Modular service provision for heterogeneous patient groups: a single case study in chronic Down syndrome care.

BACKGROUND: Service modularity could be promising for organizing healthcare delivery to heterogeneous patient groups because it enables cost reductions while also being responsive towards individual patients' needs. However, no research on the applicability of modularity in this context exists. To this end, we conducted a qualitative single-case study on chronic healthcare provision for Down syndrome patients, delivered by multidisciplinary pediatric Downteams in the Netherlands, from a modular perspective. METHODS: We conducted six semi-structured interviews with coordinators of multidisciplinary Downteams in six hospitals. In addition, we gathered data by means of observations and analysis of relevant documentation. We transcribed, coded, and analyzed the interviews utilizing the Miles and Huberman approach. The consolidated criteria for reporting qualitative research (COREQ) were applied in this study. RESULTS: In all six Downteams studied, the modular package for Down syndrome patients (i.e. the visit to the Downteams) could clearly be divided into modules (i.e. the separate consultations with the various professionals), and into different components (i.e. sub-elements of these consultations). These modules and components were linked by different types of customer-flow and information-flow interfaces. These interfaces allowed patients to flow smoothly through the system and allowed for information transfer, respectively. CONCLUSION: Our study shows a modular perspective is applicable to analyzing chronic healthcare for a heterogeneous patient group like children with Down syndrome. The decomposition of the various Downteams into modules and components led to mutual insight into each other's professional practices, both within and across the various Downteams studied. It could be used to increase transparency of delivered care for patients and family. Moreover, it could be used to customize care provision by mixing-and-matching components. More detailed research on chronic modular care provision for patients with DS is needed to explore this.

The long-term effects of early oral feeding following minimal invasive esophagectomy.

A nil-by-mouth regime with enteral nutrition via an artificial route is frequently applied following esophagectomy. However, early initiation of oral feeding could potentially improve recovery and has shown to be beneficial in many types of abdominal surgery. Although short-term nutritional safety of oral intake after an esophagectomy has been documented, long-term effects of this feeding regimen are unknown. In this cohort study, data from patients undergoing minimal invasive Ivor-Lewis esophagectomy between 04-2012 and 09-2015 in three centers in Netherlands were collected. Patients in the oral feeding group were retrieved from a previous prospective study and compared with a cohort of patients with early enteral jejunostomy feeding but delayed oral intake. Body mass index (BMI) measurements, complications, and nutritional re-interventions (re- or start of artificial feeding, start of total parenteral nutrition) were gathered over the course of one year after surgery. One year after surgery the median BMI was 22.8 kg/m2 and weight loss was 7.0 kg (9.5%) in 114 patients. Patients in the early oral feeding group lost more weight during the first postoperative month (P = 0.004). However, in the months thereafter this difference was not observed anymore. In the early oral feeding group, 28 patients (56%) required a nutritional re-intervention, compared to 46 patients (72%) in the delayed oral feeding group (P = 0.078). During admission, more re-interventions were performed in the delayed oral feeding group (17 vs. 46 patients P < 0.001). Esophagectomy reduces BMI in the first year after surgery regardless of the feeding regimen. Direct start of oral intake following esophagectomy has no impact on early nutritional re-interventions and long-term weight loss.

Atypical clinical presentation of internal herniation after laparoscopic Roux-en-Y gastric bypass.

A 60-years old women with history of Roux-en-Y gastric bypass presented with progressive abdominal pain, mainly at the left loin. Imaging was aspecific. Exploratory laparoscopy showed an internal herniation trough the Petersen space.

Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis.

