Transpleural systemic artery-to-pulmonary artery communications in the absence of chronic inflammatory lung disease. A case series and review of the literature.

AIM: To describe the causes and computed tomography (CT) and angiographic appearances of transpleural systemic artery-to-pulmonary artery shunts in patients without chronic inflammatory lung disease and determine their best management. MATERIALS AND METHODS: All patients referred to a tertiary referral unit between January 2009 and January 2020 in whom a diagnosis of a systemic-to-pulmonary artery communication without underlying chronic inflammatory lung disease was subsequently made have been included in this report. Medical records and imaging findings were reviewed retrospectively. RESULTS: Ten patients (male: female ratio = 7:3; median age 42 years [range 22-70 years]) with systemic artery-to-pulmonary artery shunts without chronic inflammatory lung disease were identified. Five were misdiagnosed as having a pulmonary arteriovenous malformation and had been referred for embolisation. In six patients, there was either a history of accidental or iatrogenic thoracic trauma or of inflammatory disease involving the pleura, and in two patients, in whom a previous medical history could not be obtained, there were CT features suggesting previous pleural inflammatory disease. Two shunts were thought to be congenital. All individuals were asymptomatic other than one with localised thoracic discomfort that dated from the time of surgery. All patients were managed conservatively and have remained well with a median follow-up of 4.5 years (range 1-11.3 years). CONCLUSIONS: Localised transpleural systemic artery-to-pulmonary artery shunts in the absence of chronic inflammatory lung disease are usually related to previous thoracic trauma/intervention or abdominal or pulmonary sepsis involving a pleural or diaphragmatic surface. Congenital shunts are rare. The present study and much of the literature supports conservative management.

Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy.

BACKGROUND: Hypertrophic scarring carries a large burden of disease, including disfigurement, pain and disability. There is currently no effective medical treatment to reduce or prevent hypertrophic scarring. Flightless I (Flii), a member of the gelsolin family of actin remodelling proteins, is an important negative regulator of wound repair. OBJECTIVES: The objective of this study was to investigate the role of Flii as a potential regulator of hypertrophic scarring. METHODS: Using human skin samples and an animal model of bleomycin-induced hypertrophic scarring in mice that overexpress or have reduced expression of Flii, we investigated its effect on dermal fibrosis and hypertrophic scarring. RESULTS: Flii expression was increased in human burns and hypertrophic scars. A similar increase in Flii was observed in hypertrophic scars formed in mice post-treatment with bleomycin. However, Flii-deficient (Flii(+/-) ) mice had reduced scarring in response to bleomycin evidenced by decreased dermal thickness, smaller cross-sectional scar areas, fewer myofibroblasts and a decreased collagen I/III ratio. In contrast, bleomycin-treated Flii-overexpressing mice (Flii(Tg/Tg) ) showed increased scar dermal thickness, larger cross-sectional scar areas, more myofibroblasts and an increased collagen I/III ratio. Injecting developing scars with a Flii neutralizing antibody led to a significant reduction in the size of the scars and a reduction in the collagen I/III ratio. CONCLUSIONS: This study identifies Flii as a profibrotic agent that contributes to excessive scar formation. Reducing its activity using neutralizing antibodies is a promising approach for reducing hypertrophic scarring.

Pulmonary arteriovenous malformations and their mimics.

Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between the pulmonary arteries and veins, which result in a right-to-left (R-L) shunt with resultant hypoxemia, the severity of which will depend upon the size and number of lesions. Most PAVMs occur in individuals with hereditary haemorrhagic telangiectasia (HHT) and are a cause of serious morbidity and mortality largely related to cerebrovascular complications secondary to paradoxical embolization. The importance of their recognition and treatment by embolization, even in the absence of symptoms, is well known. Their appearances on chest radiographs are often, but not always, characteristic and the CT appearances are diagnostic; however, there are a number of both vascular and non-vascular diseases that can cause confusion. This review serves to highlight these PAVM "mimics".

