Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

PTCH mutations in basal cell carcinomas from azathioprine-treated organ transplant recipients.

The immunosuppressant azathioprine is used to prevent graft rejection after organ transplantation. To investigate whether azathioprine-associated mutagenesis contributes to the high incidence of skin tumours in organ transplant recipients (OTRs), we analysed PTCH gene mutations in 60 basal cell carcinomas (BCC); 39 from OTRs receiving azathioprine and 21 from individuals never exposed to azathioprine. PTCH was mutated in 55% of all tumours, independent of azathioprine treatment. In both the azathioprine and non-azathioprine groups, transitions at dipyrimidine sequences, considered to indicate mutation by ultraviolet-B radiation, occurred frequently in tumours from chronically sun-exposed skin. In BCC from non-sun-exposed skin of azathioprine-treated patients, there was an over-representation of unusual G:C to A:T transitions at non-dipyrimidine sites. These were exclusive to the azathioprine-exposed group and all in the same TGTC sequence context at different positions within PTCH. Meta-analysis of 247 BCCs from published studies indicated that these mutations are rare in sporadic BCC and had never previously been reported in this specific sequence context. This study of post-transplant BCC provides the first indication that azathioprine exposure may be associated with PTCH mutations, particularly in tumours from non-sun-exposed skin.

Azathioprine treatment photosensitizes human skin to ultraviolet A radiation.

BACKGROUND: Azathioprine is used to treat a variety of conditions and to prevent graft rejection in organ transplant recipients (OTRs). OBJECTIVES: To investigate clinically our previous finding that azathioprine metabolites interact with ultraviolet (UV) A radiation to form promutagenic oxidative DNA damage and to determine whether this may be causal or contributory to the development of excess skin cancers post-transplantation. METHODS: The clinical corollary of these data were investigated. Five patients were recruited and the minimal erythema dose (MED) for UVB, UVA and solar-simulated radiation (SSR) was determined for each person before, and at least 12 weeks after, starting azathioprine therapy. RESULTS: In all five patients azathioprine treatment was associated with an increased UVA and SSR sensitivity of the skin and a significant reduction in MEDs for UVA and SSR. We found no change in UVB-induced erythema or MED. In addition, we found that DNA from the skin of patients on azathioprine contains 6-thioguanine (6-TG). CONCLUSIONS: Our findings confirm the presence of DNA 6-TG in the skin of those taking therapeutic doses of azathioprine and provide support for the hypothesis that DNA damage occurs when DNA 6-TG interacts with UVA, resulting in abnormal cutaneous photosensitivity.

The usefulness of the platelet function analyser (PFA-100) in screening for underlying bleeding disorders in women with menorrhagia.

The prevalence of underlying bleeding disorders is common in women with menorrhagia. This was a prospective study to screen for the underlying bleeding disorders in women presenting with menorrhagia by using the PFA-100 and comparing the accuracy of the results with the complete haematological assays. A total of 62 women referred to gynaecology outpatients with a history of heavy, regular periods had blood collected for analysis by the PFA-100 and also a full coagulation profile including von Willebrand factor. PFA-100 analysis suggested platelet defects in 10 (16%) women. This included five (8%) identified with von Willebrand disease, two (3.2%) with storage pool disorders and three (4.8%) without any recognisable platelet or bleeding disorders after a full coagulation profile, including von Willebrand factor, was carried out. PFA-100 results had a sensitivity of 100% and specificity of 94.8% in our study. We conclude that PFA-100 is a quick and reliable method of screening for impaired haemostasis in patients with menorrhagia.

An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to HRT.

