Rapid quasi-periodic oscillations in the relativistic jet of BL Lacertae.

Blazars are active galactic nuclei (AGN) with relativistic jets whose non-thermal radiation is extremely variable on various timescales1-3. This variability seems mostly random, although some quasi-periodic oscillations (QPOs), implying systematic processes, have been reported in blazars and other AGN. QPOs with timescales of days or hours are especially rare4 in AGN and their nature is highly debated, explained by emitting plasma moving helically inside the jet5, plasma instabilities6,7 or orbital motion in an accretion disc7,8. Here we report results of intense optical and γ-ray flux monitoring of BL Lacertae (BL Lac) during a dramatic outburst in 2020 (ref. 9). BL Lac, the prototype of a subclass of blazars10, is powered by a 1.7 × 108 MSun (ref. 11) black hole in an elliptical galaxy (distance = 313 megaparsecs (ref. 12)). Our observations show QPOs of optical flux and linear polarization, and γ-ray flux, with cycles as short as approximately 13 h during the highest state of the outburst. The QPO properties match the expectations of current-driven kink instabilities6 near a recollimation shock about 5 parsecs (pc) from the black hole in the wake of an apparent superluminal feature moving down the jet. Such a kink is apparent in a microwave Very Long Baseline Array (VLBA) image.

Blazar spectral variability as explained by a twisted inhomogeneous jet.

Blazars are active galactic nuclei, which are powerful sources of radiation whose central engine is located in the core of the host galaxy. Blazar emission is dominated by non-thermal radiation from a jet that moves relativistically towards us, and therefore undergoes Doppler beaming. This beaming causes flux enhancement and contraction of the variability timescales, so that most blazars appear as luminous sources characterized by noticeable and fast changes in brightness at all frequencies. The mechanism that produces this unpredictable variability is under debate, but proposed mechanisms include injection, acceleration and cooling of particles, with possible intervention of shock waves or turbulence. Changes in the viewing angle of the observed emitting knots or jet regions have also been suggested as an explanation of flaring events and can also explain specific properties of blazar emission, such as intra-day variability, quasi-periodicity and the delay of radio flux variations relative to optical changes. Such a geometric interpretation, however, is not universally accepted because alternative explanations based on changes in physical conditions-such as the size and speed of the emitting zone, the magnetic field, the number of emitting particles and their energy distribution-can explain snapshots of the spectral behaviour of blazars in many cases. Here we report the results of optical-to-radio-wavelength monitoring of the blazar CTA 102 and show that the observed long-term trends of the flux and spectral variability are best explained by an inhomogeneous, curved jet that undergoes changes in orientation over time. We propose that magnetohydrodynamic instabilities or rotation of the twisted jet cause different jet regions to change their orientation and hence their relative Doppler factors. In particular, the extreme optical outburst of 2016-2017 (brightness increase of six magnitudes) occurred when the corresponding emitting region had a small viewing angle. The agreement between observations and theoretical predictions can be seen as further validation of the relativistic beaming theory.

In vitro experiments demonstrate that monocytes and dendritic cells are rendered apoptotic by extracorporeal photochemotherapy, but exhibit unaffected surviving and maturing capacity after 30 Gy gamma irradiation.

Extracorporeal photochemotherapy (ECP) has been shown to induce apoptosis in lymphocytes. Until recently the prevailing opinion has been that the monocytes were mainly not affected by this treatment. This study has investigated the effect of ECP and gamma irradiation on monocytes and immature dendritic cells (DC) in vitro and followed the ability of the cells to differentiate and survive post treatment. ECP induced apoptosis in lymphocytes, monocytes and immature DC within 72 h following treatment, in contrast to 30 Gy gamma irradiation, which seemed mainly to affect lymphocytes. The minority of the surviving ECP-treated monocytes presented a reduced ability to differentiate into immature DC within this time frame. We also demonstrated that immature DC after ECP-treatment lost their normal ability to mature on stimulation with lipopolysaccharide. As monocytes and immature DC seem to have a reduced ability to differentiate after ECP-treatment, it is suggested that the therapeutic effect of ECP is caused by in vivo effects of reinfused apoptotic cells, rather than by infusion of monocytes induced to differentiate into immature DC.

Extracorporeal photochemotherapy in patients with cutaneous T-cell lymphoma: is clinical response predictable?

