Prognosis of patients with severe cerebral venous thrombosis treated with decompressive craniectomy.

INTRODUCTION: Despite the highly favorable prognosis, mortality occurs in nearly 2% of patients with cerebral venous thrombosis (CVT), in which decompressive craniectomy (DC) may be the only way to save the patient's life. The aim of this report is to describe the risk factors, neuroimaging features, in-hospital complications and functional outcome of severe CVT in patients treated with DC. MATERIALS AND METHODS: Consecutive malignant CVT cases treated with DC from a retrospective third-level hospital database were analyzed. Demographic, clinical, and functional outcomes were analyzed. RESULTS: Twenty-six patients were included (20 female, age 35.4±12.1 years); 53.8% of the patients had acute CVT, with neurological focalization as the most common symptom in 92.3% of the patients. Superior sagittal sinus thromboses were found in 84.6% of cases. Bilateral lesions were present in 10 patients (38.5%). Imaging on admission showed a parenchymal lesion (venous infarction±hemorrhagic lesion)>6cm measured along the longest diameter in 25 patients (96.2%). Mean duration of clinical neurological deterioration was 3.5 days; eleven patients (42.3%) died during hospitalization. CONCLUSION: In patients with severe forms of CVT, we found higher mortality than previously reported. DC is an effective life-saving treatment with acceptable functional prognosis for survivors.

Prognosis of patients with severe cerebral venous thrombosis treated with decompressive craniectomy.

INTRODUCTION: Despite the highly favorable prognosis, mortality occurs in nearly 2% of patients with cerebral venous thrombosis (CVT), in which decompressive craniectomy (DC) may be the only way to save the patient's life. The aim of this report is to describe the risk factors, neuroimaging features, in-hospital complications and functional outcome of severe CVT in patients treated with DC. MATERIALS AND METHODS: Consecutive malignant CVT cases treated with DC from a retrospective third-level hospital database were analyzed. Demographic, clinical, and functional outcomes were analyzed. RESULTS: Twenty-six patients were included (20 female, age 35.4±12.1 years); 53.8% of the patients had acute CVT, with neurological focalization as the most common symptom in 92.3% of the patients. Superior sagittal sinus thromboses were found in 84.6% of cases. Bilateral lesions were present in 10 patients (38.5%). Imaging on admission showed a parenchymal lesion (venous infarction±hemorrhagic lesion)>6cm measured along the longest diameter in 25 patients (96.2%). Mean duration of clinical neurological deterioration was 3.5 days; eleven patients (42.3%) died during hospitalization. CONCLUSION: In patients with severe forms of CVT, we found higher mortality than previously reported. DC is an effective life-saving treatment with acceptable functional prognosis for survivors.

Correction to: Features of intracranial hemorrhage in cerebral venous thrombosis.

The original version of this article unfortunately contained mistakes. The correct information is given below.

Features of intracranial hemorrhage in cerebral venous thrombosis.

BACKGROUND: Cerebral venous thrombosis (CVT) is associated with intracranial hemorrhage. AIM: To identify clinical and imaging features of CVT-associated intracranial hemorrhage. We hypothesized that higher clot burden would be associated with a higher risk of intracranial hemorrhage. METHODS: We performed a retrospective analysis of an international, multicenter cohort of patients with confirmed cerebral venous thrombosis who underwent computed tomography within 2 weeks of symptom onset. Clinical and imaging features were compared between patients with and without intracranial hemorrhage. Clot burden was assessed by counting the number of thrombosed venous sinuses and veins on confirmatory imaging. RESULTS: We enrolled 260 patients from 10 institutions in Europe and Mexico. The mean age was 42 years and 74% were female. Intracranial hemorrhage was found in 102 (39%). Among them parenchymal hemorrhage occurred in 64 (63%), in addition, small juxta-cortical hemorrhage was found in 30 (29%), subarachnoid hemorrhage in 24 (24%) and subdural hemorrhage in 11 (11%). Multiple concomitant types of hemorrhage occurred in 23 (23%). Older age and superior sagittal thrombosis involvement were associated with presence of hemorrhage. The number of thrombosed venous sinuses was not associated with intracranial hemorrhage (median number IQRInterquartile ratio] of sinuses/veins involved with hemorrhage 2 (1-3) vs. 2 (1-3) without hemorrhage, p = 0.4). CONCLUSION: The high rate of intracranial hemorrhage in cerebral venous thrombosis is not explained by widespread involvement of the venous sinuses. Superior sagittal sinus involvement is associated with higher bleeding risk.

