Potential drug-drug interactions with phentermine among long-term phentermine consumers: A retrospective analysis.

BACKGROUND: Phentermine is an internationally recognised amphetamine derivative with significant appetite-suppressing properties. The drug is indicated for the short-term management of obesity, as the long-term (LT) use of phentermine may potentially be associated with severe cardiovascular side-effects, abuse and dependence. The LT use hereinafter describes periods exceeding 12 consecutive weeks. This use may also be associated with potential drug-drug interactions (PDDIs), which may result in adverse drug reactions (ADRs). The literature reports that phentermine is often prescribed LT and for several other off-label indications, increasing the risk for individuals to experience adverse drug events (ADEs) and drug-drug interactions (DDIs). There are, to our knowledge, no South African (SA) studies investigating the prevalence of co-prescribing LT phentermine with drugs that may potentially cause DDIs. OBJECTIVE: To determine the prevalence of mild, moderate and severe DDIs with phentermine use when the duration of therapy in private healthcare exceeded 12 consecutive weeks. METHODS: A cross-sectional drug utilisation review (DUR) was done by using data obtained from a SA pharmacy benefit management (PBM) company's database. Retrospective data of medicine claims for phentermine, from 1  January 2015 to 31  December 2019, were extracted for analysis. The number of days phentermine was supplied was used to identify the study population, in other words, those patients who received the drug LT. A drug interaction checker (Drugs.com) was used to identify potential mild, moderate and severe DDIs when using phentermine and co-prescribed drugs concurrently. RESULTS: A total of 889 patients received phentermine LT. The top 20 drugs identified as being frequently co-prescribed in this study population demonstrated no mild PDDI, 15 (75%) moderate PDDIs and 5 (25%) severe PDDIs. The most common co-prescribed drug in the moderate group was dextromethorphan (n=282, 31.72%) and the least co-prescribed was formoterol (n=52, 5.85%). Among the drug group 'severe PDDIs', tramadol (n=416, 46.79%) was most frequently prescribed, whereas phenylpropanolamine (n=69, 7.76%) was the least prescribed to patients in this group. CONCLUSION: There are patients who receive LT phentermine therapy despite the potential severe consequences that may result. These patients may receive concomitant therapy with phentermine and other pharmaceutical constituents, which may potentially cause DDIs, more specifically, moderate and severe DDIs. As such, these patients are not only confronted with the consequences of DDIs but are also at risk to experience ADRs as the residual effect of PDDIs.

Allergic contact hand dermatitis due to constituents of nitrile gloves

Purpose: This report of a case of allergic contact hand dermatitis due to constituents of nitrile gloves is to bring to the attention of practitioners four important practice points: 1) allergic contact dermatitis may occur due to exposure to chemicals in nitrile gloves; 2) skin patch testing is used to identify the causative allergens; 3) targeted allergens may be necessary in addition to the baseline European standard series if the standard series is unhelpful; and 4) there are potential interventions to manage nitrile glove dermatitis. Findings: A laboratory analyst had occupational exposure to several allergens and had worn latex gloves. She was exposed to laboratory chemicals and powdered ore dust, containing precious metals. She developed hand dermatitis and was relocated to administrative duties not requiring glove use. Her dermatitis cleared but recurred when she returned to the laboratory and started using nitrile gloves. On history, nitrile gloves and platinum group metal ore dust were consistently associated with her hand dermatitis, but laboratory chemicals were not. Latex-specific immunoglobulin E (IgE) was negative, as were skin patch tests for 13 allergens in the metal series, including salts of platinum group metals. She had positive allergic reactions to cobalt chloride, formaldehyde, nickel sulphate, and quaternium 15 in the European standard series patch tests. She did not react to the rubber chemicals in the European standard series, including thiuram mix. The patient was then tested with the rubber additives series because of the glove-relatedness of her hand dermatitis. She had positive reactions to three thiuram compounds used as accelerators in rubber gloves. The patient went on vacation during which time her dermatitis improved. She was relocated to a position without glove use or ore contact and her dermatitis did not recur. Conclusions: An analytic laboratory worker developed hand allergic contact dermatitis due to nitrile glove constituents. The diagnosis is supported by the improvement in her dermatitis after cessation of glove use, negative metal series patch tests, and positive patch tests to accelerators found in rubber gloves. Nevertheless, a contribution to the dermatitis by metals in the platinum group metal ore dust cannot be excluded. Recommendations: Nitrile glove constituents should be considered in wearers who develop hand dermatitis. Skin patch testing is recommended to investigate putative agents. Specific patch test series for more targeted testing may be required

Reforming the workers' compensation process for occupational lung disease among miners in South Africa: an efficiency study of claims assessment.

