Central nervous system manifestations of LRBA deficiency: case report of two siblings and literature review.

BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manifestations. As no concise overview of these manifestations is available in literature, we compared our patient's presentation with a reviewed synthesis of the available literature. CASE PRESENTATIONS: The younger brother presented with enteropathy at age 1.5 years, and subsequently developed Evans syndrome and diabetes mellitus. These autoimmune manifestations led to the genetic diagnosis of LRBA deficiency through whole exome sequencing with PID gene panel. At 11 years old, he had two tonic-clonic seizures. Brain MRI showed multiple FLAIR-hyperintense lesions and a T2-hyperintense lesion of the cervical medulla.  His sister presented with immune cytopenia at age 9 years, and developed diffuse lymphadenopathy and interstitial lung disease. Genetic testing confirmed the same mutation as her brother. At age 13 years, a brain MRI showed multiple T2-FLAIR-hyperintense lesions. She received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) 3 months later. Follow-up MRI showed regression of these lesions. CONCLUSIONS: Neurological disease is documented in up to 25% of patients with LRBA deficiency. Manifestations range from cerebral granulomas to acute disseminating encephalomyelitis, but detailed descriptions of neurological and imaging phenotypes are lacking. LRBA deficiency amongst other PIDs should be part of the differential diagnosis in patients with inflammatory brain lesions. We strongly advocate for a more detailed description of CNS manifestations in patients with LRBA deficiency, when possible with MR imaging. This will aid clinical decision concerning both anti-infectious and anti-inflammatory therapy and in considering the indication for allo-HSCT.

Influence of use of a vascular closure device on incidence and surgical management of access site complications after percutaneous interventions.

AIM: The study aimed to evaluate vascular access site complications (ASCs) after percutaneous interventions (PIs) in our institution for changes in annual incidence and surgical management after increased usage of a vascular closure device (VCD; in all cases: Angioseal™). MATERIAL AND METHODS: All patients who underwent repair of arterial pseudo-aneurysms or access site stenosis/occlusion leading to leg ischaemia (LI) or new-onset disabling claudication (CI) after PIs between 2001 and 2008 were included. Annual rates of procedures and methods of repair of ASC were evaluated. RESULTS: After a total of 58 453 PIs, 352 patients (0.6%) were operated on for: pseudo-aneurysms (n = 300; 0.51%); and local stenosis/occlusion leading to LI/CI (n = 52; 0.09%). Numbers increased significantly with more widespread VCD use: group A (2001-2004: 2860 VCDs; 28 284 PIs; 10.1%): n = 132 (0.47%); and group B (2005-2008: 11,660 VCDs; 30,169 PIs; 38.6%): n = 220 (0.73%) (p < 0.001). In contrast to similar rates of pseudo-aneurysms (group A: n = 124; 0.44%; group B: n = 176; 0.58%; not significant), a significant increase of operations for local stenoses/occlusions was seen with widespread VCD use: n = 8 versus n = 44 (p < 0.001). CONCLUSIONS: In the era of VCDs, complications are rare. However, use of these devices is not without complications, and may require complex reconstructions.

Safety and efficacy of femoral artery closure with the FemoSeal(R) device after coronary angiography using a 7 French sheath.

Post-cardiac catheterization femoral artery hemostasis can be accomplished with several mechanisms, including the FemoSeal® hemostasis device which has been designed and approved for closure of 6 French (F) arterial puncture sites. The aim of this study was to investigate whether the FemoSeal® vascular closure device can effectively and safely seal 7F arterial puncture sites after diagnostic and interventional cardiac catheterizations. Femoral artery puncture sites of 50 consecutive patients undergoing cardiac catheterization were closed with the FemoSeal® vascular closure device, according to the manufacturer's instructions. Efficacy endpoints were time to hemostasis and successful ambulation. Safety endpoints included bleeding complications, vessel occlusion and pseudoaneurysms. Mean time to hemostasis was 57.8±26.3 seconds (0-125 seconds). Hemostasis was achieved in 100 percent of the 50 patients. One patient suffered minor bleeding the next day, i.e. local hematoma. This clinical study demonstrates that the FemoSeal® vascular closure device, initially approved for closure of 6F arterial puncture sites, shows promising efficacy and safety to seal a larger (7F) femoral arterial puncture sites after diagnostic and interventional cardiac catheterizations.