BACKGROUND: Alternative splicing of the interleukin-5 receptor alpha (IL-5Ralpha)-subunit leads to the generation of a signalling, membrane-anchored (TM) isoform, or a secreted [soluble (SOL)], antagonistic variant. Given the key role of IL-5 in eosinophil function, we investigated SOL IL-5Ralpha expression pattern in an eosinophil-associated disease such as nasal polyposis (NP). METHODS: An SOL IL-5Ralpha enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction (PCR) were established and applied in serum, nasal secretion and nasal tissue of controls (n = 12), and NP patients (n = 42) with or without asthma. RESULTS: Analysis of serum, nasal secretion, and nasal tissue samples revealed that SOL IL-5Ralpha protein concentrations were significantly increased in NP vs control tissue. Within the NP group, there was a significant up-regulation of SOL IL-5Ralpha in patients with systemic airway disease. These findings were confirmed at the mRNA level, using an optimized real-time reverse-transcriptase PCR procedure. CONCLUSIONS: This report demonstrates SOL IL-5Ralpha transcript and protein up-regulation in NP. Soluble IL-5Ralpha differentiates nasal polyps with or without concomitant asthma. As SOL IL-5Ralpha is strongly up-regulated for disease and has antagonistic properties in vitro, our studies shed new light on the mechanisms of specific immunomodulatory therapies, such as anti-IL-5.

[Radiation of parotid glands for salivary flow reduction in amyotrophic lateral sclerosis]. / Naruzhnoe obluchenie okoloushnykh zhelez dlia umen'sheniia sliunotecheniia pri bokovom amiotroficheskom skleroze.

Radiation of the parotid and submandibular glands was performed in 18 patients with pronounced hypersalivation at a late stage of amyotrophic lateral sclerosis (ALS). Single bilateral radiation of the parotid and posterior submandibular glands was made in the dosage of 7.0-7.5 Gy. Salivation volume was measured before and after the radiation therapy. Sixteen patients exhibited satisfactory and marked salivary flow reduction during 4-6 months. Xerostomia developed in 1 patient who needed assignment of artificial salivary substitute and 1 patient did not respond to the therapy. The patient's caregivers reported a positive effect in all the cases. Tolerance of the therapy was good except rare side effects. Radiation of the parotid glands significantly reduced salivary flow in ALS, especially in patients receiving an adequate amount of water.

Syphilis control during pregnancy: effectiveness and sustainability of a decentralized program.

OBJECTIVES: This study sought to assess the performance, effectiveness, and costs of a decentralized antenatal syphilis screening program in Nairobi, Kenya. METHODS: Health clinic data, quality control data, and costs were analyzed. RESULTS: The rapid plasma reagin (RPR) seroprevalence was 3.4%. In terms of screening, treatment, and partner notification, the program's performance was adequate. The program's effectiveness was problematic because of false-negative and false-positive RPR results. The cost per averted case was calculated to be US$95 to US$112. CONCLUSIONS: The sustainability of this labor-intensive program is threatened by costs and logistic constraints. Alternative strategies, such as the mass epidemiologic treatment of pregnant women in high-prevalence areas, should be considered.

An in vitro model for the study of microglia-induced neurodegeneration: involvement of nitric oxide and tumor necrosis factor-alpha.

The precise function of activated microglia and their secretory products remains controversial. In order to assess the role of microglial secretion products, we established an in vitro model of an inflammatory reaction in the brain by co-culturing microglial and neuronal cell lines. Upon stimulation with interferon-gamma and lipopolysaccharides, the microglial cells adopted an activated phenotype and secreted tumor necrosis factor-alpha (TNF-alpha), prostaglandin E(2) and nitric oxide (NO). Neuronal degeneration was quantified by measuring the concentrations of microtubule associated protein tau and neuron specific enolase, which are also used as diagnostic tool in Alzheimer's disease, in supernatants. In activated contact co-cultures, the levels of these neuronal markers were significantly raised compared to non-activated co-cultures. NO-synthase inhibitors significantly diminished the rise of tau in activated co-cultures, while indomethacin, superoxide dismutase, or a neutralizing TNF-alpha antibody did not. When a chemical NO-donor or TNF-alpha were added to pure neuronal cultures, cell viability was significantly reduced. TNF-alpha increased neuronal sensitivity towards NO. There were indications that a part of the cells died by apoptosis. This model demonstrates a neurotoxic role for NO in microglia-induced neurodegeneration and provides a valuable in vitro tool for the study of microglia-neuron interactions during inflammation in the brain.

Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the wild-type molecule.

In this study, we characterised the anti-tumour as well as the pro-metastatic activities of TNF mutants deficient in their lectin-like activity.1619 We report that, despite reduced systemic toxicity as compared to wild-type (wt) mTNF, a (T104A) and a (T104A-E106A-E109A) mTNF mutant (triple mTNF) retained most of their necrotic and tumouristatic activities, as measured in a CFS-1 fibrosarcoma and a B16BL6 melanoma tumour model, respectively. These mutants also conserved their anti-angiogenic activity, as measured in an in vitro endothelial morphogenesis assay.26 In contrast, the pro-metastatic activity of the T104A and the triple mTNF mutants in the CFS-1 fibrosarcoma and the 3LL-R Lewis lung carcinoma tumour model was significantly lower than that of the wt molecule. These results thus indicate that the lectin-like domain of TNF is not implicated in its necrotic, tumouristatic and anti-angiogenic activities, but that it can contribute to the pro-metastatic effect of the cytokine. In conclusion, in view of their reduced systemic toxicity and pro-metastatic capacity, but their retained anti-tumour activities, lectin-deficient TNF mutants might prove to be therapeutically interesting alternatives to wt TNF.

Model-based evaluation of single-round mass treatment of sexually transmitted diseases for HIV control in a rural African population.

OBJECTIVES: To compare the impact of single-round mass treatment of sexually transmitted diseases (STD), sustained syndromic treatment and their combination on the incidence of HIV in rural Africa. METHODS: We studied the effects of STD interventions by stochastic simulation using the model STDSIM. Parameters were fitted using data from a trial of improved STD treatment services in Mwanza, Tanzania. Effectiveness was assessed by comparing the prevalences of gonorrhoea, chlamydia, syphilis and chancroid, and the incidence of HIV, in the general adult population in simulations with and without intervention. RESULTS: Single-round mass treatment was projected to achieve an immediate, substantial reduction in STD prevalences, which would return to baseline levels over 5-10 years. The effect on syphilis was somewhat larger if participants cured of latent syphilis were not immediately susceptible to re-infection. At 80% coverage, the model projected a reduction in cumulative HIV incidence over 2 years of 36%. A similar impact was achieved if treatment of syphilis was excluded from the intervention or confined to those in the infectious stages. In comparison with sustained syndromic treatment, single-round mass treatment had a greater short-term impact on HIV (36 versus 30% over 2 years), but a smaller long-term impact (24 versus 62% over 10 years). Mass treatment combined with improved treatment services led to a rapid and sustained fall in HIV incidence (57% over 2 years; 70% over 10 years). CONCLUSIONS: In populations in which STD control can reduce HIV incidence, mass treatment may, in the short run, have an impact comparable to sustained syndromic treatment. Mass treatment combined with sustained syndromic treatment may be particularly effective.

Prevention of mother-to-child transmission of HIV in developing countries: recommendations for practice. The Ghent International Working Group on Mother-To-Child Transmission of HIV.

OBJECTIVES: Different approaches to prevent mother-to-child transmission of HIV are being evaluated in developing countries. The first trials using a short regimen of zidovudine have been successful in Thailand, Côte d'Ivoire and Burkina Faso. International and local strategies are now being considered. The Ghent International Working Group on Mother-to-Child Transmission of HIV developed public health policy options to integrate these interventions into basic and maternal and child health (MCH) services. METHODS: The following tasks were undertaken: a critical review of randomized trials; an international pooled analysis of late postnatal transmission of HIV through breastfeeding; a review of the cost-effectiveness and cost-benefit of antiretroviral prophylaxis; a feasibility assessment of preventive strategies, including a postal survey on HIV voluntary counselling and testing (VCT) of pregnant women; the identification of requirements and research priorities for prenatal, obstetric and paediatric care. These projects provided the background for a three-day workshop in Ghent, Belgium, in November 1997. Conclusions were further refined, based on 1998 research findings. RESULTS: A summary of relevant evidence and ten public health recommendations are reported. VCT for pregnant women, a short regimen of zidovudine together with alternatives to breastfeeding currently represent the best option to reduce vertical transmission in most developing countries. The primary goal of the integrated package supporting these interventions is to alleviate overall maternal and infant morbidity and mortality. CONCLUSION: Prevention of mother-to-child transmission of HIV should now be considered for integration into basic health and MCH services of selected countries, with the involvement of governments and donor agencies.