OBJECTIVE: Our study set out to test the null hypothesis that oestrogen containing continuous combined hormone replacement therapy (HRT) would not affect the hormone receptor expression (oestrogen and progesterone receptors-ER, PR) or markers of cell proliferation/apoptosis (Ki67 and Bcl-2) in endometrial polyps from postmenopausal women exposed and not exposed to HRT. DESIGN: Immunohistochemical staining for ER, PR, Ki67 and Bcl-2 was performed on polyps obtained from two groups of postmenopausal women. SETTING: Polyps were obtained from postmenopausal women attending an outpatient hysteroscopy clinic in a district general hospital (Bradford Royal Infirmary, UK). POPULATION: Twenty-five postmenopausal women presenting with abnormal bleeding subsequently diagnosed with endometrial polyps (16 from women not exposed to HRT, 9 from women exposed to HRT). METHODS: Semiquantitative immunohistochemistry was performed. MAIN OUTCOME MEASURES: Significant differences or correlations in either hormone receptor expression or markers of cell proliferation/apoptosis between the two groups of polyps. RESULTS: There were no significant differences for hormone receptor expression (ER and PR) between endometrial polyps exposed and not exposed to HRT. Bcl-2 expression was higher than Ki67 in both groups, but polyps from HRT users had increased levels reflecting decreased apoptosis in these polyps. CONCLUSIONS: HRT has no demonstrable effect on polyp ER and PR expression. However, HRT does appear to inhibit apoptosis and cell proliferation in endometrial polyps, which may affect polyp growth.

Does tamoxifen therapy affect the hormone receptor expression and cell proliferation indices of endometrial polyps? An immunohistochemical comparison of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen.

OBJECTIVE: This study set out to test the null hypothesis that tamoxifen therapy would not affect the hormone receptor expression (oestrogen and progesterone receptors-ER and PR) or markers of cell proliferation/apoptosis (Ki67 and Bcl-2) of endometrial polyps from postmenopausal women exposed and not exposed to tamoxifen. METHODS: Endometrial polyps were prospectively obtained from women presenting with abnormal bleeding attending an out-patient hysteroscopy clinic who subsequently underwent endometrial polypectomy (16 from postmenopausal women not exposed to tamoxifen, 9 from women exposed to tamoxifen). Immunohistochemical staining for ER, PR, Ki67 and Bcl-2 was performed on polyps from both groups of women. Non-parametric statistical analysis was used (Mann-Whitney and Spearmans rank correlation). RESULTS: Endometrial polyps from tamoxifen users had significantly lower oestrogen receptor but increased progesterone receptor and Bcl-2 expression. There were no significant differences for proliferation markers (Ki67) between postmenopausal endometrial polyps exposed and not exposed to tamoxifen. CONCLUSIONS: Tamoxifen has a significant affect on hormone receptor expression and markers of apoptosis in endometrial polyps. The results support the hypothesis that tamoxifen promotes polyp growth by inhibiting apoptosis. The mechanism for this does not appear to be oestrogen receptor mediated.

Are endometrial polyps from pre-menopausal women similar to post-menopausal women? An immunohistochemical comparison of endometrial polyps from pre- and post-menopausal women.

OBJECTIVE: Do endometrial polyps from pre- and post-menopausal women have similar immunohistochemical expression of oestrogen and progesterone receptors (ER, PR) and markers of cellular proliferation/apoptosis (Ki67 and Bcl-2). DESIGN: Prospective cohort study. Non-parametric statistical analysis was used. SETTING: Polyps recruited from women attending an out-patient hysteroscopy clinic in a UK district general hospital. PATIENTS: Fourteen pre-menopausal and 16 post-menopausal women who presented with abnormal bleeding with endometrial polyps. INTERVENTIONS: Immunohistochemical staining was performed on endometrial polyps. MAIN OUTCOME MEASURES: Significant differences or correlations between hormone receptor expression (oestrogen and progesterone) and cell growth indices (Ki67 and Bcl-2). RESULTS: Endometrial polyps from pre- and post-menopausal women had significant differences in their expression of hormone receptors and Ki67. However, polyps from both groups of women had similarly increased levels of Bcl-2, an inhibitor of apoptosis. CONCLUSIONS: Pre- and post-menopausal polyps exhibit differing hormone receptor and proliferation markers, presumably a result of their hormonal milieu. However, both groups appear to have lost the usual control mechanisms for apoptotic regulation, this appears to be responsible for their growth.