PURPOSE: The large burden of silicosis and tuberculosis (TB) in the South African mining industry, coupled with an under-resourcing of the compensation agencies responsible for certifying occupational lung disease, have resulted in serious backlogs. This work aimed to measure the efficiency gains from triaging occupational lung disease claims using claim type, years of mining exposure and computer aided detection (CAD) to save on scarce medical adjudicators. METHODS: During 2020, the compensation authority started to triage claims for TB and those of miners with < 10 years of service to two-person panels instead of the four-person panel plus radiologist used previously. Efficiency gain was calculated in medical person-units saved and reduction in delays. Different service thresholds predictive of silicosis were simulated, as well as the impact of pre-classification of chest X-rays with CAD using different combinations of sensitivity and specificity. RESULTS: The new triage system saved 20.3% in person-time units and reduced delays by 10-20 days. Without CAD the greatest efficiency gain (28%) was projected from dispensing with a mining service threshold and routing all non-TB claims to the small panels at the outset. Simulation of four different CAD sensitivity/specificity combinations yielded efficiency gains of 18.2-36.1%, with 31.1% judged the most realistic. Use of sensitivity of close to 100% would not be feasible because of the very low resulting specificity. CONCLUSION: Pre-adjudication triage of claims at the compensation agency is capable of saving a substantial proportion of adjudicator time and reducing certification delays. Additional efficiency gains are achievable by referring all claims to small panels to begin with and improvement of CAD performance for this ex-miner population.

Silicone adhesive multilayer foam dressings as adjuvant prophylactic therapy to prevent hospital-acquired pressure ulcers: a pragmatic noncommercial multicentre randomized open-label parallel-group medical device trial.

BACKGROUND: Silicone adhesive multilayer foam dressings are used as adjuvant therapy to prevent hospital-acquired pressure ulcers (PUs). OBJECTIVES: To determine whether silicone foam dressings in addition to standard prevention reduce the incidence of PUs of category 2 or worse compared with standard prevention alone. METHODS: This was a multicentre, randomized controlled medical device trial conducted in eight Belgian hospitals. At-risk adult patients were centrally randomized (n = 1633) to study groups based on a 1 : 1 : 1 allocation: experimental groups 1 (n = 542) and 2 (n = 545) - pooled as the treatment group - and the control group (n = 546). The experimental groups received PU prevention according to hospital protocol, and a silicone foam dressing on the relevant body sites. The control group received standard of care. The primary endpoint was the incidence of a new PU of category 2 or worse at the studied body sites. RESULTS: In the intention-to-treat population (n = 1605), PUs of category 2 or worse occurred in 4·0% of patients in the treatment group and 6·3% in the control group [relative risk (RR) 0·64, 95% confidence interval (CI) 0·41-0·99, P = 0·04]. Sacral PUs were observed in 2·8% and 4·8% of the patients in the treatment group and the control group, respectively (RR 0·59, 95% CI 0·35-0·98, P = 0·04). Heel PUs occurred in 1·4% and 1·9% of patients in the treatment and control groups, respectively (RR 0·76, 95% CI 0·34-1·68, P = 0·49). CONCLUSIONS: Silicone foam dressings reduce the incidence of PUs of category 2 or worse in hospitalized at-risk patients when used in addition to standard of care. The results show a decrease for the sacrum, but no statistical difference for the heel and trochanter areas.

Mating genes in Calonectria and evidence for a heterothallic ancestral state.

