yielded identical net growth in mice until reaching 10(6) to 10(7) CFU/ml at 12 to 18 h postinfection. At this time, the increase in the level of PLN CFU per milliliter ceased and remained constant for several days. PLN exhibited wild-type growth kinetics in mice when coinfected simultaneously with strain D39. This observation suggests that pneumolysin exerts its effects at a distance. By 12 to 18 h postinfection with PLN, mice exhibited the following evidence of an induced inflammatory response: (i) elevated plasma interleukin-6, (ii) a halt in the net growth of PLN, and (iii) control of the net growth of pneumolysin-producing D39 pneumococci upon subsequent challenge. Our data suggest that pneumolysin plays a critical role in sepsis during the first few hours after infection by enabling pneumococci to cause acute sepsis rather than a chronic bacteremia. However, once chronic bacteremia was established, it appeared that pneumolysin was no longer able to act as a virulence factor.

The hemolytic and complement-activating properties of pneumolysin do not contribute individually to virulence in a pneumococcal bacteremia model.

The virulence of pneumococcal capsular type 2 strain D39 and derivatives with mutations in the pneumolysin gene were examined in a mouse bacteremia model. In CBA/N-XID mice D39 is known to exhibit exponential growth in the blood until the death of the mice at 24 to 36 h. In contrast, PLN, a pneumolysin-deficient derivative of D39, reaches a plateau in growth that is maintained for several days. The growth patterns of D39 and PLN observed in CBA/N-XID mice were also observed in C3H/HeJ and C3H/HeOuJ mice, but not in 129/SvJ and C57BL/6J mice. These results demonstrate that the effect of pneumolysin on bacteremia is dependent on the genetic background of the mice. D39 derivatives with point mutations which abolish the cytotoxic or complement-activating properties of pneumolysin did not have major individual effects on virulence in CBA/N- XID and C3H/HeOuJ mice. A derivative with mutations affecting both the cytotoxic and complement- activating properties resulted in a modest, yet statistically significant, increase in survival time of i.v. challenged CBA/N-XID mice. However, the effect was less marked than that seen with PLN. These findings suggest that the virulence effects of pneumolysin in bacteremia must be due in part to properties other than hemolysis and complement fixation.

Role of tumor necrosis factor alpha in the host response of mice to bacteremia caused by pneumolysin-deficient Streptococcus pneumoniae.

Pneumolysin-deficient mutant strains of Streptococcus pneumoniae are known to cause less-severe sepsis than wild-type pneumococcal strains that produce pneumolysin. This difference is associated with greater host resistance in mice infected with the pneumolysin-deficient strains. These studies show that the host resistance developed during the first 1 to 2 days after infection with a pneumolysin-deficient mutant strain is dependent on tumor necrosis factor alpha but is apparently independent of interleukin 1beta (IL-1beta) or IL-6. Survival beyond 5 days appeared to depend on the ability of the mice to produce IL-1beta.

Failure of cimetidine to suppress immunoreactive parathyroid hormone and hypercalcaemia in primary hyperparathyroidism.

Cimetidine has been reported as suppressing the excess parathyroid hormone secretion and hypercalcaemia seen in hyperparathyroidism. A case of primary hyperparathyroidism is described, in which the level of circulating parathyroid hormone and hypercalcaemia remain entirely unaffected by cimetidine. The drug is implicated in the management of primary hyperparathyroidism unsuitable for surgery, but present evidence, as reviewed, is insufficient to recommend the use of cimetidine in this way.

Hypophosphataemia and phosphorus requirements during intravenous nutrition.

Seven patients with acute illnesses developed hypophosphataemia whilst receiving intravenous nutrition which included a fat emulsion, Intralipid, a possible source of phosphorus. The authors' observations cast doubt on the bio-availability of the phosphorus contained in the phospholipid content of the fat emulsion. The currently recommended allowance of phosphorus for this type of patient appears to be too low and it is suggested that 0-5-0-75 mmol/kg body weight be provided, preferably as a neutral phosphate solution. Sine hypophosphataemia can occur at various time intervals after starting intravenous nutrition and precede clinical sequelae it is recommended that routine serum phosphate measurements are made in all patients receiving this treatment.

Differences in virulence for mice among Streptococcus pneumoniae strains of capsular types 2, 3, 4, 5, and 6 are not attributable to differences in pneumolysin production.

We observed that differences in the in vivo growth kinetics of pneumococcal strains of capsular types 3, 4, 5, and 6 were reminiscent of differences that we had previously reported for type 2 strain D39 and its pneumolysin-deficient mutant, PLN. Capsular type 2 Streptococcus pneumoniae D39 exhibits exponential growth in the blood of XID mice until the death of the mice at 24 to 36 h. In contrast, PLN reaches a plateau in growth that is maintained for several days. Capsular type 3 and 5 strains exhibited exponential growth and caused rapid death of XID mice following intravenous challenge, similar to the observation with D39. Strains of capsular types 4 and 6 exhibited growth kinetics reminiscent of PLN. Since the observed differences in the pathogenesis of types 3 and 5 compared to 4 and 6 were reminiscent of the effects of pneumolysin deficiency in type 2, we examined the levels of in vitro pneumolysin production for the entire panel of strains. The onset of pneumolysin production in most strains was rapid and occurred near the end of log-phase growth. Differences in in vivo growth patterns of capsular type 2, 3, 4, 5, and 6 strains were not found to be associated with differences in the levels of pneumolysin.

Identification of a Clostridium perfringens enterotoxin region required for large complex formation and cytotoxicity by random mutagenesis.