Optimizing the outcome of vascular intervention for Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA) predisposes to the development of arterial stenoses and aneurysms, and is associated with considerable morbidity and mortality amongst young patients. The aims of this study were to analyse indications and outcomes of surgical intervention, and to assess the potential benefits of immunosuppression and the use of perioperative imaging. METHODS: This was a retrospective review of patients with TA referred between 2001 and 2012. RESULTS: A series of 97 patients with TA, seen at a single tertiary centre, is reported. Immunosuppression was required in 87 patients (90 per cent). Thirty-seven (38 per cent) underwent 64 procedures: 27 patients underwent 33 open surgical procedures and 20 patients had 31 endovascular procedures. After a median follow-up of 6 years, the overall success rate was 79 per cent for open surgery (mean graft patency 9.4 years) and 52 per cent for endovascular procedures (P = 0.035). Procedural failure was significantly reduced in patients receiving preoperative immunosuppression, and particularly endovascular procedures (P = 0.001). In addition to clinical examination and measurement of acute-phase reactants, combination non-invasive imaging including Doppler ultrasonography, [18F]fluorodeoxyglucose combined positron emission and computed tomography (CT), magnetic resonance angiography and CT angiography was used to identify arterial lesions, establish the diagnosis and monitor treatment outcomes. CONCLUSION: Outcomes of vascular intervention in TA may be improved by detailed preoperative assessment including measurement of disease activity, and by ensuring optimal immunomodulatory therapy before and after the procedure.

Laparoscopic management of insulinomas.

BACKGROUND: Conventional surgical management of insulinomas involves an open technique. The laparoscopic approach has advantages in terms of improved postoperative pain and recovery time. This retrospective study evaluated the laparoscopic management of pancreatic insulinomas. METHODS: Between December 2000 and March 2007, 23 patients were referred for consideration of laparoscopic insulinoma resection. Two patients were not deemed appropriate for the laparoscopic approach and were managed with open surgery. All surgery was performed by one experienced pancreatic surgeon. Laparoscopic intraoperative ultrasonography was not available for the first six procedures, but was used thereafter. RESULTS: Twenty-one patients (five men and 16 women, median age 46 (range 22-70) years) had a successful resection. All had single tumours, five in the head, nine in the body and seven in the tail of the pancreas. One conversion to open operation was performed in a patient with an insulinoma in the head of the pancreas who had dense adhesions resulting from pancreatitis. Three patients developed a postoperative pancreatic fistula. There has been no recurrence of symptoms in any patient. CONCLUSION: Laparoscopic management of insulinomas is feasible and safe. Laparoscopic intraoperative ultrasonography is a promising adjunct to the procedure, even after accurate preoperative localization.

Exercise capacity reflects airflow limitation rather than hypoxaemia in patients with pulmonary arteriovenous malformations.

BACKGROUND: Pulmonary arteriovenous malformations (PAVMs) generate a right-to-left shunt. Impaired gas exchange results in hypoxaemia and impaired CO2 clearance. Most patients compensate effectively but some are dyspneic, and these are rarely the most hypoxaemic. AIM: To test degrees of concurrent pathology influencing exercise capacity. DESIGN: Replicate, sequential single centre, prospective studies. METHODS: Cardiopulmonary exercise tests (CPETs) were performed in 26 patients with PAVMs, including individuals with and without known airflow obstruction. To replicate, relationships were tested prospectively in an independent cohort where self-reported exercise capacity evaluated by the Veterans Specific Activity Questionnaire (VSAQ) was used to calculate metabolic equivalents (METs) at peak exercise (n = 71). Additional measurements included oxygen saturation (SpO2), forced expiratory volume in 1 s (FEV1), vital capacity (VC), fractional exhaled nitric oxide (FeNO), haemoglobin and iron indices. RESULTS: By CPET, the peak work rate was only minimally associated with low SpO2 or low arterial oxygen content (calculated as CaO2=1.34 × SpO2 × haemoglobin), but was reduced in patients with low FEV1 or VC. Supranormal work rates were seen in patients with severe right-to-left shunting and SpO2 < 90%, but only if FEV1 was >80% predicted. VSAQ-calculated METS also demonstrated little relationship with SpO2, and in crude and CaO2-adjusted regression, were lower in patients with lower FEV1 or VC. Bronchodilation increased airflow even where spirometry was in the normal range: exhaled nitric oxide measurements were normal in 80% of cases, and unrelated to any PAVM-specific variable. CONCLUSIONS: Exercise capacity is reduced by relatively mild airflow limitation (obstructive or restrictive) in the setting of PAVMs.

Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia.

BACKGROUND: Brain abscesses and ischaemic strokes complicate pulmonary arteriovenous malformations (PAVMs). At risk individuals are poorly recognised. Stroke/abscess risk factors have not been defined. METHODS: A cohort study of 323 consecutive individuals with PAVMs (n = 219) and/or the commonly associated condition hereditary haemorrhagic telangiectasia (HHT, n = 305) was performed. Most of the 201 individuals with PAVMs and HHT had no respiratory symptoms, and were unaware they had HHT. Anderson-Gill models assessed constant and time dependent potential predictive variables for stroke/abscess, and rate reduction by PAVM embolisation. RESULTS: 57 individuals with PAVMs and HHT experienced brain abscess or ischaemic stroke, usually prior to the diagnosis of underlying PAVMs/HHT. The primary determinants of stroke and abscess risks were unrelated to severity of PAVMs. Males had higher brain abscess rates (hazard ratio 3.61 (95% CI 1.58, 8.25), p = 0.0024); interventional histories and bacteriological isolates suggested dental sources. Once adjusted for gender, there was a marginal association between brain abscess and low oxygen saturation. For ischaemic stroke, there was no association with any marker of PAVM severity, or with conventional neurovascular risk factors. Surprisingly, low mean pulmonary artery pressure was strongly associated with ischaemic stroke (hazard ratio 0.89 (95% CI 0.83, 0.95) per mm Hg increase; p = 6.2x10(-5)). PAVM embolisation significantly reduced ischaemic stroke rate (p = 0.028); no strokes/abscesses occurred following obliteration of all angiographically visible PAVMs. The mean PAVM diagnosis-treatment interval was longer, however, when neurological risks were unrecognised. CONCLUSIONS: Ischaemic strokes and brain abscesses occur commonly in undiagnosed HHT patients with PAVMs. Risk reduction could be improved.

Embolisation of pulmonary arteriovenous malformations: no consistent effect on pulmonary artery pressure.

Increasing evidence supports the use of embolisation to treat pulmonary arteriovenous malformations (AVMs). Most pulmonary AVM patients have hereditary haemorrhagic telangiectasia (HHT), a condition that may be associated with pulmonary hypertension. The current authors tested whether pulmonary AVM embolisation increases pulmonary artery pressure (P(pa)) in patients without baseline severe pulmonary hypertension. P(pa) was measured at the time of pulmonary AVM embolisation in 143 individuals, 131 (92%) of whom had underlying HHT. Angiography/embolisation was not performed in four individuals with severe pulmonary hypertension, whose systemic arterial oxygen saturation exceeded levels usually associated with dyspnoea in pulmonary AVM patients. In 143 patients undergoing pulmonary AVM embolisation, P(pa) was significantly correlated with age, with the most significant increase occurring in the upper quartile (aged >58 yrs). In 43 patients with repeated measurements, there was no significant increase in P(pa) as a result of embolisation. In half, embolisation led to a fall in P(pa). The maximum rise in mean P(pa) was 8 mmHg: balloon test occlusion was performed in one of these individuals, and did not predict the subsequent rise in P(pa) following definitive embolisation of the pulmonary AVMs. In the present series of patients, which excluded those with severe pulmonary hypertension, pulmonary artery pressure was not increased significantly by pulmonary arteriovenous malformation embolisation.

Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services.