The genus Calonectria includes many important plant pathogens with a wide global distribution. In order to better understand the reproductive biology of these fungi, we characterised the structure of the mating type locus and flanking genes using the genome sequences for seven Calonectria species. Primers to amplify the mating type genes in other species were also developed. PCR amplification of the mating type genes and multi-gene phylogenetic analyses were used to investigate the mating strategies and evolution of mating type in a collection of 70 Calonectria species residing in 10 Calonectria species complexes. Results showed that the organisation of the MAT locus and flanking genes is conserved. In heterothallic species, a novel MAT gene, MAT1-2-12 was identified in the MAT1-2 idiomorph; the MAT1-1 idiomorph, in most cases, contained the MAT1-1-3 gene. Neither MAT1-1-3 nor MAT1-2-12 was found in homothallic Calonectria (Ca.) hongkongensis, Ca. lateralis, Ca. pseudoturangicola and Ca. turangicola. Four different homothallic MAT locus gene arrangements were observed. Ancestral state reconstruction analysis provided evidence that the homothallic state was basal in Calonectria and this evolved from a heterothallic ancestor.

New Ceratocystis species associated with rapid death of Metrosideros polymorpha in Hawai'i.

The native 'ohi'a lehua (Metrosideros polymorpha) has cultural, biological and ecological significance to Hawai'i, but it is seriously threatened by a disease commonly referred to as rapid 'ohi'a death (ROD). Preliminary investigations showed that a Ceratocystis species similar to C. fimbriata s.lat. was the cause of the disease. In this study, we used a combination of the phylogenetic, morphological and biological species concepts, as well as pathogenicity tests and microsatellite analyses, to characterise isolates collected from diseased 'ohi'a trees across Hawai'i Island. Two distinct lineages, representing new species of Ceratocystis, were evident based on multigene phylogenetic analyses. These are described here as C. lukuohia and C. huliohia. Ceratocystis lukuohia forms part of the Latin American clade (LAC) and was most closely associated with isolates from Syngonium and Xanthosoma from the Caribbean and elsewhere, including Hawai'i, and C. platani, which is native to eastern USA. Ceratocystis huliohia resides in the Asian-Australian clade (AAC) and is most closely related to C. uchidae, C. changhui and C. cercfabiensis, which are thought to be native to Asia. Morphology and interfertility tests support the delineation of these two new species and pathogenicity tests show that both species are aggressive pathogens on seedlings of M. polymorpha. Characterisation of isolates using microsatellite markers suggest that both species are clonal and likely represent recently-introduced strains. Intensive research is underway to develop rapid screening protocols for early detection of the pathogens and management strategies in an attempt to prevent the spread of the pathogens to the other islands of Hawai'i, which are currently disease free.

Towards an international language for incontinence-associated dermatitis (IAD): design and evaluation of psychometric properties of the Ghent Global IAD Categorization Tool (GLOBIAD) in 30 countries.

BACKGROUND: Incontinence-associated dermatitis (IAD) is a specific type of irritant contact dermatitis with different severity levels. An internationally accepted instrument to assess the severity of IAD in adults, with established diagnostic accuracy, agreement and reliability, is needed to support clinical practice and research. OBJECTIVES: To design the Ghent Global IAD Categorization Tool (GLOBIAD) and evaluate its psychometric properties. METHODS: The design was based on expert consultation using a three-round Delphi procedure with 34 experts from 13 countries. The instrument was tested using IAD photographs, which reflected different severity levels, in a sample of 823 healthcare professionals from 30 countries. Measures for diagnostic accuracy (sensitivity and specificity), agreement, interrater reliability (multirater Fleiss kappa) and intrarater reliability (Cohen's kappa) were assessed. RESULTS: The GLOBIAD consists of two categories based on the presence of persistent redness (category 1) and skin loss (category 2), both of which are subdivided based on the presence of clinical signs of infection. The agreement for differentiating between category 1 and category 2 was 0·86 [95% confidence interval (CI) 0·86-0·87], with a sensitivity of 90% and a specificity of 84%. The overall agreement was 0·55 (95% CI 0·55-0·56). The Fleiss kappa for differentiating between category 1 and category 2 was 0·65 (95% CI 0·65-0·65). The overall Fleiss kappa was 0·41 (95% CI 0·41-0·41). The Cohen's kappa for differentiating between category 1 and category 2 was 0·76 (95% CI 0·75-0·77). The overall Cohen's kappa was 0·61 (95% CI 0·59-0·62). CONCLUSIONS: The development of the GLOBIAD is a major step towards a better systematic assessment of IAD in clinical practice and research worldwide. However, further validation is needed.

Fungal Planet description sheets: 320-370.

