Drug repurposing to treat asthma and allergic disorders: Progress and prospects.

Allergy and atopic asthma have continued to become more prevalent in modern society despite the advent of new treatments, representing a major global health problem. Common medications such as antihistamines and steroids can have undesirable long-term side-effects and lack efficacy in some resistant patients. Biologic medications are increasingly given to treatment-resistant patients, but they can represent high costs, complex dosing and management, and are not widely available around the world. The field needs new, cheap, and convenient treatment options in order to bring better symptom relief to patients. Beyond continued research and development of new drugs, a focus on drug repurposing could alleviate this problem by repositioning effective and safe small-molecule drugs from other fields of medicine and applying them toward the treatment for asthma and allergy. Herein, preclinical models, case reports, and clinical trials of drug repurposing efficacy in allergic disease are reviewed. Novel drugs are also proposed for repositioning based on their mechanism of action to treat asthma and allergy. Overall, drug repurposing could become increasingly important as a way of advancing allergy and atopic asthma therapy, filling a need in treatment of patients today.

A comparative study of vascular injection fluids in fresh-frozen and embalmed human cadaver forearms.

Over the years, various vascular injection products have been developed to facilitate anatomical dissections. This study aimed to compare the most commonly used vascular injection products in fresh-frozen and formalin-embalmed cadaver specimens. An overview of the properties, advantages and limitations of each substance was given, and a comparison of vascular infusion procedures in both preservation methods was made. A literature search was performed in order to identify the most commonly used vascular injection products. Acrylic paint, latex, gelatin, silicone, Araldite F and Batson's No. 17 were selected for the study. One fresh-frozen and one embalmed cadaver forearm were infused with each injection product according to a uniform protocol. The curing time, skin- and subcutaneous tissue penetration, degree of filling of the arterial tree, extravasations, consistency of the injected vessels during dissection, and the costs of each injection fluid were noted. There was a large variation between the injection fluids in processing- and curing time, colour intensity, flexibility, fragility, elasticity, strength, toxicity and costs. All fluids were suitable for infusion. The penetration of injection fluid into the skin and subcutaneous tissue was significantly better in fresh-frozen specimens (P = 0.002 and P = 0.009, respectively), with significantly smaller branches casted (P = 0.004). Vascular infusion of fresh-frozen cadaver specimens results in a significantly better filled coloured arterial tree, enabling more detail to be achieved and smaller branches casted. The biomechanical properties of fresh-frozen soft tissues are less affected compared with formalin fixation. All the injection fluids studied are suitable for vascular infusion, but their different properties ensure that certain products and procedures are more suitable for specific study purposes.

Computation of blood flow through collateral circulation of the superficial femoral artery.

OBJECTIVE: Obliteration of collaterals during (endo)vascular treatment of peripheral arterial occlusive disease is considered detrimental. We use a model to calculate maximum collateral bed flow of the superficial femoral artery in order to provide insight in their hemodynamic relevance. METHOD: A computational model was developed using digital subtraction angiographies in combination with Poiseuille's equation and Ohm's law. Lesions were divided into short and long (<15 cm and ≥15 cm, respectively) and into stenosis and occlusions. Data are presented in relation to the calculated maximum healthy superficial femoral artery flow. RESULTS: Stenotic lesions are longer than occlusive lesions (P < 0.05) and occlusions had more and larger collaterals (P < 0.05). In all four study groups the collateral flow significantly increased the total flow (P < 0.05). The maximum collateral system flow in the stenosis and occlusion groups was 5.1% and 20.8% of healthy superficial femoral artery flow, respectively (P < 0.05), and there were no significant differences between short and long lesions (11.2% and 6.7% of healthy superficial femoral artery flow, respectively). CONCLUSION: The maximum collateral system flow of the superficial femoral artery is only a fraction, with a maximum of one fifth, of healthy superficial femoral artery flow. Effects of collateral vessel occlusion during (endo)vascular treatment may therefore be without detrimental consequences.

Evidence for a polygenic contribution to androgenetic alopecia.