Membrane interaction of TNF is not sufficient to trigger increase in membrane conductance in mammalian cells.

Tumor necrosis factor TNF can trigger increases in membrane conductance of mammalian cells in a receptor-independent manner via its lectin-like domain. A lectin-deficient TNF mutant, lacking this activity, was able to bind to artificial liposomes in a pH-dependent manner, but not to insert into the bilayer, just like wild type TNF. A peptide mimicking the lectin-like domain, which can still trigger increases in membrane currents in cells, failed to interact with liposomes. Thus, the capacity of TNF to trigger increases in membrane conductance in mammalian cells does not correlate with its ability to interact with membranes, suggesting that the cytokine does not form channels itself, but rather interacts with endogenous ion channels or with plasma membrane proteins that are coupled to ion channels.

The lectin-like domain of tumor necrosis factor-alpha increases membrane conductance in microvascular endothelial cells and peritoneal macrophages.

Herein, we show that TNF exerts a pH-dependent increase in membrane conductance in primary lung microvascular endothelial cells and peritoneal macrophages. This effect was TNF receptor-independent, since it also occurred in cells isolated from mice deficient in both types of TNF receptors. A TNF mutant in which the three amino acids critical for the lectin-like activity were replaced by an alanine did not show any significant effect on membrane conductance. Moreover, a synthetic 17-amino acid peptide of TNF, which was previously shown to exert lectin-like activity, also increased the ion permeability in these cells. The amiloride sensitivity of the observed activity suggests a binding of TNF to an endogenous ion channel rather than channel formation by TNF itself. This may have important implications in mechanisms of TNF-mediated vascular pathology.

Declining syphilis prevalence in pregnant women in Nairobi since 1995: another success story in the STD field?

Untreated maternal syphilis during pregnancy will cause adverse pregnancy outcomes in more than 60% of the infected women. In Nairobi, Kenya, the prevalence of syphilis in pregnant women of 2.9% in 1989, showed a rise to 6.5% in 1993, parallel to an increase of HIV-1 prevalence rates. Since the early 1990s, decentralized STD/HIV prevention and control programmes, including a specific syphilis control programme, were developed in the public health facilities of Nairobi. Since 1992 the prevalence of syphilis in pregnant women has been monitored. This paper reports the findings of 81,311 pregnant women between 1994 and 1997. A total of 4244 women (5.3%) tested positive with prevalence rates of 7.2% (95% CI: 6.7-7.7) in 1994, 7.3% (95% CI: 6.9-7.7) in 1995, 4.5% (95% CI: 4.3-4.8) in 1996 and 3.8% (95% CI: 3.6-4.0) in 1997. In conclusion, a marked decline in syphilis seroprevalence in pregnant women in Nairobi was observed since 1995-96 (P<0.0001, Chi-square test for trend) in contrast to upward trends reported between 1990 and 1994-95 in the same population.

PIP: This study presents the trend in syphilis prevalence among 81,311 pregnant women in Nairobi, Kenya, from 1994 to 1997. Clinic nurses performed syphilis serology using a rapid plasma reagin (RPR) card test in 10 NCC clinics and Chi square; these were used to study trends over time. Results showed that a total of 4244 women (5.3%) tested positive with prevalence rates of 7.2% (95% CI: 6.7-7.7) in 1994, 7.3% (95% CI: 6.9-7.7) in 1995, 4.5% (95% CI: 4.3-4.8) in 1996, and 3.8% (95% CI: 3.6-4.0) in 1997. Thus, a significant decrease in syphilis seroprevalence among pregnant women in Nairobi was observed since 1995-96, by contrast with the rising trend in syphilis prevalence reported in 1990 and 1994-95 in the same population. This decline was attributable in large part to the syphilis control program initiated in Nairobi in June 1992, which focused on sexual behavior modifications, changes in health care seeking behavior and improved health care services.

