Activated STING in a vascular and pulmonary syndrome.

BACKGROUND: The study of autoinflammatory diseases has uncovered mechanisms underlying cytokine dysregulation and inflammation. METHODS: We analyzed the DNA of an index patient with early-onset systemic inflammation, cutaneous vasculopathy, and pulmonary inflammation. We sequenced a candidate gene, TMEM173, encoding the stimulator of interferon genes (STING), in this patient and in five unrelated children with similar clinical phenotypes. Four children were evaluated clinically and immunologically. With the STING ligand cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), we stimulated peripheral-blood mononuclear cells and fibroblasts from patients and controls, as well as commercially obtained endothelial cells, and then assayed transcription of IFNB1, the gene encoding interferon-ß, in the stimulated cells. We analyzed IFNB1 reporter levels in HEK293T cells cotransfected with mutant or nonmutant STING constructs. Mutant STING leads to increased phosphorylation of signal transducer and activator of transcription 1 (STAT1), so we tested the effect of Janus kinase (JAK) inhibitors on STAT1 phosphorylation in lymphocytes from the affected children and controls. RESULTS: We identified three mutations in exon 5 of TMEM173 in the six patients. Elevated transcription of IFNB1 and other gene targets of STING in peripheral-blood mononuclear cells from the patients indicated constitutive activation of the pathway that cannot be further up-regulated with stimulation. On stimulation with cGAMP, fibroblasts from the patients showed increased transcription of IFNB1 but not of the genes encoding interleukin-1 (IL1), interleukin-6 (IL6), or tumor necrosis factor (TNF). HEK293T cells transfected with mutant constructs show elevated IFNB1 reporter levels. STING is expressed in endothelial cells, and exposure of these cells to cGAMP resulted in endothelial activation and apoptosis. Constitutive up-regulation of phosphorylated STAT1 in patients' lymphocytes was reduced by JAK inhibitors. CONCLUSIONS: STING-associated vasculopathy with onset in infancy (SAVI) is an autoinflammatory disease caused by gain-of-function mutations in TMEM173. (Funded by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases; ClinicalTrials.gov number, NCT00059748.).

Ventricular pacemaker upgrade: experience, complications and recommendations.

OBJECTIVE: To assess outcomes of pacemaker upgrade from single chamber ventricular to dual chamber. DESIGN: Retrospective analysis of patients undergoing the procedure. SETTING: Specialist cardiothoracic unit. PATIENTS: 44 patients (15 female, 29 male), mean (SD) age at upgrade 68.2 (12.9) years. INTERVENTIONS: Upgrade of single chamber ventricular to dual chamber pacemaker. MAIN OUTCOME MEASURES: Procedure duration and complications. RESULTS: Principal indications for upgrade were pacemaker syndrome (17), "opportunistic"--that is, at elective generator replacement (8), heart failure (7), non-specific breathlessness/fatigue (7), and neurally mediated syncope (3). Mean (SD) upgrade procedure duration (82.9 (32.6) minutes) significantly exceeded mean VVI implantation duration (42.9 (13.3) minutes) and mean DDD implantation duration (56.6 (22.7) minutes) (both p < 0.01). Complications included pneumothorax (1), ventricular arrhythmia requiring cardioversion (2), protracted procedure (10), atrial lead repositioning within six weeks (8), haematoma evacuation (1), superficial infection (1), and admission to hospital with chest pain (1); 20 patients (45%) suffered one or more complications including four of the eight who underwent opportunistic upgrade. CONCLUSIONS: Pacemaker upgrade takes longer and has a higher complication rate than either single or dual chamber pacemaker implantation. This suggests that the procedure should be performed by an experienced operator, and should be undertaken only if a firm indication exists. Patients with atrial activity should not be offered single chamber ventricular systems in the belief that the unit can be upgraded later if necessary at minimal risk.

Late complications following permanent pacemaker implantation or elective unit replacement.

OBJECTIVE: To determine the rate of late complications following first implantation or elective unit replacement of a permanent pacemaker system. DESIGN: Analysis of pacemaker data and complications prospectively acquired on a computerised database. Complications were studied over an 11 year period from January 1984 to December 1994. SETTING: Tertiary referral cardiothoracic centre. PATIENTS: Records of 2621 patients were analysed retrospectively. MAIN OUTCOME MEASURES: Complications requiring repeat procedures occurring more than six weeks after pacemaker implantation or elective unit replacement. RESULTS: The overall rate of late complications was significantly lower after first implantation of a permanent pacemaker (34 cases, complication rate 1.4%, 95% confidence interval 0.9% to 1.9%) than after elective unit replacement (16 cases, complication rate 6.5% (3.3% to 9.7%). There were 20 cases of erosion, 18 infections, five electrode problems, and seven miscellaneous problems. Complications were more common with inexperienced operators (18.9% (6.0% to 31.8%)) than with experienced operators (0.9% (0.3% to 1.5%). CONCLUSIONS: The incidence of late complications following pacemaker implantation is low and compares favourably with early complication rates. The majority are caused by erosion and infection. Patients who have undergone elective unit replacement are at particular risk.