BACKGROUND: Male pattern baldness (androgenetic alopecia, AGA) is a highly heritable trait and the most common form of hair loss in humans. Eight genome-wide significant risk loci for AGA have been identified. OBJECTIVES: To determine whether a polygenic component contributes to the genetic risk for AGA. METHODS: This study used a German case-control sample for AGA, which comprised 581 severely affected patients and 617 controls, to determine the contribution of polygenic variance to AGA risk. The sample was divided evenly into discovery and test samples. An additive polygenic risk score was calculated from risk alleles with increasingly liberal P-values in the discovery dataset, which was then used to test for the enrichment of AGA risk score alleles in the independent test samples. RESULTS: The polygenic score analysis provided significant evidence for a polygenic contribution to AGA where the amount of variance explained was 1·4-4·5%. CONCLUSION: This study provides evidence for the specific contribution of a polygenic component to the overall heritable risk for AGA. To some degree, the polygenic architecture of AGA might reflect the complexity of the biological pathways involved. Further analyses and strategies that complement conventional genome-wide association studies are needed to identify these factors. These may include pathway-based analyses, the analysis of functional candidate genes and tests for epistatic effects with known loci.

Investigation of selected cytokine genes suggests that IL2RA and the TNF/LTA locus are risk factors for severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is the second most common cause of hair loss in humans, and has a genetically complex inheritance. The hypothesis that AA is autoimmune in nature is supported by previous studies. These report an association with specific HLA alleles, as well as genetic variants of other genes implicated in autoimmunity, such as various cytokine genes. However, these cannot yet be considered proven susceptibility loci, as many of these association findings were derived from small patient samples. OBJECTIVES: To investigate the association between AA and selected cytokine genes using a sample of 768 patients with AA and 658 controls of Central European origin. METHODS: Eleven single-nucleotide polymorphisms (SNPs) from cytokine genes implicated in previous AA studies were genotyped. These genes were IL1B, IL1A, IL1RN, MIF, IFNG and the TNF/LTA gene region. We also genotyped 15 SNPs selected from cytokine genes that have shown significant association with other autoimmune diseases. These genes were IL10, IL36RN, IL12B, IL6, IL2, IL23, IL2RA and IL4R. RESULTS: Significant association was found for two variants within both IL2RA and TNF/LTA. In the overall sample, the most significant results were obtained for the IL2RA variant rs706778 (P = 0·00038) and the TNF/LTA locus variant rs1800629 (P = 0·0017). In subgroup analyses, according to severity, age at onset and family history these effects were stronger in the severely affected patients, with the lowest P-values being obtained for rs706778 (P = 3·8 × 10(-6) ). CONCLUSIONS: Our results point to the involvement of IL2RA and the TNF/LTA region in the aetiology of AA, in particular severe AA, and provide further support for the hypothesis that AA is autoimmune in nature.

Investigation of the male pattern baldness major genetic susceptibility loci AR/EDA2R and 20p11 in female pattern hair loss.

BACKGROUND: The aetiology of female pattern hair loss (FPHL) is largely unknown. However, it is hypothesized that FPHL and male pattern baldness (AGA) share common susceptibility alleles. The two major susceptibility loci for AGA are the androgen receptor (AR)/ectodysplasin A2 receptor (EDA2R) locus on the X-chromosome, and a locus on chromosome 20p11, for which no candidate gene has yet been identified. OBJECTIVES: To examine the role of the AR/EDA2R and 20p11 loci in the development of FPHL using 145 U.K. and 85 German patients with FPHL, 179 U.K. supercontrols and 150 German blood donors. METHODS: Patients and controls were genotyped for 25 single nucleotide polymorphisms (SNPs) at the AR/EDA2R locus and five SNPs at the 20p11 locus. RESULTS: Analysis of the AR/EDA2R locus revealed no significant association in the German sample. However, a nominally significant association for a single SNP (rs1397631) was found in the U.K. sample. Subgroup analysis of the U.K. patients revealed significant association for seven markers in patients with an early onset (P = 0·047 after adjustment for the testing of multiple SNPs by Monte Carlo simulation). No significant association was obtained for the five 20p11 variants, either in the overall samples or in the analysis of subgroups. CONCLUSIONS: The observed association suggests that the AR/EDA2R locus confers susceptibility to early-onset FHPL. Our results do not implicate the 20p11 locus in the aetiology of FPHL.

