The aims of this study are to assess the extent of ovarian movement on consecutive MRI examinations in patients with gynaecological malignancies and to define potential safety volumes around the ovaries that may avoid ovarian ablation during pelvic irradiation.
Patients with cervical, vaginal and endometrial cancer who underwent MRI examinations of the pelvis before and during radiotherapy were included in the study. The position of the ovaries was retrospectively determined on two consecutive axial and sagittal T2 weighted MRI examinations of the pelvis. Ovarian movement was determined in craniocaudal, anteroposterior and mediolateral directions. Safety volumes were calculated by computing elliptical volumes based on the derived 95% and 99% reference intervals.
30 patients with a gynaecological malignancy were included. Both ovaries could be identified on the MRI examinations in all cases. The safety volumes around the ovaries encompassing 95% and 99% of ovarian movement were 11 and 25 cm3 (95%), and 24 and 54 cm3 (99%), for the left and right ovary, respectively.
Adding a safety volume around the ovaries may reduce the high radiation dose to the ovaries. This could potentially avoid ovarian ablation, reducing significant fertility morbidity.
For late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) assessment of atrial scar to guide management and targeting of ablation in atrial fibrillation (AF), an objective, reproducible method of identifying atrial scar is required.
To describe an automated method for operator-independent quantification of LGE that correlates with colocated endocardial voltage and clinical outcomes.
LGE CMR imaging was performed at 2 centers, before and 3 months after pulmonary vein isolation for paroxysmal AF (n = 50). A left atrial (LA) surface scar map was constructed by using automated software, expressing intensity as multiples of standard deviation (SD) above blood pool mean. Twenty-one patients underwent endocardial voltage mapping at the time of pulmonary vein isolation (11 were redo procedures). Scar maps and voltage maps were spatially registered to the same magnetic resonance angiography (MRA) segmentation.
The LGE levels of 3, 4, and 5SDs above blood pool mean were associated with progressively lower bipolar voltages compared to the preceding enhancement level (0.85 ± 0.33, 0.50 ± 0.22, and 0.38 ± 0.28 mV; P = .002, P < .001, and P = .048, respectively). The proportion of atrial surface area classified as scar (ie, >3 SD above blood pool mean) on preablation scans was greater in patients with postablation AF recurrence than those without recurrence (6.6% ± 6.7% vs 3.5% ± 3.0%, P = .032). The LA volume >102 mL was associated with a significantly greater proportion of LA scar (6.4% ± 5.9% vs 3.4% ± 2.2%; P = .007).
LA scar quantified automatically by a simple objective method correlates with colocated endocardial voltage. Greater preablation scar is associated with LA dilatation and AF recurrence.
2D, 2-dimensional; AF, atrial fibrillation; CMR, cardiovascular magnetic resonance; ECG, electrocardiogram; LA, left atrial/atrium; LGE, late gadolinium enhancement; MRA, Magnetic resonance angiography; PAF, paroxysmal atrial fibrillation; RF, radiofrequency; SD, standard deviation; Atrial fibrillation; Delayed-enhancement magnetic resonance imaging; Radiofrequency ablation
Pulmonary venous stenosis should be considered in patients presenting with respiratory symptoms after atrial fibrillation ablation
To determine the effects of interventricular pacing interval and left ventricular (LV) pacing site on ventricular dyssynchrony and function at baseline and during biventricular pacing, using tissue Doppler imaging.
Using an angioplasty wire to pace the left ventricle, 20 patients with heart failure and left bundle branch block underwent temporary biventricular pacing from lateral (n = 20) and inferior (n = 10) LV sites at five interventricular pacing intervals: +80, +40, synchronous, −40, and −80 ms.
LV ejection fraction (EF) increased (mean (SD) from 18 (8)% to 26 (10)% (p = 0.016) and global mechanical dyssynchrony decreased from 187 (91) ms to 97 (63) ms (p = 0.0004) with synchronous biventricular pacing compared to unpaced baseline. Sequential pacing with LV preactivation produced incremental improvements in EF and global mechanical dyssynchrony (p<0.0001 and p = 0.0026, respectively), primarily as a result of reductions in inter‐LV–RV dyssynchrony (p = 0.0001) rather than intra‐LV dyssynchrony (NS). Results of biventricular pacing from an inferior or lateral LV site were comparable (for example, synchronous biventricular pacing, global mechanical dyssynchrony: lateral LV site, 97 (63) ms; inferior LV site, 104 (41) ms (NS); EF: lateral LV site, 26 (10)%; inferior LV site, 27 (10)% (NS)). ECG morphology was identical during biventricular pacing through an angioplasty wire and a permanent lead.