Anaemia at admission is associated with poor clinical outcome in cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Anaemia is associated with poor clinical outcome after ischaemic and haemorrhagic stroke. The association between anaemia and outcome in patients with cerebral venous thrombosis (CVT) was examined. METHODS: Consecutive adult patients with CVT were included from seven centres. Anaemia at admission was scored according to World Health Organization definitions. Poor clinical outcome was defined as a modified Rankin Scale score 3-6 at last follow-up. A multiple imputation procedure was applied for handling missing data in the multivariable analysis. Using binary logistic regression analysis, adjustments were made for age, sex, cancer and centre of recruitment (model 1). In a secondary analysis, adjustments were additionally made for coma, intracerebral haemorrhage, non-haemorrhagic lesion and deep venous system thrombosis (model 2). In a sensitivity analysis, patients with cancer were excluded. RESULTS: Data for 952 patients with CVT were included, 22% of whom had anaemia at admission. Patients with anaemia more often had a history of cancer (17% vs. 7%, P < 0.001) than patients without anaemia. Poor clinical outcome (21% vs. 11%, P < 0.001) and mortality (11% vs. 6%, P = 0.07) were more common amongst patients with anaemia. After adjustment, anaemia at admission increased the risk of poor outcome [adjusted odds ratio (aOR) 2.4, 95% confidence interval (CI) 1.5-3.7, model 1]. Model 2 revealed comparable results (aOR 1.9, 95% CI 1.2-3.2), as did the sensitivity analysis excluding patients with cancer (aOR 2.3, 95% CI 1.3-3.8, model 1). CONCLUSION: The risk of poor clinical outcome is doubled in CVT patients presenting with anaemia at admission.

Evaluation of TeO2 content on the optical and spectroscopic properties of Yb3+-doped calcium borotellurite glasses.

This paper reports the synthesis and the characterization of Yb3+-doped calcium borotellurite (CaBTeX) glasses with composition 10CaF2-(29.5-0.4x)CaO-(60-0.6x)B2O3-xTeO2-0.5Yb2O3 (x=10, 16, 22, 31 and 54mol%). The results of XRD confirm the amorphous character of all the samples. The density, molar volume, refractive index and electronic polarizability values show an increase with TeO2 content. Otherwise, the optical band gap energy shows a decrease with the increase of TeO2 content. The replacement of CaO and B2O3 by TeO2 changes the glass structure, which decreases the excited Yb3+/cm3 and, consequently, the luminescence intensity. The temperature dependence of luminescence was studied for all the samples up to 420K. The fluorescence lifetime does not change significantly due to TeO2 addition. In addition, absorption and emission cross section were calculated and present high values as compared to other tellurite and phosphate glasses.

The use of 185 MBq and 740 MBq of 153-samarium hydroxyapatite for knee synovectomy in haemophilia.

The penetration of beta energy of 153-samarium ((153) Sm) (0.8 MeV) is not only appropriate for synovectomy of median articulations but is possible to improve the radiobiological effect using increased activities. The aim of this study was to assess the effectiveness of 185 MBq and 740 MBq of 153-samarium hydroxyapatite ((153) Sm-HA) in knees of haemophilic patients. Thirty-one patients--36 knees, 30 males, were divided into two groups without coinjection of corticosteroid: A - 14 patients (17 knees) treated with intra-articular dose of 185 MBq of (153) Sm-HA, average age 23 years; B--17 patients (19 knees) with 740 MBq of (153) Sm-HA, average age 21.3 years. The evaluation before and after 1 year of synovectomy used the following criteria: reduction in the number of haemarthroses and use of the coagulation factor and improvement in articular motility. Adverse-effects occurrence was considered too. Early and late scintigraphic studies were performed after synoviorthesis and no joint immobilization was recommended. The reduction in haemarthrosis and use of coagulation factor were: group 1--31.3% and 25%; group 2--81.5% and 79% with P < 0.001 respectively; no significant improvement in knees motility was noted for both groups. Four cases of mild reactional synovitis were observed in each group. The scintigraphic control showed homogenous distribution of the radiopharmaceuticals with no articular escape; the material was considered safe by its permanence in the articulation. We have significant improvement in the synovectomy of haemophilic knees with 740 MBq of (153) Sm-HA; the less penetration of its beta radiation was compensated by the increased biological effect with the higher used activity.

Performance assessment of the single photon emission microscope: high spatial resolution SPECT imaging of small animal organs.