Susceptibility variants on chromosome 7p21.1 suggest HDAC9 as a new candidate gene for male-pattern baldness.

BACKGROUND: Male-pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss among humans. Research has shown that it is caused by genetic factors. Numerous studies have unequivocally identified two major genetic risk loci for AGA: the X-chromosomal AR/EDA2R locus, and the PAX1/FOXA2 locus on chromosome 20. OBJECTIVES: To identify further candidate genes for AGA, and thus gain further insights into this phenotype. METHODS: A German sample of 581 severely affected cases and 617 controls was used to perform a genome-wide association study. The identified associated locus was further analysed by fine-mapping, and then independently replicated in an Australian sample. Expression and pathway analyses were performed to characterize the susceptibility gene identified. RESULTS: The most significant association signal was obtained for rs756853 (P = 1·64 × 10(-7) ), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine-mapping and a family-based analysis revealed that rs756853 and the 6-kb distal rs2249817 were the most highly associated single nucleotide polymorphisms. The association finding was replicated in an independent Australian sample, when the analysis was restricted to severely affected cases and unaffected controls (P = 0·026). Analysis of rs2249817 in a combined sample of severely affected German and Australian cases and unaffected controls revealed a strong association signal (P = 9·09 × 10(-8) ). Tissue expression studies demonstrated HDAC9 expression in various tissues, including tissues of relevance to AGA. No strong genotypic effects were observed in genotype-specific expression or splice studies. Pathway analyses supported the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. CONCLUSIONS: The present study suggests that HDAC9 is the third AGA susceptibility gene.

Colloid centrifugation removes seminal plasma and cholesterol from boar spermatozoa.

The objective of the present study was to investigate the effect of Single-Layer Centrifugation (SLC) on boar spermatozoa, namely the effect of removal of seminal plasma proteins and cholesterol from the surface of spermatozoa. The presence of porcine seminal plasma proteins I and II (PSP-I/PSP-II) before and after SLC was studied using immunofluorescence, whereas the removal of cholesterol was shown qualitatively by thin-layer chromatography (TLC). Finally, the integrity of the sperm plasma membrane was observed by electron microscopy. It was shown that the seminal plasma proteins PSP-I and -II were removed from spermatozoa during SLC but could be restored by adding seminal plasma to the SLC-selected sperm samples. Some cholesterol was also lost from the spermatozoa during SLC but the plasma membrane itself appeared to be morphologically intact. Further studies are underway to examine the relevance of these findings to boar sperm cryopreservation and sperm fertility.

[Hyperhidrosis of childhood and adolescence: clinical aspects and therapeutic options]. / Hyperhidrose im Kindes- und Jugendalter : Klinik und aktuelle Therapieoptionen.

Hyperhidrosis is characterized by localized or general excessive sweating which is severe enough to be perceived as pathological. Since excessive sweating often starts in childhood and adolescence, usually in children between 6 and 16 years of age, hyperhidrosis is an important disorder for children and juveniles. This condition causes considerable disruption of both social life and educational career, leading to severe deterioration in the patient's quality of life. In addition, therapy is often challenging since many treatment modalities are not approved for children. Nonetheless, there are still effective therapeutic options for children with hyperhidrosis.

[Galli-Galli disease. Clinical and histopathological investigation using a case series of 18 patients]. / Morbus Galli-Galli. Klinische und histopathologische Untersuchung anhand einer Fallserie von 18 Patienten.