Novel species of fungi described in the present study include the following from Malaysia: Castanediella eucalypti from Eucalyptus pellita, Codinaea acacia from Acacia mangium, Emarcea eucalyptigena from Eucalyptus brassiana, Myrtapenidiella eucalyptorum from Eucalyptus pellita, Pilidiella eucalyptigena from Eucalyptus brassiana and Strelitziana malaysiana from Acacia mangium. Furthermore, Stachybotrys sansevieriicola is described from Sansevieria ehrenbergii (Tanzania), Phacidium grevilleae from Grevillea robusta (Uganda), Graphium jumulu from Adansonia gregorii and Ophiostoma eucalyptigena from Eucalyptus marginata (Australia), Pleurophoma ossicola from bone and Plectosphaerella populi from Populus nigra (Germany), Colletotrichum neosansevieriae from Sansevieria trifasciata, Elsinoë othonnae from Othonna quinquedentata and Zeloasperisporium cliviae (Zeloasperisporiaceae fam. nov.) from Clivia sp. (South Africa), Neodevriesia pakbiae, Phaeophleospora hymenocallidis and Phaeophleospora hymenocallidicola on leaves of a fern (Thailand), Melanconium elaeidicola from Elaeis guineensis (Indonesia), Hormonema viticola from Vitis vinifera (Canary Islands), Chlorophyllum pseudoglobossum from a grassland (India), Triadelphia disseminata from an immunocompromised patient (Saudi Arabia), Colletotrichum abscissum from Citrus (Brazil), Polyschema sclerotigenum and Phialemonium limoniforme from human patients (USA), Cadophora vitícola from Vitis vinifera (Spain), Entoloma flavovelutinum and Bolbitius aurantiorugosus from soil (Vietnam), Rhizopogon granuloflavus from soil (Cape Verde Islands), Tulasnella eremophila from Euphorbia officinarum subsp. echinus (Morocco), Verrucostoma martinicensis from Danaea elliptica (French West Indies), Metschnikowia colchici from Colchicum autumnale (Bulgaria), Thelebolus microcarpus from soil (Argentina) and Ceratocystis adelpha from Theobroma cacao (Ecuador). Myrmecridium iridis (Myrmecridiales ord. nov., Myrmecridiaceae fam. nov.) is also described from Iris sp. (The Netherlands). Novel genera include (Ascomycetes): Budhanggurabania from Cynodon dactylon (Australia), Soloacrosporiella, Xenocamarosporium, Neostrelitziana and Castanediella from Acacia mangium and Sabahriopsis from Eucalyptus brassiana (Malaysia), Readerielliopsis from basidiomata of Fuscoporia wahlbergii (French Guyana), Neoplatysporoides from Aloe ferox (Tanzania), Wojnowiciella, Chrysofolia and Neoeriomycopsis from Eucalyptus (Colombia), Neophaeomoniella from Eucalyptus globulus (USA), Pseudophaeomoniella from Olea europaea (Italy), Paraphaeomoniella from Encephalartos altensteinii, Aequabiliella, Celerioriella and Minutiella from Prunus (South Africa). Tephrocybella (Basidiomycetes) represents a novel genus from wood (Italy). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.

Effects of JNJ-40929837, a leukotriene A4 hydrolase inhibitor, in a bronchial allergen challenge model of asthma.