Preventing HIV infection: lessons from Mwanza and Rakai.

PIP: The impact of enhanced syndromic diagnosis of symptomatic sexually transmitted infections (STIs) upon the incidence of HIV infections was evaluated in 8 paired villages in Mwanza, Tanzania, over a 2-year period. Shortly thereafter, a study was conducted in Uganda's Rakai district which focused upon treating all members of 5 clusters of paired communities, including those with symptomatic and asymptomatic STIs. In August 1995, the results of the Mwanza study showed that almost 40% of HIV infections had been prevented in the communities receiving the intervention. No other HIV intervention has had such a major effect upon infection rates. In contrast, however, no HIV infections were prevented in the Rakai intervention communities. The Mwanza results could reflect the short-term impact of STD prevention and control in an immature epidemic, while the Rakai study reflects the short-term impact in a mature epidemic. The probability of transmission, the duration of infectiousness, and the number of sex partners are discussed as factors which influence the generation of an HIV epidemic in a susceptible population. The 2 studies' results indicate that STD prevention and control is feasible, effective, and affordable.^ieng

Both TNF receptors are required for direct TNF-mediated cytotoxicity in microvascular endothelial cells.

The conditions under which tumor necrosis factor-alpha (TNF) induces apoptosis in primary microvascular endothelial cells (MVEC) were investigated. In the absence of sensitizing agents, TNF induced apoptosis after 3 days of incubation in confluent MVEC. In contrast, upon addition of the transcriptional inhibitor actinomycin D (Act. D), confluence was no longer required and apoptosis occurred already after 16 h. To assess the role of either TNF receptor (TNFR) type in apoptosis, MVEC isolated from mice genetically deficient in TNFR1 (Tnfr1o mice) or TNFR2 (Tnfr2o mice) were incubated with TNF in the presence or absence of Act. D. Under sensitized conditions, Tnfr2o MVEC were lysed like controls, whereas Tnfr1o MVEC were completely resistant, indicating an exclusive role for TNFR1. In contrast, in the absence of Act. D, confluent monolayers of wild-type cells were lysed by TNF, but both Tnfr1o and Tnfr2o MVEC were resistant to TNF-mediated toxicity, indicating a requirement for both TNFR types. Overexpression of the anti-apoptotic protein bcl-xL in MVEC led to a protection against the direct, but not the sensitized cytotoxicity of TNF. In conclusion, in pathophysiologically relevant conditions, both TNFR appear to be required for TNF-induced apoptosis in MVEC.

Systematic analysis of STD control: an operational model.

BACKGROUND: Sexually transmitted diseases (STDs) enhance HIV transmission, and improved management of STD in primary health care decreases HIV incidence. In resource poor countries, those responsible for planning and managing STD control programmes need to be able to analyse the STD situation in their setting and the interventions which are therefore likely to be most cost effective. However, the data required for such decision making are often not available in developing countries. This paper presents an operational model, developed as a practical tool to support planning, monitoring, and evaluation of STD intervention strategies in settings where data are unavailable or inadequate. METHOD: The operational model is based on the approach developed for estimating the effectiveness of control measures in tuberculosis programmes. Using available data, the model takes a step by step approach. It begins with analysis of the total male and female population, the proportion of men and women aged 15-49 years, and the proportion of these who are sexually active. Subsequent steps analyse numbers with STDs, and loss of cases to the health system at each stage between infection and cure. The model was tested in Nairobi, Kenya using available demographic, epidemiological, and public health data; no original data were collected. Data for the total population of Nairobi were not available to illustrate all the steps in the model. For these steps, relevant information was taken where available from a specific study population using a large STD referral centre. RESULTS: Despite the lack of precise data for Nairobi, the model highlighted sex imbalances in population, which has potential implications for STDs. It also showed significant disparities in terms of public health policy--for example, between the number of people infected with STDs and the number who have symptoms, and between the number with symptoms and those who seek treatment from public health facilities. It also showed differences between the numbers who attend a health facility, and those that are correctly diagnosed and treated, and, of these, the proportion that are cured. CONCLUSION: Even where data are incomplete or not available, the model can be a useful tool for analysis. Application of the model, as the Nairobi example illustrates, provides a useful starting point in terms of determining both general and specific determinants of STDs, identifying problems, highlighting significant sex differences, and indicating where it might be appropriate to focus interventions. The model showed that, in Nairobi, only a small proportion of STD cases are removed from the reservoir of infection in the community through curative services, that cases are lost to the health services at every step, and therefore that interventions are required at every step to achieve comprehensive STD control. It highlights the need for strategies to prevent infections, to identify and treat those with and without symptoms, to motivate those who are aware of their infection to seek treatment, and to improve the effectiveness of partner notification and treatment. Finally, the model points to areas where data are inadequate and where STD control programmes need to concentrate information collection efforts.