The single photon emission microscope (SPEM) is an instrument developed to obtain high spatial resolution single photon emission computed tomography (SPECT) images of small structures inside the mouse brain. SPEM consists of two independent imaging devices, which combine a multipinhole collimator, a high-resolution, thallium-doped cesium iodide [CsI(Tl)] columnar scintillator, a demagnifying/intensifier tube, and an electron-multiplying charge-coupling device (CCD). Collimators have 300- and 450-µm diameter pinholes on tungsten slabs, in hexagonal arrays of 19 and 7 holes. Projection data are acquired in a photon-counting strategy, where CCD frames are stored at 50 frames per second, with a radius of rotation of 35 mm and magnification factor of one. The image reconstruction software tool is based on the maximum likelihood algorithm. Our aim was to evaluate the spatial resolution and sensitivity attainable with the seven-pinhole imaging device, together with the linearity for quantification on the tomographic images, and to test the instrument in obtaining tomographic images of different mouse organs. A spatial resolution better than 500 µm and a sensitivity of 21.6 counts·s-1·MBq-1 were reached, as well as a correlation coefficient between activity and intensity better than 0.99, when imaging 99mTc sources. Images of the thyroid, heart, lungs, and bones of mice were registered using 99mTc-labeled radiopharmaceuticals in times appropriate for routine preclinical experimentation of <1 h per projection data set. Detailed experimental protocols and images of the aforementioned organs are shown. We plan to extend the instrument's field of view to fix larger animals and to combine data from both detectors to reduce the acquisition time or applied activity.

Performance assessment of the single photon emission microscope: high spatial resolution SPECT imaging of small animal organs

The single photon emission microscope (SPEM) is an instrument developed to obtain high spatial resolution single photon emission computed tomography (SPECT) images of small structures inside the mouse brain. SPEM consists of two independent imaging devices, which combine a multipinhole collimator, a high-resolution, thallium-doped cesium iodide [CsI(Tl)] columnar scintillator, a demagnifying/intensifier tube, and an electron-multiplying charge-coupling device (CCD). Collimators have 300- and 450-µm diameter pinholes on tungsten slabs, in hexagonal arrays of 19 and 7 holes. Projection data are acquired in a photon-counting strategy, where CCD frames are stored at 50 frames per second, with a radius of rotation of 35 mm and magnification factor of one. The image reconstruction software tool is based on the maximum likelihood algorithm. Our aim was to evaluate the spatial resolution and sensitivity attainable with the seven-pinhole imaging device, together with the linearity for quantification on the tomographic images, and to test the instrument in obtaining tomographic images of different mouse organs. A spatial resolution better than 500 µm and a sensitivity of 21.6 counts·s-1·MBq-1 were reached, as well as a correlation coefficient between activity and intensity better than 0.99, when imaging 99mTc sources. Images of the thyroid, heart, lungs, and bones of mice were registered using 99mTc-labeled radiopharmaceuticals in times appropriate for routine preclinical experimentation of <1 h per projection data set. Detailed experimental protocols and images of the aforementioned organs are shown. We plan to extend the instrument's field of view to fix larger animals and to combine data from both detectors to reduce the acquisition time or applied activity.

(67)Ga and (68)Ga purification studies: preliminary results.

The positron emission tomography technique is very useful for diagnosis of several diseases. (68)Ga is a positron emitter with half-life of 67.7 min. As it is available from (68)Ge/(68)Ga generator systems, it is not necessary to have a nearby cyclotron. However, the eluate from commercial generators contains high levels of metallic impurities, which compete with (68)Ga in biomolecular labeling. Thus, a subsequent purification step is needed after generator elution. Here we present the results of two different methods developed for handmade purification of (68)Ga and (67)Ga for subsequent radiolabeling of biomolecules. Two purification methods were employed. The first one uses a cation exchange resin, and (68)Ga is eluted with a solution of acetone/acid. The second method of purification is performed by column chromatography solvent extraction, with (68)Ga recovery in deionized water. The best result was achieved with cationic resin AG50W-X8 (>400 mesh). However, the resin is not commercially available. The extraction chromatography column based on absorption of diisopropyl ether in XAD-16 is the most promising purification method. Although the levels of (68)Ga recovery and purification were smaller with the cationic resin method, its advantage is the (68)Ga recovery in deionized water.

Separation of clavulanic acid from fermented broth of amino acids by an aqueous two-phase system and ion-exchange adsorption.

The clavulanic acid is a substance which inhibits the ß-lactamases used with penicillins for therapeutic treatment. After the fermentation, by-products of low molecular weight such as amino acids lysine, histidine, proline and tyrosine are present in the fermented broth. To remove these impurities the techniques of extraction by an aqueous two-phase system of 17% polyethylene glycol molecular weight 600 and 15% potassium phosphate were used for a partial purification. A subsequent ion-exchange adsorption was used for the recuperation of the clavulanic acid of the top phase and purification getting a concentration factor of 2 and purification of 100% in relation to the amino acids lysine, histidine, proline and tyrosine.