Sequential biventricular pacing with LV preactivation most often optimises LV synchrony and EF. An inferior LV site offers a good alternative to a lateral site. Pacing through an angioplasty wire may be useful in assessing the acute effects of pacing.
biventricular pacing; lead position; interventricular pacing interval; tissue Doppler imaging
Loss of mismatch repair (MMR) gene expression has been associated with fewer metastases and improved prognosis in various tumour types.
To evaluate the predictive and prognostic significance of loss of MMR protein MSH2 in early stage cervical cancer.
Specimens from 218 consecutive patients with early stage, surgically treated cervical cancer were analysed. Median age was 42 years (interquartile range 35–53). International Federation of Gynecology and Obstetrics (FIGO) stages were IB1 (57%), IB2 (25%) and IIA (18%). Histology was 70% squamous cell, 6% adenosquamous and 24% adenocarcinoma. Pelvic lymph node metastasis was present in 66 (30%) patients. Median follow‐up was 5.2 years (interquartile range 2.5–7.9). Tissue microarrays (TMAs) were constructed containing three cores of paraffin‐embedded tumour per case. MSH2 expression was assessed by immunohistochemistry on TMAs and full sections.
In TMAs MSH2 expression could be analysed in 184/218 (84%) tumours. Loss of MSH2 was observed in 58/184 (32%) tumours, with a moderately strong concordance between TMAs and full sections (κ = 0.47). In tumours with loss of MSH2, pelvic lymph node metastasis and cancer invasion beyond 10 mm were more frequent (48% vs 25%, and 59% vs 37%, respectively). However, loss of MSH2 expression was not related to recurrence or survival.
TMAs are powerful tools for high throughput screening of biological markers for prognostic value in cervical cancer. Absence of MSH2 expression is associated with a high‐risk profile in early stage cervical cancer, but does not predict lymph node status with sufficient accuracy to be used in the clinic.
uterine cervical neoplasms; tissue microarray; prognostic marker; MSH2 protein; human
Breast-conserving surgery (BCS) is the preferred treatment for nonpalpable breast carcinoma. The outcome, however, may be disappointing. In this study surgical outcome in a large cohort of patients diagnosed with nonpalpable breast carcinoma is evaluated.
In 833 patients with 841 nonpalpable breast carcinomas the number of re-excisions and type of surgical procedures was calculated and summed per patient. Subsequently, the number of conversions to mastectomy and the number of days until complete tumor removal were analyzed. In a subgroup analysis the patients with an in situ carcinoma were compared with the patients with an invasive carcinoma.
The initial surgery consisted of BCS for 589 tumors (70%) and of mastectomy for 242 tumors (29%). For ten tumors (1%) the initial surgery was unknown. After BCS, 158/589 tumors (27%) required a re-excision: 116/337 (34%) for the in situ carcinomas and 63/504 (13%) for the invasive carcinomas (p = 0.0001). The number of conversions from BCS to mastectomy was 106/589 (18%): 66/241 (28%) in patients diagnosed with an in situ carcinoma versus 40/348 (11%) in patients with an invasive carcinoma (p = 0.0001). The median number of days until complete tumor removal was 28, being 38 days for the in situ carcinomas and 25 days for the invasive carcinomas (p = 0.0001).
There is room for improvement in the surgical treatment of nonpalpable breast carcinoma, especially the relatively favorable in situ carcinoma, as it requires significantly more excisions, mastectomies, conversions to mastectomy, and days for complete removal.
Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the ‘kra’ monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia1,2. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated3, and it has a close phylogenetic relationship to Plasmodium vivax4, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or ‘hypnozoite’ in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone5) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome4 and other sequenced Plasmodium genomes6-8. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs9, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.
Objective: To investigate whether a rapid access approach is useful for the evaluation of patients with symptoms suggestive of a new cardiac arrhythmia.
Design: Prospective, descriptive study.
Setting: Secondary care based rapid access arrhythmia clinic in West London, UK.
Participants: Patients referred by their general practitioner or the emergency department with symptoms suggestive of a new cardiac arrhythmia.
Main outcome measures: Number of patients with a newly diagnosed significant arrhythmia. Number of patients with diagnosed atrial fibrillation. Number of eligible, moderate, and high risk patients treated with warfarin.