OBJECTIVES: Hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 individuals. Pregnancy outcomes are rarely reported. The major reason is that most women do not have their HHT diagnosed prior to pregnancy. Using a large well-characterised series, we studied all pregnancies known to have occurred in HHT-affected women, whether or not their diagnosis was known at the time of pregnancy. Our aim was to estimate rates and types of major complications of HHT in pregnancy, to guide management decisions. DESIGN: Cohort study, with prospective, retrospective and familial components. SETTING/POPULATION: Tertiary referral centre population. METHODS: All 262 pregnancies in the 111 women with HHT and pulmonary arteriovenous malformations (PAVMs) reviewed between 1999 and 2005 were studied. Eighty-two women (74%) did not have a diagnosis of HHT/PAVM at the time of pregnancy. 222 pregnancies in their 86 HHT-affected relatives were also studied. MAIN OUTCOME MEASURES: PAVM bleed, stroke and maternal death. RESULTS: Thirteen women experienced life-threatening events during pregnancy: 1.0% (95% CI 0.1-1.9) of pregnancies resulted in a major PAVM bleed; 1.2% (0.3-2.2%) in stroke (not all were HHT related); and 1.0% (0.13-1.9%) in maternal death. All deaths occurred in women previously considered well. In women experiencing a life-threatening event, prior awareness of HHT or PAVM diagnosis was associated with improved survival (P = 0.041, Fisher's exact test). CONCLUSIONS: Most HHT pregnancies proceed normally. Rare major complications, and improved survival outcome following prior recognition, means that pregnancy in a woman with HHT should be considered high risk. Recommendations for pregnancy management are provided.

Mid-trimester dilation and evacuation with laminaria does not increase the risk for severe subsequent pregnancy complications.

OBJECTIVE: To evaluate subsequent pregnancy outcomes in women with a previous mid-trimester (12-24 weeks) pregnancy termination by dilation and evacuation (D&E) as compared to women without a previous D&E. METHOD: Medical records for women who underwent a D&E between 1995 and 2003 were identified and reviewed. Women with subsequent pregnancies were compared on a 1:2 basis with women in a control group who had viable pregnancies and no previous mid-trimester DE. Outcomes of interest included preterm labor, placental abnormalities, and a composite complication outcome. RESULTS: Of the 317 women who underwent a D&E, 85 had viable subsequent pregnancies. These women delivered slightly earlier than the 170 controls (38.9 versus 39.5 weeks, p=0.001), although there was no statistically significant difference between the two groups with regard to birth weights, spontaneous preterm delivery, abnormal placentation, and overall complication rate. CONCLUSIONS: Mid-trimester termination by D&E does not increase the rate of clinically significant subsequent pregnancy complications.

An antigen immunologically related to the external domain of gp185 is shed from nude mouse tumors overexpressing the c-erbB-2 (HER-2/neu) oncogene.

An antigen, immunologically related to the external domain of the c-erbB-2 (HER-2/neu) protein, was found shed into the serum of nude mice bearing tumors that overexpress the c-erbB-2 protein (gp185). Utilizing paired combinations from a panel of monoclonal antibodies (TAbs 250-265), with specificity for extracellular epitopes of gp185, an immunoradiometric assay was developed to quantitate this shed antigen. The immunoradiometric assay detected membrane-bound and soluble gp185 as well as a soluble derivative corresponding in sequence to the extracellular domain of gp185 (designated gp75). This recombinantly expressed gp75 was immunoaffinity purified and used to generate a standard curve from which serum samples were quantitated. Increases in antigen levels measured in the sera of tumor-bearing nude mice correlated with both overexpression of the c-erbB-2 protein and increased tumor volume. Positive sera were obtained from mice given implants of NIH3T3 cells transfected with c-erbB-2 complementary DNA (NIH3T3t), or ovarian (SK-OV-3) or breast (MDA-MB-361) tumor cell lines overexpressing the c-erbB-2 protein. In mice bearing NIH3T3t tumors, increases in tumor volume from 80 to 9000 mm3 resulted in levels of shed antigen from 8 to greater than 1000 ng/ml gp75 equivalents. Sera from mice with c-erbB-2-negative tumors or tumors overexpressing the epidermal growth factor receptor were negative in the assay. This assay, and the quantitation of shed antigen levels, may have diagnostic or monitoring utility in cancers, such as breast and ovarian, in which the c-erbB-2 protein is overexpressed.

Patterns of disease in patients at a tertiary referral centre requiring reoperative parathyroidectomy.