BACKGROUND: Extracorporeal photochemotherapy (ECP) has been accepted as a standard therapy in cutaneous T-cell lymphomas (CTCL), a category of lymphomas mainly resistant to conventional therapies. Approximately one half of patients demonstrate a reduction in skin affliction by at least 50% within 12 months of therapy and are categorized as responders to ECP. Predictive criteria for selecting patients who will respond to ECP are lacking. Such criteria would however, be of great benefit. OBJECTIVES: This study compared T-cell clonality and serum levels of soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase (LD), neopterin, beta2-microglobulin (beta(2)-M) and granzyme B in CTCL patients in order to evaluate their potential usefulness as predictive markers. PATIENTS/METHODS: Serum and T lymphocytes obtained from 16 patients with CTCL receiving ECP treatment were evaluated in an open retrospective study. RESULTS: We found no evident correlation between detected T-cell clonality and response to ECP. The non-responding group had on average a higher level of serum sIL-2R. This difference was significant after 6 and 12 months of therapy, but not pretreatment. An individual reduction in serum sIL-2R, neopterin and beta(2)-M during a 6-month course of ECP was well correlated to clinical remission. CONCLUSIONS: Seven out of 16 patients were classified as responders. Neither T-cell clonality nor any of the serum markers assessed pretreatment could reliably predict the response to ECP treatment. However, the individual relative changes in sIL-2R, neopterin and beta(2)-M during 6 months of ECP treatment coherently displayed correlation to the clinical response, as assessed after 12 months of ECP treatment.

A survey of therapeutic hemapheresis in Norway year 2000.

In a survey of therapeutic hemapheresis in Norway, we sent a questionnaire to all regional and central hospitals, asking about hemapheresis activities, patients, indications, and adverse events. All units responded to the questionnaire: 17 dialysis units, 7 blood units, and 2 specialized units for stem cell apheresis. In total, they performed 2141 procedures that is 5.0 stem cell collections and 42.5 therapeutic apheresis procedures per 100,000 inhabitants. The most frequent indications were Guillain-Barré syndrome, hypercholesterolemia, and myasthenia gravis. Adverse effects were frequent, but mild. Dialysis units performed a majority of the procedures, leading to an extensive use of filtration techniques.

Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis.

BACKGROUND: The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease. METHODS: Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5-184). RESULTS: Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (rho=0.52, P=0.0004), with necrosis (rho=0.36, P=0.002) and with the percentage of normal glomeruli (rho=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (+/-26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment. CONCLUSION: Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.

Wegener's granulomatosis: inflammatory cells and markers of repair and fibrosis in renal biopsies--a clinicopathological study.

OBJECTIVE: This study aimed to quantitate inflammatory cells in renal biopsies from patients with Wegener's granulomatosis (WG) and to identify cells participating in early fibrogenesis. The goal was to determine whether these cells correlated with the severity of renal disease and whether their presence had a bearing on renal prognosis. MATERIAL AND METHODS: Sixty-one patients with WG who had a renal biopsy taken at the time of diagnosis were included in the study. Immunostaining with monoclonal antibodies towards macrophages (CD68), T- and B-lymphocytes, alpha-smooth muscle actin (alpha-SMA) and vimentin was done. RESULTS: The dominating intraglomerular leucocytes were macrophages (29.9 +/- 15 cells/glomerular cross-section) and to a lesser extent T-cells (2.57 +/- 1.8 cells/glomerular cross-section). No B-lymphocytes were detected in the glomeruli. More than two-thirds of the T-cells were CD8+ (cytotoxic) cells. Macrophages and T-lymphocytes were distributed equally in the renal interstitium and were numerous around crescentic glomeruli. Glomerular and interstitial macrophages and interstitial T-cells correlated significantly with serum (S-) creatinine at the time of biopsy but not after 1 year. S-creatinine at the time of biopsy and after 1 year differed significantly among the three levels of interstitial alpha-SMA staining. S-creatinine at biopsy was highest when tubular vimentin staining was strongest, and tubular vimentin staining was strongest in patients with acute tubular damage. CONCLUSIONS: Evidence was found for a cellular type IV immune response in WG, with CD8+ T-lymphocytes and macrophages dominating the cellular infiltrate. The detection of interstitial alpha-SMA, probably staining myofibroblasts implicated in renal fibrogenesis, indicated a low glomerular filtration rate 1 year after renal biopsy.

Wegener's granulomatosis: clinical course in 108 patients with renal involvement.

BACKGROUND: The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis and renal involvement, with special reference to relapse rate, renal and patient survival and morbidity from serious infections. METHODS: A retrospective analysis was carried out of 108 patients presenting with Wegener's granulomatosis and active renal disease in eight hospitals in Norway between 1988 and 1998. Multivariate analysis was used to investigate whether selected variables predicted relapse, renal and patient survival and serious infections. RESULTS: Median follow-up was 41.5 months. Twenty-two patients (20.4%) were admitted with a need for dialysis. Complete remission was obtained in 81.5% after a median of 4 months, and 54.7% relapsed after a median of 22. 5 months. Two- and five-year renal survival was 86 and 75%, respectively, and 22.8% developed end-stage renal disease (ESRD). Two- and five-year patient survival was 88 and 74%, respectively, and the cumulative mortality was 3.8 times higher than expected. The relative risk of relapse increased with the use of intravenous pulse cyclophosphamide compared with daily oral cyclophosphamide. Initial renal function predicted renal survival, and low serum albumin and high age at treatment start increased the mortality risk. Thirty one per cent of the patients were hospitalized for serious infections during follow-up. Old age increased the risk of having an infection. CONCLUSIONS: The current treatment of Wegener's granulomatosis does not prevent relapse, development of ESRD and serious treatment-induced infections in a considerable fraction of the patients. Alternative strategies for the management of this disease will be an important objective for further studies.