Clostridium perfringens enterotoxin (CPE), a single polypeptide of 319 amino acids, has a unique multistep mechanism of action. In the first step, CPE binds to claudin proteins and/or a 50-kDa eukaryotic membrane protein receptor, forming a small ( approximately 90-kDa) complex. This small complex apparently then associates with a 70-kDa eukaryotic membrane protein, resulting in formation of a large complex that induces the onset of membrane permeability alterations. To better define the boundaries of CPE functional regions and to identify specific amino acid residues involved in various steps of CPE action, in this study we subjected the cloned cpe gene to random mutagenesis in XL-1 Red strains of Escherichia coli. Seven CPE random mutants with reduced cytotoxicity for Vero cells were phenotypically characterized for the ability to complete each step in CPE action. Five of these seven recombinant CPE (rCPE) random mutants (G49D, S59L, R116S, R137G, and S167P) exhibited binding characteristics similar to those of rCPE or native CPE, while the Y310C and W226Stop mutants showed reduced binding and no binding, respectively, to brush border membranes. Interestingly, two completely nontoxic mutants (G49D and S59L) were able to bind and form small complex but they did not mediate any detectable large complex formation. Another strongly attenuated mutant, R116S, formed reduced amounts of an anomalously migrating large complex. Collectively, these results provide further support for large complex formation being an essential step in CPE action and also identify the CPE region ranging from residues approximately 45 to 116 as important for large complex formation. Finally, we also report that limited removal of extreme N-terminal CPE sequences, which may occur in vivo during disease, stimulates cytotoxic activity by enhancing large complex formation.

PspA, a protection-eliciting pneumococcal protein: immunogenicity of isolated native PspA in mice.

PspA is a surface exposed virulence factor of S. pneumoniae that can elicit protective immunity to pneumococcal sepsis in mice. It can be released from pneumococci by washing them with a solution containing 2% choline chloride, by growing pneumococci in media containing 1.2% choline chloride, or by growing pneumococci in media in which the choline has been replaced by ethanolamine. Our results indicate that PspA is the major protection-eliciting antigen in each of these preparations. Two injections of < or = 1 microgram of native PspA purified by use of a choline-Sepharose column are highly immunogenic in BALB/c and CBA/N mice, and even in the absence of adjuvant can elicit protection against otherwise fatal sepsis with 100 times the LD50 of S. pneumoniae. Fragments comprising the N-terminal 115 and 245 amino acids of PspA were able to elicit protection but only in the presence of complete Freund's adjuvant (CFA). In the absence of CFA the 245 amino acid fragment was less than 1/100 as immunogenic as native PspA.

Heterosubtypic immunity to influenza A virus in mice lacking IgA, all Ig, NKT cells, or gamma delta T cells.

The mechanisms of broad cross-protection to influenza viruses of different subtypes, termed heterosubtypic immunity, remain incompletely understood. We used knockout mouse strains to examine the potential for heterosubtypic immunity in mice lacking IgA, all Ig and B cells, NKT cells (CD1 knockout mice), or gamma(delta) T cells. Mice were immunized with live influenza A virus and compared with controls immunized with unrelated influenza B virus. IgA(-/-) mice survived full respiratory tract challenge with heterosubtypic virus that was lethal to controls. IgA(-/-) mice also cleared virus from the nasopharynx and lungs following heterosubtypic challenge limited to the upper respiratory tract, where IgA has been shown to play an important role. Ig(-/-) mice controlled the replication of heterosubtypic challenge virus in the lungs. Acute depletion of CD4+ or CD8+ T cell subsets abrogated this clearance of virus, thus indicating that both CD4+ and CD8+ T cells are required for protection in the absence of Ig. These results in Ig(-/-) mice indicate that CD4+ T cells can function by mechanisms other than providing help to B cells for the generation of Abs. Like wild-type mice, CD1(-/-) mice and gamma(delta) (-/-) mice survived lethal heterosubtypic challenge. Acute depletion of CD4+ and CD8+ cells abrogated heterosubtypic protection in gamma(delta) (-/-) mice, but not B6 controls, suggesting a contribution of gamma(delta) T cells. Our results demonstrate that the Ab and cellular subsets deficient in these knockout mice are not required for heterosubtypic protection, but each may play a role in a multifaceted response that as a whole is more effective than any of its parts.

Pneumococcal diversity: considerations for new vaccine strategies with emphasis on pneumococcal surface protein A (PspA).

Streptococcus pneumoniae is a problematic infectious agent, whose seriousness to human health has been underscored by the recent rise in the frequency of isolation of multidrug-resistant strains. Pneumococcal pneumonia in the elderly is common and often fatal. Young children in the developing world are at significant risk for fatal pneumococcal respiratory disease, while in the developed world otitis media in children results in substantial economic costs. Immunocompromised patients are extremely susceptible to pneumococcal infection. With 90 different capsular types thus far described, the diversity of pneumococci contributes to the challenges of preventing and treating S. pneumoniae infections. The current capsular polysaccharide vaccine is not recommended for use in children younger than 2 years and is not fully effective in the elderly. Therefore, innovative vaccine strategies to protect against this agent are needed. Given the immunogenic nature of S. pneumoniae proteins, these molecules are being investigated as potential vaccine candidates. Pneumococcal surface protein A (PspA) has been evaluated for its ability to elicit protection against S. pneumoniae infection in mouse models of systemic and local disease. This review focuses on immune system responsiveness to PspA and the ability of PspA to elicit cross-protection against heterologous strains. These parameters will be critical to the design of broadly protective pneumococcal vaccines.