INTRODUCTION: Reoperative parathyroidectomy is required when there is persistent or recurrent hyperparathyroidism following the initial surgery (at least 5% of parathyroidectomies nationally). By convention, 'persistent disease' is defined as the situation where the patient has not been cured by the first operation. The term 'recurrent hyperparathyroidism' is used when the patient was confirmed to be biochemically cured for six months from the first operation but has hyperparathyroidism after this date. Reoperative surgery is associated with higher rates of postoperative complications as well as a greater rate of failure to cure. The aim of our study was to review our departmental experience of reoperative parathyroidectomy, with a view to identify patterns of disease persistence and recurrence. METHODS: Using a departmental database, patients were identified who had undergone reoperative parathyroidectomy between 2006 and 2014. All the pre, intra and postoperative information was documented including the operative note so as to record the location of the abnormal parathyroid gland found at reoperation. RESULTS: Almost two-thirds (63%) of patients had negative, equivocal or discordant conventional imaging so secondary investigative tools were required frequently. The majority of abnormal glands were found in eutopic locations. The most common locations for ectopic glands were intrathyroidal, mediastinal and intrathymic. A third (33%) of the patients had multigland disease and over a quarter (28%) had coexisting thyroid disease. CONCLUSIONS: Persistent hyperparathyroidism represents a challenging patient subgroup for which access to all radiological modalities and intraoperative parathyroid hormone monitoring are required. Patient selection for reintervention is a key determinant in the reoperation cure rate.

Localization of insulinomas by selective intraarterial calcium injection.

This study examines the role of selective intraarterial calcium injection and hepatic venous sampling in the localization of insulinomas. Seven patients were studied. In all cases, ultrasound and computerized tomography scans were either negative or equivocal. Calcium gluconate was injected directly into the arteries supplying the pancreas after standard selective angiography. Insulin levels were measured in samples taken from the right hepatic vein before and 30, 60, 90, 120, and 180 s after each injection. Two doses were used, 0.025 milliequivalents Ca/kg (1 mg/kg) for the first two subjects and 0.00625 milliequivalents Ca/kg (0.25 mg/kg) for the remaining five subjects. Serum insulin levels rose at least 2-fold, the proposed diagnostic rise, from basal in six subjects; one test was negative. Of the six positive studies, a diagnostic rise was seen only in one artery in five cases. One patient did not undergo surgery. In the remaining five patients, surgery confirmed the position and histology of the tumor. The one patient with a diagnostic rise in more than one artery, however, had residual disease after surgery. The seventh subject referred specifically for localization had a negative calcium stimulation study and a subsequent diagnosis of intermittent sulfonylurea abuse was made after a positive screen. The present study shows that preoperatively, selective intraarterial calcium injection with hepatic venous sampling is a powerful technique for the localization of insulinomas. Smaller doses of calcium than previously reported can be used and may reduce the risk of hypoglycemia during the procedure.

Effects of histamine-2 receptor blockade on lidocaine kinetics.

The hypothesis that the H2-receptor blockers cimetidine and ranitidine have different effects on the disposition of lidocaine, a microsomally metabolized drug dependent on hepatic blood flow for elimination, was tested. Six normal men received lidocaine infusions (2 mg/kg over 10 minutes) and lidocaine levels were determined by HPLC. Lidocaine kinetics were studied in the untreated state (O) and in a double-blind, double-dummy design after 2 days of placebo (P), cimetidine (C, 300 mg every 6 hours by mouth), or ranitidine (R, 160 mg every 12 hours by mouth). Model-independent kinetics were estimated by the statistical moment theory. The steady-state volume of distribution was lower after cimetidine (means +/- SD: O, 156 +/- 39 L; P, 156 +/- 48 L; C, 123 +/- 20 L; and R, 174 +/- 38 L). A trend toward decreased lidocaine clearance after cimetidine was also noted (O, 1011 +/- 140 ml/min; P, 1087 +/- 227 ml/min; C, 886 +/- 214 ml/min; and R, 1143 +/- 225 ml/min). Elimination rate constants were of the same order in all four treatments. Only higher levels of alpha 1-acid glycoprotein appeared to limit the lidocaine steady-state volume of distribution. Cimetidine and ranitidine have distinctly different effects on lidocaine kinetics in normal subjects. The absence of ranitidine effects on the disposition of lidocaine, a high-extraction, high-clearance drug, suggests that H2-receptor blockade may not decrease hepatic blood flow, and that cimetidine impairs drug elimination only by inhibition of hepatic microsomal enzymes. Such interactions are not likely to occur with ranitidine.