Prospective evaluation of a flow chart using a risk assessment for the diagnosis of STDs in primary healthcare centres in Libreville, Gabon.

BACKGROUND: The serious impact of STDs on women and children in particular, and the linkage between STDs and HIV infection are a profound concern to public health worldwide. One of the main strategies against STDs is based on early diagnosis and treatment. However, this approach is limited by the lack of appropriate laboratory facilities. A syndromic approach has been recommended by the WHO but needs to be evaluated under field conditions. A preliminary cross sectional study on STD prevalence and risk factors in Libreville showed that 13.5% of pregnant women had gonococcal and/or chlamydial infection which justifies systematic screening of STDs. Based on the results of this study, different flow charts with or without a risk factor assessment (score) were designed. The flow chart with the best performances for diagnosing chlamydial or gonococcal cervical infection and routinely acceptable, was a score algorithm, based on two risk factors (age and marital status) and four simple clinical signs (pelvic or lumbar pain, vaginal discharge and its characteristics). Sensitivity and specificity were 76.9% and 40.4% respectively. Thus, the objective of this study was to evaluate this strategy under field conditions. METHODS: A prospective study among pregnant women attending antenatal clinics was done. The score was applied to each woman by a midwife and a physician, and specimens were collected for the reference laboratory tests. Validation of the algorithm was done by comparing the performances with the gold standard laboratory diagnosis. RESULTS: 646 pregnant women were enrolled. The prevalence of cervical infection was 11.3. The sensitivity and specificity of this algorithm recorded by the midwives were 73.3% and 54.8%, respectively and by the physician 76.7% and 50.6%. The proportion of women correctly classified by the midwives and by the physician was not significantly different. CONCLUSION: The score applied was well accepted by healthcare workers and patients, and was routinely practised. Results obtained by the midwives and by the physician were similar. Thus, the use of flow charts which adds a risk assessment to the syndromic approach for diagnosing cervical infections is feasible. However, the performances of such flow charts need to be improved before being used routinely.

Drugs for STD management in developing countries: choice, procurement, cost, and financing.

