Background Strain typing is a tool for determining diversity and epidemiology of infections. Methods T. pallidum DNA was isolated from 158 syphilis patients from the US, China, Ireland, and Madagascar and from 15 T. pallidum isolates. Six typing targets were assessed: 1) number of 60 bp repeats in acidic repeat protein gene; 2) restriction fragment length polymorphism (RFLP) analysis of T. pallidum repeat (tpr) subfamily II genes; 3) RFLP analysis of tprC gene; 4) determination of tprD allele in tprD gene locus; 5) presence of 51 bp insertion between tp0126/tp0127; 6) sequence analysis of 84 bp region of tp0548. The combination of #1 and #2 comprises the CDC T. pallidum subtyping method. Results Adding sequence analysis of tp0548 to the CDC method yielded the most discriminating typing system. Twenty-four strain types were identified and designated as CDC subtype/tp0548 sequence. Type 14d/f was seen in 5 of 6 locations. In Seattle, strain types changed from 1999– 2008 (p<0.001). Twenty-two (50%) of 44 patients infected with type 14d/f had neurosyphilis compared to 9 (23%) of 39 infected with the other types combined (p=0.01). Conclusion We describe an enhanced T. pallidum strain typing system that shows biological and clinical relevance.
The new england journal of medicine n engl j med 351;2 www.nejm.or decades, syphilis infection has been treated with penicillin , and Treponema pallidum has not developed resistance to penicillin. In many countries, the recommended treatment for early syphilis is a single dose of penicillin G benzathine, which maintains bactericidal levels for weeks, killing the slowly metabolizing treponemes. Azithromycin, which has a long tissue half-life and can be administered orally, was found to be effective in the treatment of syphilis in a rabbit model 1 and in small studies in humans. 2-6 Because of its convenience and efficacy, azithromycin is increasingly being used for the treatment of syphilis by clinicians and in disease-control activities in Canada and the United States, although it is not currently recommended by the Centers for Disease Control and Prevention. 7 We discuss one patient with clinical failure of azithromycin therapy for syphilis, among several cases that have been recognized. 8 We identified a mutation in the 23S ribosomal RNA (rRNA) genes in a specimen of T. pallidum obtained from this patient, and we confirmed functional azithromycin resistance in vivo in a strain of T. pallidum that contain this mutation. Testing of T. pallidum samples obtained at four geographically diverse sites revealed a high frequency of this mutation in clinical specimens. samples Swab samples were collected from primary or moist secondary syphilis lesions in patients at
Aim: To examine the potential of p16INK4A as a biomarker for dysplastic squamous and glandular cells of the cervix in tissue sections and ThinPrep™ smears. Methods: Immunocytochemical analysis of p16INK4A expression was performed on 22 normal cervical tissue samples, five cervical glandular intraepithelial neoplasia (cGIN), 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, and 10 invasive cancer cases (eight squamous and two adenocarcinomas). All samples were formalin fixed and paraffin wax embedded, and immunohistochemical analysis was carried out using a mouse monoclonal anti-p16 INK4A antibody after antigen unmasking. The staining intensity was assessed using a 0 to 3 scoring system. In addition, the expression status of p16 INK4A was examined in 12 normal ThinPrep smears, one smear exhibiting cGIN, and a total of 20 smears exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) detection was carried out using a modified SYBR green assay system. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing. Results: p16INK4A immunoreactivity was absent in all normal cervical tissues examined. Dysplastic squamous and glandular cells were positive for p16INK4A expression in all cases included in this study, except for one CIN3 case. p16INK4A expression was mainly nuclear in CIN1 cases, and both nuclear and cytoplasmic in CIN2, CIN3, cGIN, and invasive cases. All cases positive for HPV expressed the p16 INK4A protein, although not all cases found positive for p16 INK4A were HPV positive. In general, the p16 INK4A staining intensity was lower in cases negative for HPV or those containing a low risk HPV type. Conclusion: This pattern of overexpression demonstrates the potential use of p16INK4A as a diagnostic marker for cervical squamous and also glandular neoplastic lesions. In addition, the technique can be used to identify individual dyskaryotic cells in ThinPrep smears. Thus, p16 INK4A is a useful marker of cervical dyskaryosis. C ervical cancer is one of the most common forms of cancer in women worldwide. In developing countries, cancer of the uterine cervix is ranked second, with a relative frequency of 15% of all cancers in women, whereas in developed countries cervical cancer is ranked fifth, with a relative frequency of 4.4%.1 The Papanicolaou (Pap) test, as described by G Papanicolaou, is a cytological staining technique, which allows the identification of asymptomatic women who have preneoplastic lesions or early cancer of the uterine cervix. Although the introduction of mass screening programmes in developed countries has been effective in reducing cervical cancer mortality and morbidity rates, the success of the Pap smear test is limited with respect to sensitivity and specificity. False negative rates for cervical premalignant lesions and cervical cancer lie between 15% and 50% and false positive rates of approximately 30% have been reported.2 This failure may reflect the subjectivity of cytological diagnosis. In addition...