A banded topography in the developing rat's olfactory epithelial surface.

In situ hybridization studies from various laboratories have shown that the rat's olfactory epithelium has four distinct regions in which most putative odor receptors are located. To determine whether morphological features accompany this biochemical patterning, olfactory epithelial surfaces of rat nasal endoturbinates and septa were examined with scanning electron microscopy, placing particular emphasis on endoturbinate IIb. There was some morphological patterning at embryonic day 15 (E15), but distinct regions were not yet discernible. Regionalization became distinct at E16 and E18. Posterior regions (Regions 1 and 2) had much higher receptor cell knob densities than more anterior regions closer to the respiratory epithelium (Regions 3 and 4). Supporting cell microvilli were longer in Region 1 than in Region 2. Apices of cells surrounding the receptor cells were flatter in Regions 1 and 2 than in Regions 3 and, especially, Region 4. In Regions 1-3, these surrounding cells were made up mainly of supporting cells; in Region 4 they included respiratory cells. Regions 3 and 4 also had glandular openings and scattered microvillous cells that resemble hair cells of the ear. Older fetuses and adults showed similar evidence of patterning, but detailed examination was precluded by the increased length and entanglement of receptor cell cilia and supporting cell microvilli. In conclusion, a distinct topographic pattern, involving both receptor and surrounding cells, emerges during development of the rat olfactory epithelial surface. Location of the bands roughly matches the zones seen by in situ hybridization.

Passive transfer experiments in amyotrophic lateral sclerosis.

To test the hypothesis that a serum factor might play a role in the pathogenesis of amyotrophic lateral sclerosis, whole plasma obtained by plasmapheresis from patients with the disease was injected daily intraperitoneally into mice for periods of up to three months. Similar experiments were carried out with an isolated immunoglobulin fraction. Control experiments were carried out simultaneously. The animals were tested electrophysiologically, and histologic examinations of the brain, spinal cord, and peripheral nerves were performed. No ill effects were noted in the animals, and no neurophysiologic or microscopic abnormalities were detected.

Clinical criteria for the diagnosis of vascular dementia: a multicenter study of comparability and interrater reliability.

BACKGROUND: Several clinical criteria have been developed to standardize the diagnosis of vascular dementia (VaD). Significant differences in patient classification have been reported, depending on the criteria used. Few studies have examined interrater reliability. OBJECTIVE: To assess the concordance in classification and interrater reliability for the following 4 clinical definitions of VaD: the Hachinski Ischemic Score (HIS), the Alzheimer Disease Diagnostic and Treatment Centers (ADDTC), National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN), and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). METHODS: Structured diagnostic checklists were developed for 4 criteria for VaD, 2 criteria for Alzheimer disease (AD), and 4 criteria for dementia. Twenty-five case vignettes, representing a spectrum of cognitive impairment and subtypes of dementia, were prepared in a standardized clinical format. Concordance in case classification using different criteria and interrater reliability among 7 ADDTCs given a specific set of criteria was assessed using the kappa statistic. RESULTS: The frequency of a diagnosis of VaD was highest using the modified HIS or DSM-IV criteria, intermediate using the original HIS and ADDTC criteria, and lowest using the NINDS-AIREN criteria. Scores for interrater reliability ranged from kappa = 0.30 (ADDTC) to kappa = 0.61 (original HIS). CONCLUSIONS: Clinical criteria for VaD are not interchangeable. Depending on the criteria selected, the reported prevalence of VaD will vary significantly. The traditional HIS has higher interrater reliability than the newer criteria for VaD. Prospective longitudinal studies with clinical-pathological correlation are needed to compare validity.