Aim: To analyse and compare expression patterns of three potential biomarkers—p16INK4A, CDC6, and MCM5—and evaluate their use as predictive biomarkers in squamous and glandular cervical preinvasive neoplasia. Methods: Immunocytochemical analysis of p16INK4A, MCM5, and CDC6 expression was performed on 20 normal, 38 cervical intraepithelial neoplasia 1 (CIN1), 33 CIN2, 46 CIN3, 10 squamous cell carcinoma, 19 cervical glandular intraepithelial neoplasia (cGIN), and 10 adenocarcinoma samples. Staining intensity was assessed using a 0–3 scoring system. p16INK4A, MCM5, and CDC6 expression was also examined in ThinPrep slides exhibiting mild, moderate, and severe dyskaryosis. Human papillomavirus (HPV) was detected using a modified SYBR green assay. Fluorogenic polymerase chain reaction (PCR) and solution phase PCR were used for specific HPV typing. Results: All three markers showed a linear correlation between expression and grade of dysplasia. p16INK4A and MCM5 protein expression was upregulated in all grades of squamous and glandular dysplasia. CDC6 protein was preferentially expressed in high grade lesions and in invasive squamous cell carcinoma. Conclusion: p16INK4A expression was closely associated with high risk HPV infection—all grades of squamous and glandular cervical lesions were immunohistochemically positive. MCM5 staining intensity was independent of high risk HPV infection, highlighting its potential as a biomarker in both HPV dependent and independent cervical dysplasia. CDC6 may be a biomarker of high grade and invasive lesions of the cervix, with limited use in low grade dysplasia. p16INK4A was the most reliable marker of cervical dysplasia. Combinations of dysplastic biomarkers may be useful in difficult diagnostic cases.,Multiple fistulous communications between the left anterior descending coronary artery and the left ventricle were found in a 55 year old woman with congenital hepatic fibrosis presenting with breathlessness. At cardiac catheterisation severe pulmonary hypertension was also found. In view of the persistent hypoprothrombinaemia, severe thrombocytopenia, and the multiple fistulas the risk of operation was thought to be unacceptable and she continues on medical treatment.
The seronegative spondyloarthropathies (SpAs) are associated both with clinical and subclinical colitis. Recently biological blockade with the tumour necrosis factor alpha (TNFα) antagonists infliximab and etanercept has been shown to be effective in the treatment of SpA. However, only infliximab is efficacious in the treatment of colitis in patients with Crohn’s SpA. We report on two patients with SpA and associated Crohn’s disease treated with etanercept whose arthritis showed an excellent response with complete resolution of spinal pathology, whereas their Crohn’s disease persisted or flared. These findings suggest that the effect of TNFα blockade in SpA differs between the joint and the bowel.,In preterm babies both haemoglobin and total neutrophil count values from capillary sites are significantly and variably higher than those from simultaneous arterial samples. Comparing simultaneous venous and arterial samples, the mean haemoglobin was slightly higher but the total neutrophil counts were similar.,A 19 year old woman with Ullrich-Noonan syndrome presented with a six month history of progressive dyspnoea and cyanosis. Clinical features were suggestive of severe pulmonary hypertension. Cross sectional echocardiography showed pronounced right ventricular pressure overload with right ventricular hypertrophy. Cardiac catheterisation confirmed severe pulmonary hypertension. Attempts to reduce pulmonary artery pressure with calcium channel blockers were unsuccessful. The patient died shortly after investigation. Necropsy confirmed primary pulmonary hypertension.
During the course of a case of primary pulmonary hypertension occurring in a 24 year old man lung tissue became available at heart-lung transplantation in 1986 and from a lung biopsy carried out in 1981. In 1986 the sections showed classic plexogenic pulmonary arteriopathy. In 1981 they revealed migration of myofibroblasts into the intima and lumen of pulmonary arteries and arterioles, the identification of the cells being confirmed by electron microscopy. During the five years that the pulmonary vascular pathology progressed to the formation of plexiform lesions there was an increase in the number of bronchiolar endocrine cells that were immunoreactive to bombesin and calcitonin. This study demonstrates that the classic pathogenesis of primary plexogenic pulmonary arteriopathy originates years earlier as a migration of cells of muscular pedigree from the media into the intima of the pulmonary arteries and arterioles.,Background: Proinflammatory leukotrienes, which are not completely inhibited by inhaled corticosteroids, may contribute to asthmatic problems. A 16 week multicentre, randomised, double blind, controlled study was undertaken to study the efficacy of adding oral montelukast, a leukotriene receptor antagonist, to a constant dose of inhaled budesonide. Methods: A total of 639 patients aged 18–70 years with forced expiratory volume in 1 second (FEV1) ≥55% predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were randomised to receive montelukast 10 mg (n=326) or placebo (n=313) once daily for 16 weeks. All patients received a constant dose of budesonide (400–1600 μg/day) by Turbuhaler throughout the study. Results: Mean FEV1 at baseline was 81% predicted. The median percentage of asthma exacerbation days was 35% lower (3.1% v 4.8%; p=0.03) and the median percentage of asthma free days was 56% higher (66.1% v 42.3%; p=0.001) in the montelukast group than in the placebo group. Patients receiving concomitant treatment with montelukast had significantly (p<0.05) fewer nocturnal awakenings and significantly (p<0.05) greater improvements in β agonist use and morning peak expiratory flow rate (PEFR). Conclusions: For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment, concomitant treatment with montelukast significantly improves asthma control.