Hepatitis B virus vaccination and revaccination response in children diagnosed with coeliac disease : a multicentre prospective study.

AIM: This study evaluates hepatitis B virus (HBV) vaccination response in children with celiac disease (CD). Response in initial non-responders after a single booster vaccination as well as factors influencing HBV vaccination response were evaluated. METHODOLOGY: Anti-hepatitis B surface antibodies (a-HBsAB) were checked in all children with CD and a documented complete HBV vaccination. An a-HBsAB <10 U/L was considered as non-response. A single intramuscular HBV-vaccine booster was advised to all non-responders. Response was checked at the next appointment. RESULTS: 133 children with CD were included, median age of 7.3 years (range 1.7-17.3) and 46 (35%) were male. The age at CD diagnosis was 6.0 years (range 1.1-15.7). HBV non-response was documented in 55% (n=73/133). No other factors were influencing the response. A booster was documented in 34/73 (47 %) initial non-responders (3 refused (4%), 36 (49%) had no follow up). Response after booster vaccination resulted in immunity in 22/34 (65%) and persisting non-response in 12/34 (35%). A single booster is able to reduce non-response from 55% (73/133) to 23% (22/94). CONCLUSION: A significantly lower immune response following HBV vaccination in children with CD was confirmed. A single intramuscular booster vaccination is able to induce a serologic response in two thirds of the initial non-responders. Control of HBV vaccination response has to become part of the follow-up in CD patients.

Cardiac troponin I to diagnose percutaneous transluminal coronary angioplasty-related myocardial injury.

The purposes of the present study were to evaluate cardiac troponin 1 (cTnl) in the diagnosis of percutaneous transluminal coronary angioplasty (PTCA)-related myocardial injury in comparison with cardiac troponin T (cTnT) and creatine kinase (CK) MB mass concentration, and to investigate the frequency of myocardial injury, as indicated by myocardial protein release, after clinically symptomless side-branch occlusion (SBO) which may occur in the proximity of the attempted stenosis. The final study population comprised 80 patients undergoing elective, single vessel PTCA. Blood samples were drawn before, 6, 24 and 48 h after PTCA. cTnI, cTnT and CKMB mass baseline values were within the reference intervals in all patients (cTnI < 0.1 microgram/l, cTnT < 0.2 microgram/l, CKMB < 5 micrograms/l). Two patients presented with primary failure of PTCA, and visually successful PTCA was performed in all remaining patients. Seven patients (four with SBO) subsequently developed acute myocardial infarction (AMI). Symptomless SBO occurred in 16 patients. In controls (n = 55) there were no significant increases in cTnI, cTnT, or CKMB concentrations compared with baseline values, and all markers stayed within their reference intervals. In half the patients with symptomless SBO (n = 8) all markers were slightly to moderately increased, in two additional patients only CKMB was elevated (cTnI: 0.1-1.0 microgram/l; cTnT: 0.25-0.81 microgram/l and CKMB: 7.9-25.6 micrograms/l). In the majority of patients with primary failure or AMI we found pronounced increases in all tested markers (cTnI: 0.2-12.0 micrograms/l; cTnT: 0.44-12.10 micrograms/l; CKMB: 19.2-423.0 micrograms/l). The results of this study indicate that cTnI is comparably useful to cTnT or CKMB mass for diagnosing myocardial injury in PTCA patients. From our results a preference for one of the tested parameters cannot be clearly derived. Post-procedural cTnI, cTnT, and CKMB mass values are not higher than baseline values in uncomplicated cases, whereas AMI after PTCA leads to pronounced marker increases. SBO, even when symptomless, leads frequently (in about half the patients) to slight marker increases.