Giant esophageal varices. An unusual cause of a posterior mediastinal mass.

Esophageal pathology rarely presents as posterior mediastinal abnormalities on chest roentgenograms, with the most common being hiatal hernia. We describe a patient with giant esophageal varices manifesting as a retrocardiac, posterior mediastinal mass.

Computerized tomographic densitometry of the solitary pulmonary nodule using a nodule phantom.

The successful application of computerized tomographic density analysis for evaluating the solitary pulmonary nodule has previously been described and the technique has since been simplified by using a calcium-equivalent nodule reference phantom. Because published experience with this technique remains limited, the current research reports the Cleveland Clinic experience with the CIRS model III pulmonary nodule reference phantom. Without knowledge of the final diagnosis, the nodule phantom was used as the standard for categorizing 31 nodules in 29 patients as either benign or indeterminate. Secure diagnoses were obtained in all cases. Eleven nodules were called benign and ten proved so, whereas 20 nodules were classified as indeterminate. One lesion, an adenocarcinoma, was falsely called benign using this technique. The excellent density discrimination achieved with CT makes this a superior tool for analysis of the solitary pulmonary nodule, and the nodule reference phantom has greatly simplified the technique of CT densitometry. As demonstrated by this and prior studies, calcification is not a unique feature of the benign lesion and successful clinical application of this technique requires cautious interpretation of results.

Acute pulmonary edema after lung transplantation: the pulmonary reimplantation response.

BACKGROUND: Although the development of noncardiogenic pulmonary edema or pulmonary reimplantation response (PRR) after lung transplantation has been well described, the incidence has not been established and the relationship of PRR to clinical risk factors has not been analyzed. STUDY OBJECTIVES: (1) To describe the incidence of PRR in lung transplant recipients, (2) to identify the predictors of PRR, (3) to examine the correlation of suspected predictors with the severity of PRR, and (4) to evaluate the impact of PRR on morbidity and mortality of lung transplant recipients. DESIGN: Retrospective review of clinical records and radiographic studies. SETTING: Tertiary care referral center. PATIENTS: Ninety-nine consecutive patients with end-stage lung disease undergoing lung transplantation between February 1990 and October 1995. METHODS: Review of clinical records and postoperative chest radiographs of all lung transplant recipients to identify patients who experienced PRR. Chest radiographs of patients with PRR were graded for severity on a scale of 0 (none) to 5 (very severe). Demographic, pre- and perioperative factors were also evaluated along with short- and long-term survival of patients with PRR. RESULTS: Fifty-six of 99 lung transplant recipients (57%) experienced PRR. The median ischemia time of patients with and without PRR was 168 and 180 min, respectively (p = 0.62). The incidence of PRR was 51% in patients without preoperative pulmonary hypertension, 78% in mild to moderate pulmonary hypertension, and 58% in patients with severe pulmonary hypertension (p = 0.10). Incidence and severity of PRR was similar in patients receiving right, left, or double-lung transplantation. Similarly, age and sex of the recipients and underlying lung disease did not affect the incidence or severity of PRR. The incidence and severity of PRR was higher in patients undergoing cardiopulmonary bypass during lung transplantation. Patients with PRR had prolonged duration of mechanical ventilation and ICU stay. Overall, PRR did not affect the survival of the patients. However, survival of female lung transplant recipients was significantly better than male recipients (median survival, 60 vs 21 months; p = 0.02). CONCLUSIONS: Acute pulmonary edema or PRR occurs frequently (57%) after lung transplantation. In this series, PRR was not associated with a prolonged ischemia time, preoperative pulmonary hypertension, the type of lung transplant, underlying lung disease, or age or sex of recipients. However, use of cardiopulmonary bypass during surgery was associated with increased incidence and severity of PRR. Also, the development of PRR resulted in prolonged mechanical ventilation and a longer ICU stay, but did not affect survival. Female lung transplant recipients survived significantly longer than male recipients. The reason for this difference in survival is unclear.