The paucity of data on the natural history of primary pulmonary hypertension (PPH), and the observation that some patients awaiting heart-lung transplantation (HLT) appeared to be living longer than expected, led us to analyze the survival data of patients with PPH who had been referred for consideration of HLT. Ninety patients (female: male = 3.6:1) met clinical and hemodynamic criteria for PPH. Age at diagnosis was 29.8 +/- 7.9 years (mean +/- SD) (range 13-48 years). Symptom duration was 65.9 +/- 47.4 months, while survival from diagnosis was 42.9 +/- 42.6 months, giving a mean lead time of 23 months. Mean pulmonary artery pressure (PAP) at diagnosis was 61.6 +/- 15.0 mm Hg. The incidence of patent foramen ovale (PFO) was 19 percent, postpartum onset 16 percent, family history 6 percent, and cirrhosis 3 percent. The survival of 27 patients who died without operation was 50.3 +/- 52.5 months (median 37 months), with a symptom duration of 68.4 +/- 57.5 months (median 64 months). Both a high mean right atrial pressure (RAP) (p less than 0.025) and high mean PAP (p less than 0.025) correlated inversely with survival. For the whole group, none of the variables, age at diagnosis, sex, mean PAP or mean RAP at diagnosis, symptom duration prior to diagnosis or the presence of a PFO, postpartum onset or positive family history, significantly influenced survival. However, a low cardiac output (p less than 0.05) adversely influenced prognosis. The discrepancy between the mean and median length of survival in our group and previous reports confirms the need for further clarification of natural history and for appropriate clinical trials to assess therapeutic endeavors.
The extent of exercise limitation and the mechanisms for that limitation in 11 patients with primary pulmonary hypertension (PPH) were studied by progressive, upright cycle ergometry. All patients had a mean pulmonary artery pressure of 30 mm Hg or higher (mean, 56±15), normal pulmonary function testing, normal pulmonary capillary wedge pressure, and pulmonary angiography consistent with the diagnosis. Rest and exercise data obtained from the patients with PPH were compared with data obtained from 11 matched, sedentary control subjects. Mean maximal oxygen consumption ( ) was 13±4 ml/kg/min in the PPH group compared with 28±7 ml/kg/min in the controls. At maximal the minute ventilation ( ) was similar; however, the at any level of carbon dioxide production ( ) during rest and exercise was significantly higher in the PPH group. Maximal heart rate and oxygen pulse ( /heart rate) was significantly higher in the control group (148±18 vs 180±24, and 6.3±2.2 vs 9.9±3.9, respectively). Anaerobic threshold occurred earlier during progressive exercise in the PPH group and correlated positively with the maximal oxygen pulse achieved in patients with PPH. In conclusion, patients with PPH have severe exertional limitation due to cardiovascular factors with an inability to maintain appropriate oxygen delivery to the body during exercise. No respiratory impairment was recognized; however, an exaggerated ventilatory response to exercise at any level of was found.
During the course of a case of primary pulmonary hypertension occurring in a 24 year old man lung tissue became available at heart-lung transplantation in 1986 and from a lung biopsy carried out in 1981. In 1986 the sections showed classic plexogenic pulmonary arteriopathy. In 1981 they revealed migration of myofibroblasts into the intima and lumen of pulmonary arteries and arterioles, the identification of the cells being confirmed by electron microscopy. During the five years that the pulmonary vascular pathology progressed to the formation of plexiform lesions there was an increase in the number of bronchiolar endocrine cells that were immunoreactive to bombesin and calcitonin. This study demonstrates that the classic pathogenesis of primary plexogenic pulmonary arteriopathy originates years earlier as a migration of cells of muscular pedigree from the media into the intima of the pulmonary arteries and arterioles.
Thromboxane synthetase inhibitors have been shown to reduce thromboxane, a potent vasoconstrictor, and increase prostacyclin, a potent vasodilator, in normal subjects. We evaluated the acute and chronic (three months) effects of the thromboxane synthetase inhibitor CGS13080 administered 200 mg every six hours on the resting hemodynamics in ten patients with primary pulmonary hypertension (PPH), and on their response to 20 mg of nifedipine given sublingually before and after the thromboxane synthetase inhibitor treatment. It was concluded that one can modulate the levels of endogenous thromboxane and prostacyclin in patients with primary pulmonary hypertension using a thromboxane synthetase inhibitor. Although the thromboxane synthetase inhibitor alone produced only modest hemodynamic changes over time, the addition of nifedipine was able to produce a further lowering of pulmonary artery pressure and pulmonary vascular resistance.