Complete hepatic venous isolation and extracorporeal chemofiltration as treatment for human hepatocellular carcinoma: a phase I study.

BACKGROUND: We performed a phase I study of a novel system of complete hepatic venous isolation and extracorporeal chemofiltration in patients with unresectable hepatocellular carcinoma (HCC) to determine (a) whether systemic exposure to doxorubicin could be limited after high-dose hepatic arterial infusion (HAI), and (b) the hepatic maximum tolerated dose (MTD) of doxorubicin. METHODS: Ten patients with biopsy-proven HCC were treated with 20-min HAI of doxorubicin (17 total treatments). Two patients were treated with doxorubicin 60 mg/m2, three patients were treated at 90 mg/m2, and five patients received 120 mg/m2. A newly developed dual-balloon vena cava catheter was advanced from the femoral vein, and the balloons were inflated to isolate and capture total hepatic venous outflow. The hepatic venous blood was pumped through extracorporeal carbon chemofilters before return of the blood to the systemic circulation. RESULTS: Peak systemic doxorubicin levels were an average 85.6% lower than were peak prefilter levels (p < 0.01). Because all catheters were placed percutaneously and because the chemofiltration markedly limited systemic chemotherapy exposure, patients were discharged 1 day after 16 of the 17 treatments. The hepatic and systemic MTD of doxorubicin in this treatment protocol was 120 mg/m2. CONCLUSIONS: This novel system of complete hepatic venous isolation and chemofiltration limits systemic chemotherapy toxicity and will allow use of higher doses of chemotherapeutic agents to treat HCC.

Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration.

We evaluated a novel system of complete hepatic venous isolation and chemofiltration (CHVI-CF) to reduce systemic drug exposure following regional hepatic infusion of doxorubicin. Rabbits bearing hepatic VX-2 tumors were given doxorubicin via either hepatic arterial infusion (HAI) or portal venous infusion (PVI). A dual-balloon vena cava catheter and extracorporeal chemofilter were used to capture and filter hepatic venous blood in experimental animals. Control animals received chemotherapy without hepatic venous isolation and chemofiltration. Following a 5-min HAI of doxorubicin (3 or 5 mg/kg), control and experimental animals had similar doxorubicin levels in their livers and VX-2 tumors, but experimental animals showed a significant reduction in doxorubicin levels in systemic plasma, heart, and kidney tissue as compared with control animals (P < 0.01). HAI produced a 4-fold increase in doxorubicin levels in VX-2 tumors as compared with the drug levels obtained using PVI (P < 0.01). A single HAI of 3 mg/kg doxorubicin in animals treated with CHVI-CF produced marked tumor necrosis at 7 and 14 days after treatment. By increasing the total body clearance of doxorubicin, this system will allow HAI of higher doses of drug in attempts to improve the antitumor response.

Hemodynamic evaluation of the Monostrut and spherical disc Björk-Shiley aortic valve prosthesis with Doppler echocardiography.

A Doppler echocardiographic study was performed to assess whether the Monostrut model of the Björk-Shiley valve (Shiley, Inc., Irvine, Calif.) had an improved hemodynamic performance in comparison with the spherical disc model in the aortic position. Twenty retrospectively randomly selected patients were studied, 10 with each valve type. Within each valve type two sizes of valve were studied, 21 and 23 mm. The two groups were comparable with respect to age, postoperative time, fractional shortening, New York Heart Association functional class preoperatively, and body surface area. Pulsed and continuous wave Doppler measurements were recorded at rest. Continuous wave Doppler recordings were performed every 2 minutes after exercise with supine bicycle ergometry until 10 minutes after exercise. Peak and mean gradients across the aortic valve prostheses were estimated. Both groups achieved a significant and comparable rise in heart rate with exercise. The mean gradients +/- standard error of the mean at rest and 2 minutes after exercise were 19.7 +/- 1.9 mm Hg and 30.9 +/- 2.2 mm Hg, respectively in the spherical disc group compared with 14.9 +/- 1.1 mm Hg and 23.6 +/- 1.7 mm Hg in the Monostrut group (p < 0.05 and p < 0.025, respectively). Peak transvalvular gradient at rest was 30.7 +/- 2.7 mm Hg in the spherical group compared with 23.9 +/- 1.9 mm Hg in the Monostrut group (p < 0.05). We conclude that the Monostrut Björk-Shiley valve prosthesis has better hemodynamic performance than the spherical disc model in the aortic position.