Galli-Galli disease, a rare genodermatosis belonging to the spectrum of reticulate pigment dermatoses, is classified as an acantholytic variant of Dowling-Degos disease on the basis of its characteristic clinical and histological findings. In the context of this case series, Galli-Galli disease is characterized in detail based on the clinical and histopathological evaluation of 18 patients. The disease pattern is discussed in view of the current literature. In addition, a classification into two clinical subtypes is made and a genotype/phenotype correlation with mutations in the keratin 5 (KRT5) gene is established.

Prenatal phthalate exposure and reduced masculine play in boys.

Foetal exposure to antiandrogens alters androgen-sensitive development in male rodents, resulting in less male-typical behaviour. Foetal phthalate exposure is also associated with male reproductive development in humans, but neurodevelopmental outcomes have seldom been examined in relation to phthalate exposure. To assess play behaviour in relation to phthalate metabolite concentration in prenatal urine samples, we recontacted participants in the Study for Future Families whose phthalate metabolites had been measured in mid-pregnancy urine samples. Mothers completed a questionnaire including the Pre-School Activities Inventory, a validated instrument used to assess sexually dimorphic play behaviour. We examined play behaviour scores (masculine, feminine and composite) in relationship to (log(10)) phthalate metabolite concentrations in mother's urine separately for boys (N = 74) and girls (N = 71). Covariates (child's age, mother's age and education and parental attitude towards atypical play choices) were controlled using multivariate regression models. Concentrations of dibutyl phthalate metabolites, mono-n-butyl phthalate (MnBP) and mono-isobutyl phthalate (MiBP) and their sum, were associated with a decreased (less masculine) composite score in boys (regression coefficients -4.53,-3.61 and -4.20, p = 0.01, 0.07 and 0.04 for MnBP, MiBP and their sum respectively). Concentrations of two urinary metabolites of di(2-ethylhexyl) phthalate (DEHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and the sum of these DEHP metabolites plus mono(2-ethylhexyl) phthalate were associated with a decreased masculine score (regression coefficients -3.29,-2.94 and -3.18, p = 0.02, 0.04 and 0.04) for MEHHP, MEOHP and the sum respectively. No strong associations were seen between behaviour and urinary concentrations of any other phthalate metabolites in boys, or between girls' scores and any metabolites. These data, although based on a small sample, suggest that prenatal exposure to antiandrogenic phthalates may be associated with less male-typical play behaviour in boys. Our findings suggest that these ubiquitous environmental chemicals have the potential to alter androgen-responsive brain development in humans.

Systematic mutation screening of KRT5 supports the hypothesis that Galli-Galli disease is a variant of Dowling-Degos disease.

BACKGROUND: Galli-Galli disease (GGD) is a rare genodermatosis. Its clinical presentation is identical to that of Dowling-Degos disease (DDD), but the presence of the histopathological feature of acantholysis in GGD is thought to distinguish the two disorders. Mutations in the keratin 5 gene (KRT5) have been identified in the majority of patients with DDD and in a small number of patients with GGD. OBJECTIVES: To provide further support for the hypothesis that GGD is merely a variant of DDD, and to examine whether acantholysis is genuinely rare in DDD or rather a common but under-reported histological feature of DDD. METHODS: We conducted the first systematic mutational investigation of patients with GGD and re-examined the histopathology of patients previously assigned a diagnosis of DDD. For the mutational investigation, KRT5 was sequenced in seven unrelated patients with clinically and histopathologically confirmed GGD. In addition, the histopathological findings of six patients with DDD were re-evaluated. RESULTS: The mutation c.418dupA was found in five patients with GGD. The typical histopathological features of GGD were identified in six patients who had previously been assigned a diagnosis of DDD. CONCLUSIONS: We found further evidence to suggest that GGD is indeed a variant of DDD and not a distinct disease entity. Two facts in particular support this conclusion: the same KRT5 mutation was found in patients with GGD and in patients with DDD, and acantholysis seems to be present in a large number of patients who had previously been assigned a diagnosis of DDD.

The TRAF1/C5 locus confers risk for familial and severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). OBJECTIVES: To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1,195 patients with AA and 1280 controls. METHODS: We genotyped the two most significant single nucleotide polymorphisms (SNPs) (rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. RESULTS: While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0.004, P(corr) = 0.026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. CONCLUSIONS: Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.