There are 3 groups of drugs available for the treatment of patients with HIV disease. These are the nucleoside reverse transcriptase inhibitors ('nucleoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and abacavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir). The preferred initial regimen should reduce and maintain plasma HIV RNA below the level of detection. Presently, the regimen of choice consists of 2 nucleoside analogues plus a protease inhibitor with high in vivo efficacy. An alternative combination consists of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor. Drug interactions are one of the major problems associated with these multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely to be of clinical relevance as drug effect is mainly dependent on the rate and extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy of some nucleoside analogues, e.g. stavudine, may be compromised by prior treatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of other antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. Combination protease inhibitor therapy can result in drug interactions mediated by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavir the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug metabolising enzymes and may reduce plasma concentrations of protease inhibitors. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metabolising enzymes and increases the plasma concentration of coadministered protease inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentration-time curve of delavirdine, there are no reports of clinically significant interactions of other antiretrovirals with the non-nucleoside reverse transcriptase inhibitors. Triple therapy is the current standard of care for patients with HIV disease. However, studies of quadruple therapy are already under way. Drug interactions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.
Aims St John's Wort (SJW) is widely used in the treatment of depression but concerns have been raised about its potential to interact with other drugs. Co-administration with SJW has resulted in signi®cant reductions in trough plasma concentrations of indinavir and cyclosporin [1,2]. Induction of cytochrome P450 3A4 (CYP3A4) has been implicated as the most likely interaction mechanism. However, the magnitude of the interaction seen in clinical practice is greater than that predicted by in vitro studies suggesting additional interaction mechanisms may exist. As indinavir and cyclosporin are substrates for both CYP3A4 and the multi drug transporter P-glycoprotein we hypothesized that modulation of P-glycoprotein expression and function by SJW may contribute to the development of potentially harmful drug±drug interactions. Methods Healthy volunteers were randomized to either SJW (0.15%) 600 mg three times daily for 16 days (n=15) or placebo (n=7). Blood samples were obtained for P-glycoprotein expression and function at baseline, 16 and 32 days post treatment. Peripheral blood lymphocytes (PBMCs) were isolated by Ficoll density gradient centrifugation, ®xed and permeabilized. Cells were stained with a P-glycoprotein speci®c antibody, quanti®ed by¯ow cytometry and median¯uorescence intensity (MFI) values obtained. Vimentin and IE (nonsense antibody) were used as controls. The presence of the MDR 1 gene product was con®rmed by RT-PCR. P-glycoprotein mediated drug ef¯ux was determined as a function of rhodamine ef¯ux in the absence and presence of ritonavir. Data are expressed as meants.d. and were subjected to nonparametric analysis. Results P-glycoprotein expression increased 4.2 fold from baseline in subjects treated with SJW (7.0t1.9 vs 29.5t14.3 (MFI); P<0.05). There was no effect with placebo (5.1t1.3 vs 6.0t1.9 MFI). SJW increased P-glycoprotein mediated rhodamine ef¯ux (reduced ratio) compared with baseline (0.12t0.04 vs 0.24t0.18 P<0.05).There was no change with placebo. Ritonavir (5 mM) inhibited P-glycoprotein mediated ef¯ux in both groups producing greater intracellular accumulation of rhodamine. However, this effect was attenuated following treatment with SJW (23.9t15.3% vs 75.4t16.4% P<0.05). Conclusions SJW increased expression and enhanced the drug ef¯ux function of the multi drug transporter P-glycoprotein in PBMCs of healthy volunteers. This may represent a second mechanism for the drug±herb interactions seen in clinical practice and account for the discrepancies between in vitro and in vivo data. Since P-glycoprotein and CYP3A4 have distinct though overlapping substrates, patients receiving drugs, which are P-glycoprotein substrates should be warned against self-medication with SJW as clinically signi®cant drug interactions may occur.
For some patients, administration of SQV 600 mg three times daily results in very low SQV plasma levels and possibly little antiviral effect. Combination of SQV with RIT results in a significant drug interaction mediated by enzyme inhibition which exposes patients to very high SQV concentrations and potential toxicity. If combination therapy with SQV plus RIT is considered then the dose of SQV should be greatly reduced.
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