Fetal breathing movements and the diagnosis of labor: a prospective analysis of 100 cases.

One hundred patients self-admitted to the hospital with a diagnosis of labor, were observed for up to 45 minutes with real-time ultrasonography to determine if the presence or absence of fetal breathing movements was helpful in separating false labor from true labor. Fetal breathing movements were not detected in 31 patients, and 30 of these delivered spontaneously within 48 hours; fetal breathing movements were present in 69 cases, and pregnancy continued for at least 48 hours in 56; of the remaining 13, labor occurred spontaneously within 48 hours in eight, whereas five had labor induced. Assessment of the cervix by Bishop score after ultrasound further improved diagnostic precision; none of 13 patients with a score greater than 9 exhibited fetal breathing movements, and all delivered within 48 hours. Gestational age did not influence outcome; 25 patients were preterm, and all 22 in whom fetal breathing movements were present continued for more than 48 hours. The results suggest that the absence of fetal breathing movements differentiates true labor from false labor.

Cervical pregnancy managed by suction evacuation and balloon tamponade.

A woman with a very poor obstetric history with a cervical pregnancy was managed without hysterectomy. Diagnosis was made by the transvaginal ultrasound. Haemorrhage was controlled by suction evacuation and balloon tamponade. Although cervical perforation occurred, the tamponade was able to control haemorrhage after repair of the perforation.

A national confidential survey of obstetrician's personal preferences regarding mode of delivery.

OBJECTIVE: To survey the personal preferences of obstetricians regarding mode of delivery, and relate these to hospital caesarean section rates. STUDY DESIGN: A confidential, questionnaire based survey to all obstetricians working in the Republic of Ireland (n=234). RESULTS: The response rate was 71% (n=165). Seven percent of Irish obstetricians would choose an elective caesarean section for themselves (or their partners) if they were primigravida with an uncomplicated, singleton cephalic presentation at term in the absence of any clinical indication. Caesarean section was the preferred mode of delivery for 38% of respondents if the estimated foetal weight was 4.5kg. There was a highly significant association between consultant obstetricians' personal preferences of towards caesarean section and their working in a hospital with a caesarean section rate greater than 16% (P<0.005). CONCLUSIONS: Irish obstetricians' personal preferences towards elective caesarean section for an uncomplicated, cephalic pregnancy at term are significantly lower than published data examining London based obstetricians' choices. There is a consistent trend against vaginal delivery if the obstetrician is female or younger. The association between a personal preference of the consultant for abdominal delivery and the caesarean section rate of the hospital that they work in may hamper efforts to decrease the rising numbers of caesarean sections.

The mobile mesoazygos.

We describe surgical relocation of the mesoazygos without its visceral pleura, from an intrapulmonary location to a normal right superior mediastinal position. The pictorial sequence presented confirms the postulated theory of azygos disimpaction and excludes the theory of symphysis of the azygos fissure.

Evaluation of the reliability of computed tomographic criteria used in the diagnosis of round atelectasis.

The purpose of this controlled study was to determine the diagnostic accuracy of computed tomography (CT) in the diagnosis of round atelectasis (RA). We reviewed two groups of chest CT scans of 22 patients (with 24 masses). Group 1 scans represent 10 patients (12 masses) known to have RA, and Group 2 scans represent 12 patients with "RA look-alike" masses. Scans in both groups were selected for review by two of the authors and later independently reviewed by the other authors, who were blind to the actual diagnosis. Scans were rated for the presence/absence of 18 features ascribed to RA in the literature and assigned a percent probability of RA by each rater. Consensus was achieved for discordant ratings, and the individual percent probabilities were averaged to create a consensus probability. ROC curve analysis of the consensus percent probability showed that diagnostic accuracy significantly exceeded chance [area under curve (AUC) = 0.95, p < 0.001]. Of all the features of RA examined, the presence of converging bronchovascular markings discriminated best between RA and "RA look-alikes" (sensitivity 83%, specificity 92%, likelihood ratio 11). Presence of adjacent pleural thickening and pleural-based location were even more sensitive features of RA (100% each), but lacked specificity (33 and 67%, respectively; likelihood ratios 3 and 1.5, respectively). We conclude that (a) although the diagnostic accuracy of CT for RA was high in this series, radiographic diagnosis is imperfect and that (b) the presence of converging bronchovascular markings was the best discriminator between the two groups, but that no single CT feature permitted perfect discrimination.