Renal involvement in primary Sjögren's syndrome.

Renal involvement was evaluated in 62 patients with primary Sjögren's syndrome, classified according to criteria proposed by The European Classification Criteria Group. Urine concentration capacity was tested using intranasal 1-desamino-8-D-arginine-vasopressin. For patients with urine pH>5.5 without metabolic acidosis (n=28), an acidification test with ammonium chloride was performed. Urinary citrate, albumin, NAG, ALP and beta2-microglobulin were measured and creatinine clearance was calculated. Maximum urine concentration capacity and creatinine clearance were reduced in 13 (21%). Albumin excretion was >30 microg/min in only one patient (1.6%). Seven patients (11.3%) had complete or incomplete distal renal tubular acidosis (dRTA), four had reduced creatinine clearance and five had reduced maximum urine concentration capacity. The ratio of citrate/creatinine in spot urine was below the 2.5 percentile in all patients with complete or incomplete dRTA. The prevalence of dRTA was lower than in previous studies. There were also few patients with signs of glomerular disease (1.6%). The use of citrate:creatinine ratio in spot urine can be a helpful method in identifying patients with complete or incomplete dRTA.

Effects of cascade apheresis in patients with psoriasis and psoriatic arthropathy.

Eight patients with psoriasis, all with skin scales and 7 with disabling psoriatic arthritis, were subjected to cascade apheresis starting with three treatments per week for 2 weeks, followed by one treatment a week, comprising ten treatments in all. Six out of 7 patients (86%) with arthropathy and 3 out of 8 patients (38%) with scales experienced a beneficial effect. There was a large drop in the levels of circulating immune complexes (CIC) due to the treatment, and the removal of CIC was followed by reduced inflammatory activity in skin lesions and joints as evaluated by pain, morning stiffness, grip strength, plaque score, and PASI index. However, there was no correlation between the level of CIC, disease activity, or treatment response. From the present results it is concluded that CIC may play a more significant role regarding psoriatic arthropathy than in skin manifestations, and apheresis may be beneficial in patients not responding to conventional therapy.

Pharmacokinetics of transperitoneal insulin transport.

Seven type I insulin-dependent diabetic patients on continuous ambulatory peritoneal dialysis treatment were selected for this study. Each patient participated in three different 6-hour 'single-dwell' studies on 3 consecutive days. A mean dose of 33 +/- 1.3 U Insulin Actrapid Human was given intraperitoneally each day. The procedures for intraperitoneal insulin administration were: (1) with 1,000 ml Ringer lactate; (2) with 1,000 ml 3.86% glucose-containing dialysate, and (3) into an empty peritoneal cavity. The calculation of the intraperitoneal volume was done with a single injection indicator dilution technique in which 100 kBq radioiodinated serum albumin (RISA) was added into the fluid prior to instillation. Free insulin and glucose were analyzed at 16 time intervals in blood and in dialysate during each dwell. After drainage the peritoneal cavity was rinsed with 1,000 ml Ringer lactate followed by two consecutive 5-hour exchanges with 2,000 ml glucose-containing dialysate. Recovery of insulin and RISA was measured in rinsing fluid and in sampled dialysate during the 6-hour dwell. The kinetic calculations made for insulin were disappearance rate (mU/min) from the peritoneal cavity, and appearance rate in circulating blood. After drainage and rinsing, 66.0 +/- 10 and 71.8 +/- 9.8% of the insulin instilled had disappeared after 6 h from the glucose fluid and from the Ringer solution respectively and did not differ significantly. However, the estimated disappearance rate from the peritoneal cavity was significantly higher in Ringer than in glucose from the time interval 120 to 360 min. A high and peak-shaped insulin concentration in the plasma was found following insulin injection into an empty peritoneal cavity, and was significantly higher than when insulin was dissolved in a 1,000-ml fluid volume. However, a higher blood concentration was also found when Ringer was instilled than when a hyperosmolal glucose solution was instilled. A high first-pass elimination in the liver is suggested. In conclusion, fluid volume and also the osmolality of the solution in the peritoneal cavity decreases the transport rate, but not the bioavailability of insulin given intraperitoneally. Both a high peak shape and a continuous insulin appearance in blood can be achieved. It is suggested that there is a high first-pass elimination of insulin during absorption from the peritoneal cavity. However, the values are uncertain and extended investigations must be done.