Results: Over a 25 month period 984 referrals were assessed. The mean age was 55 years (range 20–90 years) and 56% were women. The median time from referral to assessment was one day. A significant cardiac arrhythmia was newly diagnosed in 40% of patients referred to the RAAC. The most common arrhythmia was atrial fibrillation, with 203 new cases (21%). Of these, 74% of eligible patients over 65 were treated with warfarin. Other arrhythmias diagnosed were supraventricular tachycardias (127 (13%)), conduction disorders (43 (4%)), and non-sustained ventricular tachycardia (21 (2%)). Vasovagal syncope was diagnosed for 53 patients (5%). The most frequent diagnosis was symptomatic ventricular and supraventricular extrasystoles (355 (36%)).
Conclusion: A rapid access arrhythmia clinic is an innovative approach to the diagnosis and management of new cardiac arrhythmias in the community. It provides a rapid diagnosis, stratifies risk, and leads to prompt initiation of effective treatment for this population.
arrhythmias; atrial fibrillation; rapid access arrhythmia clinic; warfarin
Aim: To examine whether the detection of either telomerase and its components or high risk human papillomavirus (HPV) are of value in predicting the presence of cervical intraepithelial neoplasia (CIN) grade II/III in women referred because of cervical cytology reports showing at most moderate dyskaryosis.
Methods: Cervical scrapings of 50 women referred with cytological borderline, mild, or moderate dyskaryosis were analysed. Telomerase activity was assessed by a commercially available telomere repeat amplification protocol assay and its components human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) were assessed by reverse transcriptase polymerase chain reaction (PCR). HPV was detected by GP5+/6+ PCR enzyme immunosassay. Histological findings on colposcopy guided biopsies or excised cervical tissue were regarded as the final pathological diagnosis. The sensitivity and specificity for detecting CIN II/III were calculated.
Results: Twenty eight women were diagnosed with CIN II/III. Telomerase activity was detected in none, hTR in 88%, hTERT in 23%, and high risk HPV was detected in 79% of these women. As a diagnostic test none of the described analyses combined a sensitivity of at least 90% with a specificity ≥ 90%. Despite the small numbers, calculation of the 95% confidence intervals excluded a combined sensitivity and specificity of at least 90% for all of the evaluated parameters.
Conclusions: Neither detection of telomerase or its components, nor detection of high risk HPV seem suitable for the triage of women with borderline, mild, and moderate cytological dyskaryosis.
human papillomavirus; cervical neoplasia; telomerase activity; human telomerase RNA; human telomerase reverse transcriptase
Objective: To explore whether the presence of Chlamydia trachomatis antibodies is associated with the severity of neoplastic lesions in women with cervical dyskaryosis.
Methods: In a cross sectional study in two groups of women referred for an abnormal Papanicolaou smear (group A: 296, group B: 331 women) blood samples were analysed for antichlamydial antibodies by enzyme immunoassay. Cervical neoplasia was graded histologically.
Results: In group A no association was found between increasing grade of CIN and the presence of antichlamydial antibodies. The proportion (93%) of women with antichlamydial antibodies was higher in 14 women with (micro)invasive carcinoma than in women with CIN (35%). As the high prevalence of antichlamydial antibodies in women with cervical carcinoma is not consistent with prevalences reported in recent literature, we analysed a second group of women in which indeed the high prevalence was not confirmed
Conclusion: Our results suggest that the presence of circulating antichlamydial antibodies is not associated with the severity of neoplastic lesions and it seems unlikely that C trachomatis has a role in the progression of cervical neoplasia.
Key Words: cervical neoplasia; Chlamydia trachomatis
We have identified a cluster of six genes involved in trehalose transport and utilization (thu) in Sinorhizobium meliloti. Four of these genes, thuE, -F, -G, and -K, were found to encode components of a binding protein-dependent trehalose/maltose/sucrose ABC transporter. Their deduced gene products comprise a trehalose/maltose-binding protein (ThuE), two integral membrane proteins (ThuF and ThuG), and an ATP-binding protein (ThuK). In addition, a putative regulatory protein (ThuR) was found divergently transcribed from the thuEFGK operon. When the thuE locus was inactivated by gene replacement, the resulting S. meliloti strain was impaired in its ability to grow on trehalose, and a significant retardation in growth was seen on maltose as well. The wild type and the thuE mutant were indistinguishable for growth on glucose and sucrose. This suggested a possible overlap in function of the thuEFGK operon with the aglEFGAK operon, which was identified as a binding protein-dependent ATP-binding transport system for sucrose, maltose, and trehalose. The Kms for trehalose transport were 8 ± 1 nM and 55 ± 5 nM in the uninduced and induced cultures, respectively. Transport and growth experiments using mutants impaired in either or both of these transport systems show that these systems form the major transport systems for trehalose, maltose, and sucrose. By using a thuE′-lacZ fusion, we show that thuE is induced only by trehalose and not by cellobiose, glucose, maltopentaose, maltose, mannitol, or sucrose, suggesting that the thuEFGK system is primarily targeted toward trehalose. The aglEFGAK operon, on the other hand, is induced primarily by sucrose and to a lesser extent by trehalose. Tests for root colonization, nodulation, and nitrogen fixation suggest that uptake of disaccharides can be critical for colonization of alfalfa roots but is not important for nodulation and nitrogen fixation per se.