UNLABELLED: Leukotriene B4 (LTB4) is a chemotactic mediator implicated in the pathogenesis of asthma. JNJ-40929837 is an oral inhibitor of LTA4 hydrolase, which catalyzes LTB4 production. We evaluated the effects of JNJ-40929837 in a human bronchial allergen challenge (BAC) model. In this double-blind, 3-period crossover study, 22 patients with mild, atopic asthma were randomized to one of three treatments per period: 100 mg/day JNJ-40929837 for 6 days followed by 50 mg/day on day 7; 10 mg/day montelukast for 6 days; and matched placebo. The BAC was performed on day 6 of each treatment period. Primary outcome was BAC-induced late asthmatic response (LAR) measured by maximal percent reduction in forced expiratory volume (FEV1) in one second. Secondary outcomes included early asthmatic response (EAR) by maximal percent reduction in FEV1, EAR and LAR evaluated by area under the FEV1/time curve (AUC0-2, AUC3-10, respectively), change in baseline FEV1 after 5-day treatment, safety, and correlation of JNJ-40929837 to the divalent cation ionophore A23187-stimulated whole blood LTB4 levels and sputum basal LTB4 levels. No significant differences were observed in the primary or secondary FEV1 endpoints with JNJ-40929837 versus placebo. Compared with placebo (n = 17, LS mean = 27.7), there was no significant attenuation of the maximal percent reduction in the LAR FEV1 with JNJ-40929837 (n = 16, LS mean = 28.6, P = 0.63) but montelukast (n = 17, LS mean = 22.6, P = 0.01) significantly attenuated the LAR. JNJ-40929837 substantially inhibited LTB4 production in whole blood, decreased sputum LTB4 levels and was well-tolerated. The number of adverse events leading to study withdrawal was the same in JNJ-40929837 and placebo groups. In conclusion, JNJ-40929837 demonstrated target engagement in blood and sputum. No significant impact in response to allergen inhalation was observed with JNJ-40929837 versus placebo. REGISTRATION: This study is registered at ClinicalTrials.gov: NCT01241422.

Sensitization and symptoms associated with soybean exposure in processing plants in South Africa.

BACKGROUND: Following the results of a previous study that highlighted the potential for significant levels of dust exposure in South African soybean processing plants, a clinical investigation was undertaken to study the respiratory health of workers in this industry. METHODS: Workers from three soybean-processing plants were studied with a respiratory questionnaire and estimation of atopy and specific soybean IgE. RESULTS: A total of 144 of the 181 (79.6% participation rate) plant employees completed the questionnaire and 136 (75.1%) gave blood samples for analysis of specific IgE. There was a significant association between work-related chest tightness (OR 4.0 [95% CI 1.3-12.6]), work-related nasal symptoms (OR 4.3 [95% CI 1.3-14.6]) and cough or chest tightness after handling soybean (OR 3.6 [95% CI 1.1-11.6]) and soybean sensitization. There was a significant association between current exposure to dust during soybean off-loading and "flu-like" illness (OR 2.7 [95% CI 1.0-7.2]), and cough or chest tightness after such work (OR 7.4 [95% CI 2.4-23.6]). The strongest predictor of work related nasal symptoms was sensitization to soybean, the latter strongly predicted by the presence of atopy (OR 34.7 [95% CI 6.6-182.5]). CONCLUSIONS: Exposure and sensitization to soybean were associated with the presence of work related symptoms, including flu-like symptoms, cough, chest tightness, and nasal symptoms. The aetiology of these symptoms and more particularly the best intervention strategies require more detailed investigation.

Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase.

BACKGROUND AND PURPOSE: Leukotriene B(4) (LTB(4)), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A(4) hydrolase (LTA(4)H), is a pro-inflammatory mediator implicated in the pathogenesis of inflammatory bowel disease. However, inhibitors of 5-LO have not proved to be consistent in their therapeutic efficacy in colitis. Another approach to inhibiting LTB(4) synthesis is through the use of inhibitors of LTA(4)H, such as the novel, potent and selective compound, JNJ 26993135. EXPERIMENTAL APPROACH: The effect of oral administration of JNJ 26993135 has been evaluated in a rat model of colitis provoked by colonic instillation of trinitrobenzenesulphonic acid (TNBS). The extent and severity of the macroscopic inflammatory response, the colonic levels of myeloperoxidase (MPO) and LTB(4) and of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured. KEY RESULTS: Oral administration of JNJ 26993135 (5, 15 and 30 mg kg(-1), twice a day) dose-dependently reduced both the extent and intensity of the colonic inflammatory damage observed 3 days after TNBS challenge. JNJ 26993135 also dose-dependently reduced the elevated colonic levels of LTB(4), as well as the inflammatory biomarkers, MPO, IL-6 and TNF-alpha. This dosing regimen was supported by the pharmacokinetic profile of JNJ 26993135, along with the demonstration of the inhibition of ex vivo production of LTB(4) in whole blood following oral administration. CONCLUSIONS AND IMPLICATIONS: These results with JNJ 26993135 in the rat TNBS model support the role of LTB(4) in colitis and the potential value of targeting LTA(4)H for the treatment of inflammatory bowel diseases.

Preferential flow in municipal solid waste and implications for long-term leachate quality: valuation of laboratory-scale experiments.