Rare pulmonary manifestation of Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is an inherited disorder of connective tissue with multiple thoracic manifestations. We present an unusual thoracic manifestation of EDS consisting of parenchymal cysts and fibrous and fibroosseous nodules. These manifestations may be related to an abnormal attempt at repair of parenchymal or vascular tears.

Computed tomography and magnetic resonance findings in long-standing patent ductus. Case reports.

Two adult patients with patent ductus arteriosus (PDA), resulting in Eisenmenger's syndrome, were evaluated by computed tomography and Magnetic Resonance imaging of the chest, which clearly demonstrated the patent arterial duct as well as the morphologic features of long-standing pulmonary arterial hypertension. Massively dilatated, calcified pulmonary arteries were seen, and the arterial duct was identified as a vascular channel between the distal aortic arch and the main pulmonary artery.

An angiographic dilemma: bronchopulmonary sequestration versus pseudosequestration: case reports.

Bronchopulmonary sequestration is a congenital anomaly in which part of the pulmonary tissue is detached from the normal lung and is supplied by anomalous systemic arteries. The sequestered, aberrant lung tissue does not have normal connections with the tracheobronchial tree or pulmonary arteries. In some patients with angiographic characteristics of this disorder, no sequestration is found at the time of surgery. We present three cases in which systemic arterialization of a portion of lung occurred without actual sequestration. Such cases of pseudosequestration can present a diagnostic challenge preoperatively and should be considered whenever angiographic findings compatible with bronchopulmonary sequestration are found.

Pleural changes in malignant pleural effusions: appearance on computed tomography.

BACKGROUND: Tumors metastatic to the pleura are a leading cause of pleural effusions. The computed tomographic (CT) appearance of malignant pleural effusions varies from uniformly low attenuation without pleural abnormalities to thickened, irregular, contrast-enhanced pleura with or without discrete masses. There may be associated changes in the subcostal tissues. OBJECTIVE: To determine the prevalence of abnormalities observed with CT scanning in patients with malignant pleural effusion. METHODS: We analyzed the CT appearance of the pleura in 86 patients with documented malignant pleural effusions. Patients with primary malignancy of the pleura (mesothelioma) were excluded. RESULTS: In 98% of the malignant effusions the fluid was homogeneous. Focal tumor masses were identified within the effusion in 10%. CT evidence of fluid loculation was seen in 40%. Pleural thickening, either smooth or irregular, was identified in 62%. CONCLUSIONS: The transaxial anatomic display afforded by CT scanning facilitates demonstration of several features that should arouse the suspicion of the radiologist and the clinician to the possibility of malignancy involving the pleura.

Intrathoracic lymph node evaluation by CT and MRI with histopathologic correlation in non-small cell bronchogenic carcinoma.

Twenty patients with non-small cell bronchogenic carcinoma were prospectively studied for intrathoracic lymphadenopathy using computed tomography (CT) and magnetic resonance imaging (MRI). The CT and MRI results were correlated with the surgical histopathology results of 103 harvested lymph nodes. Based on node dimension (utilizing a 1-cm cutoff value), neither imaging modality was accurate in predicting the histopathology of the nodes. CT had a sensitivity of 21%, specificity of 95%, and an overall accuracy of 85%; MRI had a sensitivity of 14%, specificity of 97%, and an overall accuracy of 85%. Moreover, CT and MRI detected preoperatively only 17% and 14%, respectively, of the harvested nodes. In summary, lymph node sizes measured by CT and MRI are inaccurate in predicting the benignity or malignancy of lymph nodes. Lymphadenopathy can be present even with a "negative" CT or MRI scan of the thorax.