OBJECTIVE—Treatment of ventricular tachycardia (VT) in coronary heart disease has to date been limited to palliative treatment with drugs or implantable defibrillators. The results of curative treatment with catheter ablation have proved disappointing because the complexity of the VT mechanism makes identification of the substrate using conventional mapping techniques difficult. The use of a mapping technology that may address some of these issues, and thus make possible a cure for VT with catheter ablation, is reported.
PATIENTS AND INTERVENTION—The non-contact system, consisting of a multielectrode array catheter (MEA) and a computer mapping system, was used to map VT in 24 patients. Twenty two patients had structural heart disease, the remainder having "normal" left ventricles with either fasicular tachycardia or left ventricular ectopic tachycardia.
RESULTS—Exit sites were demonstrated in 80 of 81 VT morphologies by the non-contact system, and complete VT circuits were traced in 17. In another 37 morphologies of VT 36 (30)% (mean (SD)) of the diastolic interval was identified. Thirty eight VT morphologies were ablated using 154 radiofrequency energy applications. Successful ablation was achieved by 77% of radiofrequency within diastolic activation identified by the non-contact system and was significantly more likely to ablate VT than radiofrequency at the VT exit, or remote from diastolic activation. Over a mean follow up of 1.5 years, 14 patients have had no recurrence of VT and only two target VTs have recurred. Five patients have had recurrence of either slower non-sustained, undocumented or fast non-target VT. Five patients have died, one from tamponade from a pre-existing temporary pacing wire, and four from causes unrelated to the procedure.
CONCLUSION—The non-contact system can safely be used to map and ablate haemodynamically stable VT with low VT recurrence rates. It is yet to be established whether this system may be applied with equal success to patients with haemodynamically unstable VT.
Keywords: ventricular tachycardia; mapping; ablation
OBJECTIVE—To assess the efficacy and safety of sulphasalazine in reactive arthritis.
METHODS—Double blind placebo controlled trial of six months duration comparing sulphasalazine 2-3 g per day (n = 37) with matching placebo (n = 42) in adults with active reactive arthritis (age 19-57 years, median 34). Treatment response was evaluated once a month by changes in erythrocyte sedimentation rate (ESR), pain, peripheral arthritis, tender iliosacral joints, entesopathy, extra-articular manifestations, and working ability.
RESULTS—15 patients in the sulphasalazine group and eight in the placebo group withdrew from the study prematurely. Adverse events, primarily gastrointestinal, were the main reason for withdrawal in the actively treated group. Intention-to-treat analyses showed significant improvements over time in both groups in ESR, pain, and number of swollen joints (P < 0.01). Number of days on sick leave decreased significantly in the sulphasalazine group only (P < 0.01). No significant differences between the two groups were present after six months. Among the patients completing the trial according to protocol, persistent complete remission had occurred within two months in five (23%) of the actively treated, but in no placebo treated patients (P = 0.013).
CONCLUSIONS—Sulphasalazine seemed to improve only the very short term outcome of reactive arthritis. The possible beneficial effect of the drug should also be weighed against the risk of adverse events. Although these were mainly mild, almost 25% of the patients in the actively treated group gave up treatment for this reason.
Crude bean root extracts of Phaseolus vulgaris were tested for inhibition of the growth of several polysaccharide mutants of Rhizobium etli biovar phaseoli CE3. Mutants deficient only in exopolysaccharide and some mutants deficient only in the O-antigen of the lipopolysaccharide were no more sensitive than the wild-type strain to the extracts, whereas mutants defective in both lipopolysaccharide and exopolysaccharide were much more sensitive. The inhibitory activity was found at much higher levels in roots and nodules than in stems or leaves. Inoculation with either wild-type or polysaccharide-deficient R. etli did not appear to affect the level of activity. Sequential extractions of the crude root material with petroleum ether, ethyl acetate, methanol, and water partitioned inhibitory activity into each solvent except methanol. The major inhibitors in the petroleum ether and ethyl acetate extracts were purified by C18 high-performance liquid chromatography. These compounds all migrated very similarly in both liquid and thin-layer chromatography but were distinguished by their mass spectra. Absorbance spectra and fluorescence properties suggested that they were coumestans, one of which had the mass spectrum and nuclear magnetic resonances of coumestrol. These results are discussed with regard to the hypothesis that one role of rhizobial polysaccharides is to protect against plant toxins encountered during nodule development.