OBJECTIVES: (i) To compare acquisition costs of drugs between countries to treat one standardised STD episode. (ii) To explain variations, treatment protocols, purchasing policies, procurement systems, and sources of financing. METHODS: National STD guidelines, purchasing mechanisms, and drug acquisition costs from 15 countries were compiled, using information from ministries of health and European Commissions headquarters. Prices were converted in European currency unit (ecu). Acquisition costs per episode were calculated for the four main STD syndromes--urethral discharge, vaginal discharge, lower abdominal pain in women, and genital ulcer disease (GUD). To compare costs in different countries the relative distribution of the four main STD syndromes was calculated. RESULTS: Treatment protocols. All 15 countries recommended treatment for urethral discharge with drugs effective against Neisseria gonorrhoeae and Chlamydia trachomatis. For vaginal discharge two patterns emerged. In 11 countries women with vaginal discharge were divided into high risk of STDs and low risk of STDs. Women at low risk were treated for candidiasis, trichomoniasis, and bacterial vaginosis and those at high risk were also treated for N gonorrhoeae and C trachomatis. Guidelines for abdominal pain all included treatment for N gonorrhoeae, C trachomatis, and anaerobic infections. All countries except the Philippines recommended treating GUD with drugs effective against chancroid and syphilis. Costs per episode. Acquisition costs per episode varied from 0.40 ecu to 7.89 ecu with wide variations. The standardised acquisition cost of STD drugs for the public sector varied between 0.54 ecu in Tanzania and 5.80 ecu in Swaziland. The choice of drugs was the main factor explaining this difference. In countries which only use generic drugs, acquisition costs were lower (between 0.54 ecu and 1.07 ecu). However, important variations exist between countries which use similar treatment protocols (for example, 2.54 ecu in Namibia, 5.80 ecu in Swaziland). These variations are mainly explained by differences in procurement methods. Acquisition costs for peripheral public services are higher than at central level (for example, 0.89 ecu versus 0.54 ecu in Tanzania) as a result of mark ups for transport, handling, and inflation. Acquisition cost of drugs per standardised STD episode for patients through private pharmacies may be as high as 11.93 ecu in Senegal. This is more than 10 times the acquisition cost for public sector at central level in this country (of 1.04 ecu) and is mainly due to the fact that drugs in private pharmacies are branded drugs, which are imported at a high price, taxes, and mark ups in the distribution chain. In 11 of the 15 countries studied, effective STD drugs are now available through public services, in at least in a part of the country. In Botswana, Ghana, Ivory Coast, Mauritania, Lesotho, Namibia, Senegal, Seychelles, and Swaziland these drugs are supplied throughout the country within the existing essential drug programme and financed by the government budget or through a revolving fund for drugs. In Tanzania and Mozambique, all STD drugs in the public sector are funded through donor support. In Nepal recommended STD drugs are widely available at low cost through private outlets. CONCLUSIONS: Reducing antimicrobial susceptibility of N gonorrhoeae and Haemophilus ducreyi is a continuous threat for sustainable STD drug supply as alternative patented drugs are more expensive. If patented STD drugs are required drug cost may be minimised by selecting the most appropriate management protocols and by improving procurement. Moreover, recent studies have confirmed the continued susceptibility of N gonorrhoeae to low cost generic drugs in some countries (Mozambique, Tanzania, and Senegal). Even under these circumstances, continued donor support will be needed for the poorest countries to ensure the availability of effective STD management as an esse

Generation of a mouse tumor necrosis factor mutant with antiperitonitis and desensitization activities comparable to those of the wild type but with reduced systemic toxicity.

In this study, we investigated whether the recently identified lectin-like domain of tumor necrosis factor (TNF) is implicated in its biological activities on mammalian cells. To this end, a mouse TNF (mTNF) triple mutant, T104A-E106A-E109A mTNF (referred to hereafter as triple mTNF), lacking the lectin-like affinity of mTNF for specific oligosaccharides, was compared with the wild-type molecule for various TNF effects in vitro and in vivo. The triple mTNF displayed a 50-fold-reduced TNF receptor 2 (TNFR2)-mediated bioactivity but only a 5-fold-reduced TNFR1-mediated bioactivity in vitro. The specific activity of the triple mutant on L929 fibrosarcoma cells was slightly reduced compared with that of the wild type. We subsequently assessed the systemic toxicity of triple versus wild-type mTNF, since TNFR2 is partially implicated in this activity. The triple mTNF had a significantly reduced toxicity compared with that of wild-type mTNF in vivo. Moreover, we compared the effects of the triple and the wild-type mTNFs in TNFR1-mediated phenomena, such as (i) induction of tolerance towards a lethal mTNF dose and (ii) protective activity in cecal ligation and puncture-induced septic peritonitis. No significant differences between the mutant and wild-type forms were observed. In conclusion, these results indicate that triple mTNF, lacking TNF's lectin-like binding capacity, has reduced systemic toxicity but retains the tolerance-inducing and peritonitis-protective activities of wild-type mTNF.