[Pulmonary lymphangioleiomyomatosis]. / Pulmonal lymfangioleiomyomatose.

Pulmonary lymphangioleiomyomatosis is a rare disease with a haphazard proliferation of smooth muscle throughout the lung. Little knowledge about the disease, its clinical presentation and the diagnostic methods used may be a reason for underdiagnosing the disease. In Ostfold county, Norway, with only 250,000 inhabitants, we have seen four patients with this disease in the last few years. The diagnosis was based on histological examination of transbronchial biopsy material in three patients who underwent bronchoscopy the presence of lymphangioleiomyomatosis was not recognized at the initial pathological examination. The disease can be misinterpreted as fibrosis at histological examination. Specific procedures for detecting smooth muscle can be used, eradicating the need for open lung biopsy. Transbronchial biopsy is a valid and useful method for confirming the diagnosis of lymphangioleiomyomatosis. High resolution CT has also shown to be an important diagnostic tool. We emphasize the importance of raising the question of lymphangioleiomyomatosis with the pathologist when this rare, but probably underdiagnosed disease, is suspected by the clinician.

[Diagnosis and treatment of high blood pressure. How to invest?]. / Diagnostikk og behandling av høyt blodtrykk. Hvordan investere?

High blood pressure is a major risk factor for development of cardiovascular diseases. During 1992 and 1993, several national consensus reports about treatment of arterial hypertension have been published. There are discrepancies between the recommendations contained in the reports, which has caused uncertainty among physicians. We discuss the basic problems connected to evaluation and recommendation, and the demand for standardization and organization of the health service programme for patients with high blood pressure. It is possible to learn from, and thereby achieve better quality of medical practice, through a continuous registration of our routines and results. The Trondheim model is designed to depict specific information from the primary health services in a follow-up programme. This information is sampled in a data base from which primary physicians can obtain feedback on statistical evaluations twice a year. This is defined as a quality assurance programme to secure and improve the quality of the medical service to patients with high blood pressure.

Systemic cardiovascular response in hemodialysis without and with ultrafiltration with membranes of high and low biocompatibility.

In order to test whether dialyzer membrane biocompatibility influences systemic cardiovascular function, we treated 8 hemodialysis patients (4 men and 4 women, aged 24-73 years) with a low-biocompatible (cuprophane) and a high-biocompatible (polyacrylonitrile) membrane in a randomized double-blind crossover protocol using bicarbonate hemodialysis without ultrafiltration for the first 60 min and with ultrafiltration for the remaining treatment time. Left ventricular function and systemic hemodynamics were assessed noninvasively at baseline and during treatment by Doppler echocardiography combined with external subclavian artery pulse trace calibrated with oscillometrically measured brachial artery blood pressures. There was no significant difference in the cardiovascular response to the 2 membranes, neither during isolated hemodialysis nor when ultrafiltration was added. Mean arterial pressure increased 10% (p < 0.001) during isolated hemodialysis and returned to baseline levels with ultrafiltration. The cardiac index decreased 22% (p < 0.001) during ultrafiltration, due to the greater decrease in left ventricular stroke index (30%, p < 0.001) than increase in heart rate (9%, p < 0.05). Total peripheral resistance increased 10% (p < 0.05) during isolated hemodialysis and a further 19% (p < 0.01) when ultrafiltration was added. Hence, profound cardiovascular alterations were observed during hemodialysis treatment; however, these changes were not related to the biocompatibility of the membranes.

Intravascular ultrasonographic assessment of thrombus formation on central venous catheters.

In vitro experiments were performed in order to investigate the appearance of different types of central venous catheters at intravascular ultrasonography. The experiments were repeated with artificially produced thrombi which were made adherent to the catheter wall. All thrombi larger than 1 mm could be identified. In a clinical study including 12 patients who had a central venous catheter, transfemoral intravascular ultrasonography was performed. The catheters had been in place for an average period of 54 days (range 1-360 days). In 3 patients a catheter thrombus, mural thrombus, or occlusive vein thrombosis was found. In 2 of these patients the catheter was occluded, in the 3rd patient it was malpositioned into the contralateral brachiocephalic vein. There were no complications following the ultrasonographic procedures. Mean catheterization time was 7.5 min (range 3-20 min). The advantages of this new method compared with conventional phlebographic studies and its impact on further clinical investigations are discussed.

Acute abdominal pain as presenting symptom in lymphangiomyomatosis. Case report.

A case of lymphangiomyomatosis presenting with acute abdominal pain is described. Laparotomy revealed a multiloculated cystic mass on the posterior abdominal wall with typical histological pattern. In the ensuing 3 years the respiratory manifestations of this rare disorder have slowly progressed. Possible causal factors and management are discussed.