Single coronary artery bypass grafting--a comparison between minimally invasive 'off pump' techniques and conventional procedures.

OBJECTIVE: At present, few studies directly comparing minimally invasive and conventional coronary artery bypass grafting are available. The aim of the present study was to evaluate the clinical outcome of the two techniques. METHODS: We retrospectively compared our first consecutive 20 patients undergoing minimally invasive coronary artery single bypass grafting on the beating heart (group I) with 23 consecutive patients receiving single coronary artery bypass via sternotomy using cardiopulmonary bypass and cardioplegia (group II). The procedures were performed during the period from Jan 1, 1994 to Feb 20, 1997. There were no significant differences in demographic data. RESULTS: Statistically significant differences were found concerning total operative time (172.6 min in group I and 149.6 min in group II P = 0.0009) and myocardial ischemic time (23.7 min local coronary occlusion time in group I and 17.6 min aortic cross-clamp time in group II P = 0.03. Patients treated minimally invasive received significantly fewer blood transfusions (25.0% vs. 69.6% P = 0.0035) and were discharged significantly earlier from the hospital (admission rate on the fifth postoperative day 68.4% in group I vs. 100.0% in group II P = 0.0004). CONCLUSION: We conclude that minimally invasive coronary artery bypass grafting on the beating heart in comparison to conventional single coronary artery bypass grafting during the learning curve requires longer operative times but can reduce blood transfusion requirements and hospital stay.

[Quantitative computed tomographic flow measurements of aortocoronary venous bypass grafts. II. Correlation with angiographic measurements]. / Quantitative computertomographische Flussmessungen in aortokoronaren Venenbrücken. Teil II: Korrelation mit angiographischen Messungen.

In 26 patients with 35 aortocoronary venous bypass grafts (ACVB) quantitative invasive angiographic parameters were compared with flow parameters of contrast medium, assessed by computed tomography. Out of seven different CT-parameters, the maximum decrease of concentration of contrast medium (40 +/- 5 HE/sec; mean +/- SEM) showed a correlation with the angiographic parameter of contrast medium quantitative flow rate (7.2 +/- 0.5 cm/sec) and this correlation (r = 0.536/SEE = 23.17) is significant (p less than 0.001). We conclude that for the single patient assessment of quantitative flow in ACVB by CT with a 3-second repetition rate could be performed with limited accuracy.

[The value of CT and MRT in assessing aortocoronary venous bypasses in comparison with coronary angiography]. / Die Wertigkeit von CT und MRT bei der Erfassung von aortokoronaren Venenbrücken im Vergleich zur Koronarangiographie.

In a follow-up study of 20 patients with a total of 52 aortocoronary venous bypass grafts (ACVB) three months after surgery, the patency of the grafts was assessed by magnetic resonance tomography (MR) followed by contrast enhanced CT-scan and selective coronary angiography on the following day. Each examination was interpreted independently and immediately after the procedure for the visibility and patency of the grafts. The statistical figures for the non-occluded grafts showed a sensitivity of 90.24% and a specificity of 54.54% for the CT scans and a sensitivity of 73.17% with a specificity of 72.72% for the MR. Although the sensitivity of the CT is somewhat higher than that of MR, neither procedure offers a clear advantage over each other and neither of both methods alone is adequate for the assessment of ACVB's. They are therefore only valuable as an adjunct to clinical data and as a screening procedure for selective coronary angiography.

[Cardiokymography: relative quantification of results in normal probands]. / Kardiokymographie: Relative Quantifizierung der Ergebnisse bei Normalpersonen.