Performance of ePTFE-covered endograft in patients with occlusive disease of the superficial femoral artery: a three-year clinical follow-up study.

AIM: Feasibility of ePTFE-covered endoprosthesis for treatment of atherosclerotic stenosis or occlusions of the SFA. This was a prospective follow-up study on intention-to-treat basis. ePTFE-covered endoprosthesis were used. METHODS: From November 2001 to December 2006, 96 patients were treated for invalidating claudication, critical ischemia or gangrene. ABI and ischemia severity score according to Rutherford were defined. Morphology of the lesions was classified according to the Trans-Atlantic InterSociety Consensus. Clinical outcome was investigated by ABI, Duplex-ultrasound, and luminal diameter measurements inside grafts. Follow-up visits were conducted at six weeks and six months, and yearly thereafter. RESULTS: Significant clinical improvement was achieved in all patients. ABI increased to normal, and did not fall during three-year follow-up. Kaplan-Meier estimates for primary patency were 76% (N.=77), 70% (N.=56) and 67.7% (N.=40), and for secondary patency 86.9% (N.=85), 82.2 (N.=63) and 79.8% (N.=45) at 1, 2, and 3 years. Intraluminal graft diameters did not decrease significantly during follow-up. Graft occlusion was seen in 21/96 endografts; 20 patients underwent additional PTAs, only three patients had intragraft stenosis. Occluded grafts did not show reduction of luminal diameters on follow-up examinations before occlusion. CONCLUSION: ePTFE-covered endografts have excellent properties for treatment of SFA stenosis or occlusions. There was no intimal hyperplasia inside endografts, and graft occlusion occurred due to progression of atherosclerotic disease outside the graft.

Treatment of dilated venous bypass grafts with an expanded polytetrafluoroethylene-covered nitinol endoprosthesis.

An above-knee femoropopliteal bypass graft constructed of great saphenous vein became dilated in 2 patients 12 and 25 years after surgery. Both patients had several concomitant disorders. The dilations were treated by insertion of an expanded polytetrafluoroethylene-covered nitinol endoprosthesis. There were no major procedural complications. One minor endoleak that developed immediately after endograft placement resolved within 6 weeks. The leg swelling subsided, and the endoprostheses have remained patent for 18 and 24 months, respectively. To our knowledge, these were the first cases in which an endoprosthesis was used to treat dilation of a venous bypass graft.

Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism.

Streptozotocin (STZ) given intravenously destroys pancreatic beta cells and is widely used in animal models to mimic type 1 diabetes. The effects of STZ on the clinical state of health and metabolism were studied in six high health certified domestic pigs weighing 19+/-1.3 kg at the start of the experiment. A single STZ dose of 150 mg/kg of body weight successfully induced hyperglycaemia and alterations in amino acid metabolism. Within 9 h after STZ administration, the blood glucose values fell from 5.4-7.5 mmol/L to 0.8-2.2 mmol/L. Hypoglycaemia was treated with 0.5 g glucose/kg body weight. In all pigs, hyperglycaemia was produced 24 h after STZ treatment, and 3 days after STZ injection, the glucose concentration was >25 mmol/L. Mean C-peptide concentration was 0.25+/-0.16 microg/L since 2 days after STZ injection until the end of the study. The serum concentration of the branched-chain amino acids (BCAA) increased four-fold, and alanine and taurine decreased by approximately 70% and 50%, respectively, after STZ treatment. All but one pig remained brisk and the physical examination was normal except for a retarded growth rate and a reduction of the skeletal muscle. At the end of the study, the pigs were moderately emaciated. Postmortem examination confirmed muscle wasting and a reduction of abdominal and subcutaneous fat. In conclusion, STZ-induced diabetes in pigs fulfils the requirements for a good animal model for type 1 diabetes with respect to clinical signs of the disease and alterations in the carbohydrate and amino acid metabolism.

[Tuberculosis cutis colliquativa. Even today an important differential diagnosis]. / Tuberculosis cutis colliquativa. Auch heute eine wichtige Differenzialdiagnose.