Between August 1983 and December 1988, 47 patients with metastatic testicular tumours (44 non-seminomatous, three seminomas) were treated with two to six courses of bleomycin, etoposide, cisplatin and vincristine (BEPV). Five stage I tumours were included, three because of raised tumour markers following orchidectomy, one with vascular invasion of spermatic cord vessels and the other with both these features. Forty-four patients (93.6%) are alive and disease free 12-75 months (median 39 months) after completion of BEPV. Further treatment was necessary in 12 of the survivors. Eight had residual disease excised, one of whom received radiotherapy, one additional chemotherapy and one both radiotherapy and chemotherapy. Of the remaining four, two had radiotherapy and two second line chemotherapy. Thirty-one non-seminomatous and the three seminoma patients had small volume disease and all are in complete remission. Ten of the 13 patients with bulky disease are alive. It is concluded that BEPV is a well-tolerated, effective, first line therapy for patients with metastatic testicular tumour.
To explore the role of rhizobitoxine in Bradyrhizobium-legume symbiosis, 11 rhizobitoxine mutants of B. japonicum USDA61 were isolated on the basis of their inability to synthesize the toxin in culture. Each mutant is prototrophic and symbiotically effective on soybean, cowpea, siratro, and Glycine soja. The rhizobitoxine mutants differ in their chlorosis phenotypes and rhizobitoxine production in planta. As expected, one group of mutant fail to make toxin in planta, resulting in the absence of chlorosis. Another group of mutants causes severe chlorosis on all cultivars of soybean tested. Surprisingly, this group of mutants makes more rhizobitoxine in soybean nodules than the wild-type strain does. This phenotype is only observed on soybean and not on other hosts such as cowpea, siratro, or G. soja. The remaining mutants all produce rhizobitoxine in planta but vary in the amount of toxin they produce and the severity of chlorosis they induce in soybean plants. Biochemical analysis of mutants demonstrates that one mutant is unable to synthesize serinol, a molecule hypothesized to be an intermediate in rhizobitoxine biosynthesis. By using these mutants, it was found that rhizobitoxine plays no apparent role in the nodulation of rj1 soybeans. Recently, it was found that inhibition of ethylene biosynthesis allows Rhizobium meliloti to overcome nitrate inhibition of nodule formation on alfalfa. Because rhizobitoxine also inhibits ethylene biosynthesis, we tested the ability of mutants which accumulate high levels of toxin in planta to overcome nitrate inhibition of nodule formation on soybean plants and found that the nodule formation induced by the wild type and that induced by mutant strains were equally suppressed in the presence of nitrate.
Rhizobitoxine is a phytotoxin synthesized by some strains of the legume symbiont genus Bradyrhizobium and the plant pathogen Pseudomonas andropogonis. We demonstrate here a new enzymatic assay which is 100-fold more sensitive than previous assays and can detect as little as 1.0 pmol of rhizobitoxine. The assay is based on the inhibition of Salmonella typhimurium beta-cystathionase by rhizobitoxine. Interestingly, beta-cystathionase from Bradyrhizobium japonicum is insensitive to rhizobitoxine at concentrations lower than 75 microM.
Serious ventricular arrhythmias are known to occur in patients with long QT intervals. We describe a case of torsade de pointes occurring in a patient with a prolonged QT interval while taking a 1000 calorie diet, diethylpropion hydrochloride (Tenuate Dospan) and bendrofluazide. In patients with long QT intervals, hypokalaemia and drugs which further delay repolarization may facilitate the development of life threatening arrhythmias.
The core-antigen-coding region of all hepadnaviruses is preceded by a short, in-phase open reading frame termed precore whose expression can give rise to core-antigen-related polypeptides. To explore the functional significance of precore expression in vivo, we introduced a frameshift mutation into this region of the duck hepatitis B virus (DHBV) genome and examined the phenotype of this mutant DNA by intrahepatic inoculation into newborn ducklings. Animals receiving mutant DNA developed DHBV infection, as judged by the presence in hepatocytes of characteristic viral replicative intermediates; molecular cloning and DNA sequencing confirmed that the original mutation was present in the progeny genomes. Infection could be efficiently transmitted to susceptible ducklings by percutaneous inoculation with serum from mutant-infected animals, indicating that infectious progeny virus was generated. These findings indicate that expression of the precore region of DHBV is not essential for genomic replication, core particle morphogenesis, or intrahepatic viral spread.