The main problem with cardiokymography (CKG) and the principal reason for its limited clinical application to date is the deficiency of calibration and quantification of results. We tried to improve the value of the procedure by quantification of the results in 14 healthy young men (age: 23, 18-31 years) in place of subjective assessment. Before and after a bicycle exercise stress test CKG tracings were obtained in a lying position at rest, immediately after exercise and after recovery. Two different methods were applied to quantify the CKG tracings (distance method and area method). The relative height of the curves at rest was 89 +/- 72% (68 +/- 39%), immediately after exercise 111 +/- 60% (73 +/- 27%) and, after recovery 121 +/- 88% (78 +/- 49%). The relative change in the height of the curves between rest and exercise was not significant according to both methods (+22 +/- 64%/+5 +/- 32%), but the variation of values in an individual patient between rest and exercise was large. Interobserver variability was rather large, according to two independent investigators. Hence, it was not possible to establish limits of normal values in quantitative CKG, but only mean values.

[Prevention of neonatal tetanus in developing countries hampered by local organization and limited knowledge of health personnel and traditional midwives; North Sulawesi (Indonesia)]. / Preventie van neonatale tetanus in ontwikkelingslanden bemoeilijkt door lokale organisatie en beperkte kennis bij gezondheidswerkers en traditionele vroedvrouwen; Noord-Sulawesi (Indonesië).

OBJECTIVE: Evaluation of the policy to prevent neonatal tetanus in North-Sulawesi (Indonesia). DESIGN: Descriptive and questionnaire study. SETTING: Twelve villages in the district of Minahassa, Sulawesi, Indonesia. METHOD: The policy aimed at preventing neonatal tetanus was studied during the period April-June 1992. The relevant knowledge was tested of the community health workers (CHWs, n = 142) and traditional birth attendants (TBAs, n = 37) active in the 12 villages. To this purpose, 54 and 27 workers, respectively, were interviewed using a standard questionnaire. RESULTS: Not all women were vaccinated sufficiently to prevent their unborn children from tetanus; mostly, adequate vaccination records were lacking. 33% of the TBAs were unaware that neonatal tetanus can be prevented by hygienic delivery; in this respect there was no difference between trained and untrained TBAs. Of the CHWs, 39% were familiar with the correct vaccination policy and 26% did not know that pregnant women have to be vaccinated. 70% of the CHWs and TBAs wrongly believed that neonatal tetanus no longer occurred in their village. CONCLUSION: CHWs and TBAs showed little interest in neonatal tetanus, so that they were lacking in motivation regarding hygienic delivery procedures and preventive tetanus toxoid vaccination. Implementation of a good preventive programme in developing countries mostly requires organizatory rather than biomedical improvement.

Severe dysimmune cytopenia in children treated with tacrolimus after organ transplantation.

Rare cases of dysimmune phenomena after solid organ transplantation were described in the past. In the present series, we describe six children who developed severe dysimmune anemia or thrombocytopenia while treated with tacrolimus after liver or small bowel transplantation. All patients were off steroids or under low doses alternate day steroid medication when dysimmune cytopenia developed. All patients had positive anti-platelets antibodies and/or Coombs' positive anemia. Therapy was successful in all six patients with a rapid response to corticosteroids in three children, and to anti-CD20 monoclonal antibodies (rituximab) in the three others. The pathogenesis of these rare dysimmune/autoimmune disorders might be related to the interference of tacrolimus with T-cell functions and/or the endogenous control mechanisms of T-lymphocyte activation and down-regulation. Although rare, these complications must be known when discussing protocols of immunosuppression.

[Decrease in left ventricular stroke performance following bypass of a significant main coronary artery stenoses]. / Abnahme linksventrikulärer Schlagarbeit nach Uberbrückung signifikanter Hauptstammstenosen.