Improved selection of patients for aneurysmectomy by combined phase and amplitude analysis of gated cardiac scintigraphy.

Twelve patients undergoing left ventricular aneurysmectomy were studied by combined phase and amplitude analysis of gated blood pool scintigraphy before and after operation, to establish whether the presence of paradoxical systolic movement, as defined by this method, influenced the result of surgical treatment. There was a significant increase in the ejection fraction after operation in those patients with paradoxical systolic movement and no improvement in those with akinesis. The extent of the increase in ejection fraction was related to the size of paradoxical segment resected. It is argued that this improvement in left ventricular function reflects a reduction in the left ventricular and diastolic volume and improved efficiency of ejection of the stroke volume, resulting from resection of the scar. Combined phase and amplitude analysis may help in selecting patients most likely to benefit from aneurysmectomy.

Arrhythmias after coronary bypass surgery.

Ninety patients undergoing coronary bypass surgery were studied prospectively by bedside and subsequent ambulatory electrocardiographic monitoring to investigate the incidence, possible causes, and prevention of atrial fibrillation. Patients with good left ventricular function were divided randomly into a control group or groups treated with digoxin or propranolol. In the control group the incidence of atrial fibrillation was 27% and of significant ventricular extrasystoles 3%. Propranolol reduced the incidence of atrial fibrillation (14.8%), whereas digoxin had no effect and increased the incidence of ventricular extrasystoles. Age, sex, severity of symptoms, cardiomegaly, heart failure, previous myocardial infarction, and number of grafts did not affect the result. The operative myocardial ischaemic time was related to the occurrence of atrial fibrillation. There was also a significant relation between atrial fibrillation and bundle branch block. Atrial fibrillation is common after coronary artery grafting; it may be due to diffuse myocardial ischaemia or hypothermic injury. The incidence may be reduced by beta blockade.

Patient noncompliance with postvasectomy semen examination protocol.

This study determined the degree of patient compliance with postvasectomy semen examination protocol for verbal instructions as compared with verbal augmented by written instructions. The addition of written instructions did not improve patient compliance, and for a significant majority of patients (68 to 76 percent) there was no laboratory verification of the effectiveness of the vasectomy procedure. Results of the study raise serious concerns about physician reliance on patient compliance for postvasectomy semen examination protocol as assurance of successful vasectomy. When the potential for fertility among vasectomized men is uncertain, the complication of an unwanted pregnancy will fall on the woman. Educating physicians in the problems and strategies for gaining patient compliance is as essential as education in competent surgical technique.

X-linked ocular albinism. An oculocutaneous macromelanosomal disorder.

Three unrelated kindreds with the Nettleship-Falls type of X-linked ocular albinism were studied. Postmortem examination of the eyes of an affected man revealed the presence of macromelanosomes in the pigment epithelia. Skin biopsy specimens of this patient, seven other affected male, and nine carrier female kindred members revealed the presence of Fontana-positive and dopa oxidase-positive macromelanosomes within the epidermis and dermis. Although clinically this disorder has been considered to be a form of albinism confined to the eyes, these findings indicate that an unusual disturbance in melanosome production characterized by macromelanosome formation affects the skin and the eyes. Histopathologic study of the skin is a useful adjunct in the diagnosis of X-linked ocular albinism, both in the affected and the carrier states. Linkage studies confirmed the close association of the Xg blood group with this disorder.

Ultrastructure of keratoconus with healed hydrops.

The corneas of three patients with keratoconus were examined by light and electron microscopy within approximately four months after onset of severe hydrops. The rupture and detachment of Descemet's membrane resulted in formation of extensive ledges. New endothelium completely resurfaced the exposed posterior stroma and the corresponding anterior aspect of the ledges. The endothelium also regenerated considerable basement membrane. In one case, clustered endothelium near the free end of the ledge appeared to have undergone fibrous metaplasia with secretion of extensive fibrillar and basement membrane material.

Congenital central corneal leukoma (Peters' anomaly).

Corneal buttons from three patients with congenital central corneal leukoma (Peters' anomaly) were examined by light and electron microscopy. All cases exhibited a central absence of Bowman's membrane and iris synechiae to the periphery of the leukoma. In the first patient, extensive keratolenticular adhesion with retrocorneal fibrous tissue filling the central defect of endothelium and Descemet's membrane implicated late anterior displacement of the normally developed lens as the cause of secondary endothelial degeneration. In the second patient, attenuated endothelium and abnormally composed Descemet's membrane indicated primary dysgenesis of the endothelium. In the third patient, the extensive defect of posterior stroma with anterior stromal disorganization and endothelial metaplasia suggested dysgenesis of both the keratocytic and endothelial mesoderm. Thus, although no unified pathogenic mechanism was consistently applicable, either primary or secondary dysgenesis of the corneal mesoderm must be responsible.