In this paper, we study and quantify pollutant concentrations after long-term leaching at relatively low flow rates and residual concentrations after heavy flushing of a 0.14 m3 municipal solid waste sample. Moreover, water flow and solute transport through preferential flow paths are studied by model interpretation of experimental break-through curves (BTCs), generated by tracer tests. In the study it was found that high concentrations of chloride remain after several pore volumes of water have percolated through the waste sample. The residual concentration was found to be considerably higher than can be predicted by degradation models. For model interpretations of the experimental BTCs, two probabilistic model approaches were applied, the transfer function model and the Lagrangian transport formulation. The experimental BTCs indicated the presence of preferential flow through the waste mass and the model interpretation of the BTCs suggested that between 19 and 41% of the total water content participated in the transport of solute through preferential flow paths. In the study, the occurrence of preferential flow was found to be dependent on the flow rate in the sense that a high flow rate enhances the preferential flow. However, to fully quantify the possible dependence between flow rate and preferential flow, experiments on a broader range of experimental conditions are suggested. The chloride washout curve obtained over the 4-year study period shows that as a consequence of the water flow in favoured flow paths, bypassing other parts of the solid waste body, the leachate quality may reflect only the flow paths and their surroundings. The results in this study thus show that in order to improve long-term prediction of the leachate quality and quantity the magnitude of the preferential water flow through a landfill must be taken into account.

Measured gas emissions from four landfills in south africa and some implications for landfill design and methane recovery in semi-arid climates.

The magnitude of annual global emissions of methane from municipal solid waste landfills without landfill gas control systems implies that these landfills are significant contributors to the atmospheric load of greenhouse gases. There have been a number of field studies undertaken internationally to measure actual fluxes of methane and carbon dioxide from landfills, with a view to corroborating modelled predictions of the contribution of landfills to the global greenhouse gas budget. The vast majority of these studies have been undertaken in more temperate climates and in developed countries. This paper reports a study of landfill gas emissions from four large landfills located in the semi-arid interior of South Africa. A static accumulation chamber was used and measurements were made at each site over a period of two to three days. The results were analysed by three different methods, all of them leading to the same general conclusion that landfill gas emission rates were lower than expected. A common conclusion based on results from all four sites was that capping of landfills in semi-arid climates with low permeability covers would probably significantly retard the already low rate of waste degradation and thus gas generation. While this may be regarded as advantageous in the short term, it cannot be relied upon in perpetuity as clayey landfill covers will inevitably desiccate and crack in a semiarid environment. In addition, reasonable after-care periods for such landfills are likely to extend well beyond the currently stipulated 30-year period, and efforts to encourage energy recovery from landfills may be hampered because gas generation rates decrease as the waste dries out under conditions of minimal recharge from precipitation. A landfill cover that allows small amounts of percolation of rainfall into the waste may therefore in fact be beneficial in semiarid climates, although care would need to be taken to carefully regulate this infiltration.

HLA class I and class II antigens associated with multiple myeloma in southern Africa.

While the exact aetiology of myeloma is unknown, genetic factors feature among the potential risk factors. The HLA phenotypes in African blacks with myeloma (the commonest haematopoietic malignancy in this group) have not been characterized. The purpose of this study was to determine the HLA class I and class II phenotypes of patients with multiple myeloma and to compare the findings to an ethnically matched control group of 100 individuals. Analysis of the HLA class I and class II phenotypes in 62 myeloma patients revealed: (i) a corresponding statistically significant association with HLA B18 [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.013-39.727; P < 0.005]; (ii) no statistically significant association with HLA B13, Cw2, Cw6 or the DR and DQ antigens; and (iii) a statistically significant negative (protective) association with HLA Cw7 (OR 0.4; 95% CI 0.21-0.87; P < 0.005). This study suggests that although genetic factors may play a role in the multifactorial aetiology of multiple myeloma, with the exception of HLA B18, there is no specific association between HLA types and multiple myeloma in South African blacks.

Leprosy in Mpumalanga Province, South Africa--eliminated or hidden?