Hemodynamic parameters and left ventricular function were assessed 14 +/- 4 (means +/- SEM) days preoperatively and 101 +/- 5 days after aortocoronary bypass surgery in eight men (51-65 years of age) with left main coronary stenosis (greater than or equal to 75%). Working capacity on bicycle exercise stress test increased from 43 +/- 7 to 68 +/- 7% of age-, and body-surface matched normals; at the same time cardiac output (thermodilution) decreased from 5.7 +/- 0.5 to 4.7 +/- 2 l/min (p less than 0.05), stroke volume decreased from 78 +/- 6 to 63 +/- 3 ml (p less than 0.01), stroke work from 1.16 +/- 0.10 to 0.89 +/- 0.07 Joule (p less than 0.001), and stroke power from 4.0 +/- 0.3 to 3.4 +/- 0.2 Joule/s (p less than 0.01) postoperatively. Left ventricular volumes decreased postoperatively but not significantly, ejection fraction remained unchanged (57 +/- 13/59 +/- 13%). A control group (PTCA of LAD) showed no significant changes of these parameters. As all patients had a good postoperative result, decrease of stroke work after aortocoronary bypass surgery is not necessarily an expression of postoperative deterioration, since it can coincide with good left ventricular function, angiographically successful revascularization, and an increase in working capacity.

[Complications during directional coronary atherectomy (DCA): catheter fracture between housing assembly and shaft point with subsequent vascular occlusion]. / Komplikation während direktionaler koronarer Atherektomie (DCA): Katheterbruch zwischen Housing-Anteil und Schaftspitze mit nachfolgendem Gefässverschluss.

Directional coronary atherectomy of a severe stenosis of the left anterior descending coronary artery was complicated by device fracture between the cylindric housing portion and the distal nose-cone collecting chamber. After successful removal of the DCA device, an early occlusion of the coronary vessel occurred, which could be successfully treated by perfusion balloon catheter.

[Comparison of methods for the relative quantification of the hump in cardiokymographic tracings]. / Methodenvergleich zur relativen Quantifizierung des Buckels kardiokymographischer Registrierungen.

Exercise stress testing in a sitting position was carried out preoperatively and three months post aortocoronary bypass surgery in 125 men. Before exercise, immediately after exercise and after 5 minutes of recovery cardiokymography (CKG) was performed in a lying position. So called "bulges" in the CGK-tracings, defined as Type I, II or III registration by non quantitative judgement so far, were set out quantitatively by evaluation of area (Flächen-method) or distance (Distanzmethod) of the bulge. We found a significant increase (p less than 0.001) of bulges according to both methods after exercise but no difference between rest and after recovery concerning the area method. The distance method showed higher values (p less than 0.05) after recovery than at rest. All mean values postoperatively were not significantly lower than the corresponding values preoperatively. Our results show, that CKG-tracings can be quantitatively assessed both by the area or by the distance method. The latter is easier to apply and has comparable results to the area method.

[Mitochondria number as a prognostic parameter in dilated cardiomyopathy. A long-term follow-up study]. / Die Mitochondrienzahl als prognostischer Parameter bei dilatativer Kardiomyopathie. Eine Langzeitstudie.

According to morphological criteria of the myocardium, patients with clinical and hemodynamic signs of dilated cardiomyopathy were divided into three groups. Group I: patients with 1-2 mitochondria per 2 sarcomeres (n = 46); Group II: patients with more than 2 mitochondria per 2 sarcomeres (n = 47); Group III: patients with histological findings of myocarditis in the past (n = 33). Mean follow-up in groups I, II, III was 29, 22, 26 months, respectively (6-58, 3-52, 3-62/median 29, 18, 22). Clinical parameters were evaluated at the beginning and at the end of the prospective observation and were classified clinically as "improved, unchanged, deteriorated"; "heart transplantation", "death of cardial causes", "death of other than cardial causes" or "lost to follow up" were the other endpoints of the observation. At the beginning there were no hemodynamic differences between groups I, II, III, except significant difference in ejection fraction and mean ventricular shortening velocity between groups I and II. Scored together with the clinical symptoms "deterioration" and "death of cardial causes" as endpoints, survival rates without event up to 5 years in group I were 83 +/- 7% compared with group II 33 +/- 13% and group III 86 +/- 8%. There were significant differences (p less than 0.01). We conclude that the increased number of mitochondria per 2 sarcomeres in biopsy specimen of patients with dilated cardiomyopathy can be a significant parameter of deteriorated prognosis.