An 82-year-old woman presented with perforating abscesses in the cervical and axillary region over 7 months. Histopathological and extensive microbiological examinations lead to the diagnosis of tuberculosis cutis colliquativa, a form of postprimary cutaneous tuberculosis. Tuberculosis cutis colliquativa can be caused by either contiguous spread from an underlying structure, direct inoculation or hematogenous dissemination. Morphologically it is characterized by a subcutaneous node forming an abscess with secondary perforation of overlying skin. The parotid, submandibular, and supraclavicular regions are the sites most likely to be affected. Today it still remains an important differential diagnosis for an abscess with fistulas. Correlation with histopathologic findings and microbiological examinations including polymerase chain reaction and mycobacterial culture being the most reliable method is required. Standard therapy regimens consist of 2 months of quadruple therapy followed by another 4 months of a continuation phase using a two-drug regimen.

Placental expression of microRNAs in infants born small for gestational age.

INTRODUCTION: The molecular mechanisms behind poor foetal growth are not fully known. The aim of this study was to explore global microRNA expression in placentas of infants born small for gestational age (SGA) compared to infants with a normal birth weight (NBW). METHODS: Placental biopsies from term infants were identified in a biobank and divided into four groups: infants born SGA with (n = 13) or without (n = 9) exposure to low maternal gestational weight gain (GWG) and infants born with NBWs with (n = 20) or without (n = 26) exposure to low GWG. All women and infants were healthy, and no woman smoked during pregnancy. Only vaginal deliveries were included. Next-generation sequencing was performed with single read sequencing of >9 million reads per sample. Differential microRNA expression was analysed using ANOVA for unequal variances (Welch) with multiple testing corrections through the Benjamini-Hochberg method. A fold change >2 and a corrected p value < 0.05 were considered significant. Adjustments for possible confounding factors were made using a linear regression model. RESULTS: A total of 1870 known, mature human microRNAs were detected in the sample. MiR-3679-5p and miR-193b-3p were significantly upregulated, and miR-379-3p, miR-335-3p, miR-4532, miR-519e-3p, miR-3065-5p, and miR-105-5p were significantly downregulated after adjustment for potential confounding factors in SGA infants with normal GWG compared to infants with NBWs and normal GWG. DISCUSSION: Infants born unexplained SGA show differential microRNA expression in their placenta. Important pathways for the differentially expressed microRNAs include inflammation and the insulin-IGF system.

Diagnosis and management of pulmonary infection due to Rhodococcus equi.

BACKGROUND: Rhodococcus equi is a recognized cause of disease in humans, especially in individuals who are immunocompromised. Because diphtheroids are regarded as part of normal respiratory flora, the importance of R. equi as a pulmonary pathogen may not be fully appreciated and its prevalence may be underestimated. Most treatment recommendations for R. equi infection were established before antiretroviral drugs became available for human immunodeficiency virus/AIDS therapy, and therapeutic strategies may need to be updated. OBJECTIVES: To review the role of R. equi as a cause of pulmonary infection; to highlight its importance for clinicians and microbiologists; and to challenge current approaches to treatment, whether in immunodeficient or immunocompetent individuals. SOURCES: A PubMed search using combinations of the following terms: 'Rhodococcus (automatically including Corynebacterium) equi' AND 'pneumonia' OR 'pulmonary' infection, then cross-checking references in the resulting cases, case series and reviews. CONTENT: We provide a review that details the challenges in the diagnosis, microbiology and pathogenesis of pulmonary infection caused by R. equi and the options for treatment. IMPLICATIONS: Ten to 14 days of treatment may be effective for pneumonia due to R. equi. Our review suggests that longer courses of therapy are needed for cavitary lesions and lung masses. However, recommendations for excessively prolonged treatment of all pulmonary infections arose during a time when many cases occurred in individuals with AIDS and before effective antiretroviral therapy was available. We suggest that the rationale for prolonged therapy with multiple antibiotics needs to be re-evaluated.