In South Africa, leprosy has been a notifiable condition since 1921. Although the WHO elimination target of less than one case per 10,000 population has been achieved at country level, the distribution of leprosy in the country is distinctly heterogeneous, with a prominent 'leprosy belt' of greater prevalence stretching across Mpumalanga Province into northern Kwa-Zulu Natal. The highest prevalence in this 'belt' has historically been in Ermelo District. Recent trends of few newly detected leprosy patients in this district raised concerns that health system changes may have resulted in failure to detect leprosy cases. Thus a large-scale community awareness campaign was conducted followed by an intensively advertised screening programme of 3-month duration at schools and central gathering points in villages and farms from 1 June to 31 August 2000. One thousand one hundred and seventy-seven people presented for clinical screening at designated points, while 790 scholars were screened at schools and an additional 1433 people were screened at their homes by the field team. Forty-four people with skin or nervous system lesions compatible with leprosy were referred for specialized assessment and biopsy where indicated. Four new leprosy patients were diagnosed, including an elderly lady with pronounced disability. Two of these patients had prior contact with the health service due to dermatological manifestations of leprosy without diagnosis being made. All patients provided a history of close prolonged contact with known leprosy patients. Ongoing intense tracing and follow-up of close contacts of proven leprosy cases may be a more efficient method of detecting leprosy cases in areas with relatively stable populations that have accomplished 'leprosy elimination', than resource intensive community surveys.

Characterization and regulation of the major histocompatibility complex-encoded proteins Hsp70-Hom and Hsp70-1/2.

Vertebrate cells contain at least 12 different genes for Hsp70 proteins, 3 of which are encoded in the major histocompatibility complex (MHC) class III region. In the human MHC, these are named Hsp70-1, -2, and -Hom. To characterize these proteins, we have determined their substrate binding specificity, their cellular and tissue distribution, and the regulation of their expression. We show for the first time (1) peptide binding specificity of Hsp70-Hom; (2) endogenous expression of Hsp70-Hom in human cell lines; (3) cytoplasmic location of Hsp70-Hom protein under basal conditions and concentration in the nucleus after heat shock; (4) unique RNA expression profiles in human tissues for each of the MHC-encoded Hsp70s, significantly different from that for the constitutive Hsc70; (5) a relative increase in levels of Hsp70-Hom protein, compared with other Hsp70s, in response to interferon gamma; and (6) a specific increase on lipopolysaccharide (LPS) treatment of in vivo messenger RNA levels for the MHC-encoded Hsp70s and the DnaJ homologue, hdj2, relative to other chaperones. The unique tissue distributions and specific up-regulation by LPS of the MHC-encoded Hsp70s suggest some specialization of functions for these members of the Hsp70 family, possibly in the inflammatory response.

Impaired immunoproteasome assembly and immune responses in PA28-/- mice.

In vitro PA28 binds and activates proteasomes. It is shown here that mice with a disrupted PA28b gene lack PA28a and PA28b polypeptides, demonstrating that PA28 functions as a hetero-oligomer in vivo. Processing of antigenic epitopes derived from exogenous or endogenous antigens is altered in PA28-/- mice. Cytotoxic T lymphocyte responses are impaired, and assembly of immunoproteasomes is greatly inhibited in mice lacking PA28. These results show that PA28 is necessary for immunoproteasome assembly and is required for efficient antigen processing, thus demonstrating the importance of PA28-mediated proteasome function in immune responses.

HSP70 binding sites in the tumor suppressor protein p53.

Mutations within conserved regions of the tumor suppressor protein, p53, result in oncogenic forms of the protein with altered tertiary structures. In most cases, the mutant p53 proteins are selectively recognized and bound by members of the HSP70 family of molecular chaperones, but the binding site(s) in p53 for these chaperones have not been clearly defined. We have screened a library of overlapping biotinylated peptides, spanning the entire human p53 sequence, for binding to the HSP70 proteins, Hsc70 and DnaK. We show that most of the high affinity binding sites for these proteins map to secondary structure elements, particularly beta-strands, in the hydrophobic core of the central DNA binding domain, where the majority of oncogenic p53 mutations are found. Although peptides corresponding to the C-terminal region of p53 also contain potential binding sites, p53 proteins with C-terminal deletions are capable of binding to Hsc70, indicating that this region is not required for complex formation. We propose that mutations in the p53 protein alter the tertiary structure of the central DNA binding domain, thus exposing high affinity HSP70 binding sites that are cryptic in the wild-type molecule.