Acute and long-term effects of stressors on pulmonary immune functions.

To study the effects of different types or intensities of stressors on immune reactivity in the lungs, we studied the ex vivo production of nitric oxide (NO) and IL-1beta by alveolar macrophages (AM) after short exposure of rats to restraint stress or inescapable electric footshocks. Exposure to electric footshocks of various intensities resulted in an intensity-dependent decrease in NO production whereas the IL-1beta production by AM had increased. The secretory activity was similarly affected by restraint stress. When the time course of electric footshocks on secretory functions of AM was studied, it was found that the effects on NO and IL-1beta production by AM were normalized 3 days after the stress induction, but reappeared when cells were isolated 1 to 2 wk after stress exposure. Analysis of the effects of electric footshocks of various intensities on antibody production 10 days after the stress session and subsequent lung immunization with trinitrophenyl conjugated keyhole limpet hemocyanin (TNP-KLH), showed a footshock intensity-dependent response. Although exposure to stress induced an increase in plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hormone levels did not differ between the various stress-exposed groups. This suggests that the observed stress effects on pulmonary immune functions were not mediated by ACTH or CORT but point to a direct involvement of the autonomic nervous system.

Side-branch occlusion during percutaneous transluminal coronary angioplasty.

Concentrations of creatine kinase (CK) MB mass and cardiac troponin T were measured in serial peripheral venous blood samples from 21 patients who underwent percutaneous transluminal coronary angioplasty (PTCA). Angiography showed side-branch occlusion during PTCA without clinical signs of myocardial injury in 5 patients. After PTCA, CKMB mass concentrations were substantially higher than normal in all 5 patients with side-branch occlusion, and troponin T concentrations were high in 3. By contrast, only 2 patients and 1 patient, respectively, without side-branch occlusion had slight rises in CKMB and troponin T. Release of the contractile protein troponin T reflects more severe damage to myocytes than simple leakage of CKMB. Therefore, myocardial damage induced by side-branch occlusion can be graded by measurement of troponin T in plasma.

Renovascular arteriovenous differences in Lp[a] plasma concentrations suggest removal of Lp[a] from the renal circulation.

High plasma concentrations of lipoprotein[a] (Lp[a]) are considered a genetically determined risk factor for atherosclerosis. Lp[a] is produced by the liver. The site(s) and mechanism(s) of catabolism are presently unclear. Lp[a] is elevated secondary to end-stage renal disease which suggests a direct or indirect role of the kidney in the metabolism of Lp[a]. We therefore investigated, by a simple in vivo approach, whether Lp[a] is removed by the human kidney. Lp[a] plasma concentrations were measured simultaneously by various methods in the ascending aorta and renal vein of 100 patients undergoing coronary angiography or coronary angioplasty. Lp[a] levels differed significantly between the two vessels even after correcting for hemoconcentration (20.1 +/- 21.6 mg/dL versus 18.7 +/- 20.3 mg/dL, P < 0.001). This corresponds to a mean arteriovenous difference of -1.4 mg/ dL or -9% of the arterial concentration. No Lp[a] or intact apo[a] could be detected in urine from healthy probands. Although we cannot assign the kidney a regulatory role for Lp[a] plasma levels in humans with normal renal function, we conclude from our data that substantial amounts of this atherogenic lipoprotein are taken up by the kidney. The underlying mechanisms are unknown at the moment. This study therefore demonstrates for the first time that the human kidney plays an active role in the catabolism of Lp[a]. This may explain the elevated Lp[a] concentrations found in patients with chronic renal insufficiency.