Estabilización dinámica con ligamentoplastia interespinosa en discopatía degenerativa de columna vertebral lumbar / Dynamic stabilization with interspinous ligamentoplasty in degenerative discopaty of lumbar spine

El tratamiento de la Discopatía Degenerativa lumbar, mediante dispositivo suave de estabilización dinámica, con el uso de ligamento para reforzamiento interespinoso, altera favorablemente el movimiento y la transmisión de carga de un segmento vertebral, proporcionando estabilidad y previniendo la enfermedad del segmento adyacente. Por lo tanto se realiza un estudio prospectivo, longitudinal con 25 pacientes con edades comprendidas entre 15 y 58 años, con diagnóstico de Discopatia degenerativa lumbar; con estudios de imágenes previos con radiografias en proyección AP, lateral y laterales dinámicas además de Resonancia Magnética, con los cuales se confirmo el diagnóstico, al igual que control radiológico postoperatorio, a los que se les practico semihemilaminectomia mas discectomíamas foraminectomía mas ligamentoplastia interespinosa del segmento afectado y adyacentes. Se obtuvo como resultado mejoría clínica inmediata en la mayoría de los pacientes y con pronto reintegro a sus actividades habituales luego de la cirugía.

The treatment of lumbar degenerative discopaty, by means of a soft dynamic stabilization device, with the use of ligament for interspinous reinforcement, alter favorably the movement and load transmission of a vertebral segment, providing stability and preventing the disease of the adjacent segment. Therefore a prospectivelongitudinal study is carried out on 25 patients with ages ranging from 15 to 58 years, with a lumbar degenerative disease diagnosis; previous radiographicstudies in AP, lateral and dynamic-laterals projectionsand also Magnetic Resonance Imaging confirm the diagnosis, along with postoperative radiological controls. The patients received semi-hemilaminectomy plus discectomy plus foraminectomy plus interspinous ligamentoplasty of affected and adjacent segments. As result, inmediate clinical improvement in most patients was obtained and a soon return to their usual activities after the surgery.

Radioactive synovectomy with Yttrium9° citrate in haemophilic synovitis: Brazilian experience.

Recurrent haemarthroses leading to chronic synovitis and arthropathy remain a major cause of morbidity in patients with haemophilia. Radioactive synovectomy (RS) is considered the first choice of treatment for chronic haemophilic synovitis. The aim of this study was to evaluate the effect of RS with Yttrium(90) citrate (C-Y(90)) in the joints of patients with chronic haemophilic synovitis. From 2003 to 2007, 245 joints (118 knees, 76 elbows, 49 ankles and two shoulders) of 190 patients with haemophilia or von Willebrand disease were submitted to RS with C-Y(90) at Hemocentro de Mato Grosso, Brazil. Forty joints had radiographic Pettersson scores above 8. There were 36 joints of 22 patients with inhibitors to factor VIII. The procedure was safe with low occurrence of adverse events. The main effect was the overall reduction in joint bleeding frequency, from 19.8 to 2.6 per year post-RS. Similar results were obtained in cases with high radiographic scores and in inhibitor patients. Pain reduction was observed in most cases. Average range of motion was maintained or increased 1 year post-RS in most joints. Extension was stable or increased in 88.2% of the knees and 86.5% of the elbows. Ankle plantarflexion was stable or increased in 90.9%, whereas dorsiflexion was maintained or increased in 87.9%. Worsening of the range of motion, when present, ranged from 14 to 17 degrees. We concluded that RS with C-Y(90) represents an important resource for the treatment of chronic haemophilic synovitis, markedly reducing joint bleeding frequency and pain, irrespective of the radiographic stage and inhibitor status.

In vivo comparative study of hydroxyapatite labeled with different radioisotopes: evaluation of the scintigraphic images.

Radyosinovectomy (RSV) is a radiotherapeutic modality where a beta-emitting radionuclide is administered locally by intra-articular injection on the form of a colloid or radiolabeled particulate. RSV is a well-accepted therapeutic procedure in inflammatory joint diseases and has been successfully employed for more than 50 years as a viable alternative to surgical and chemical synovectomy. The aim of this work is to compare the in vivo stability of hydroxyapatite labelled with (177)Lu, (90)Y and (153)Sm. All radionuclides were labelled with high yield and were retained in the joint for 7 days, showing stability and usefulness as tools in the RSV treatment. A similar retention of the products in the muscle was observed when the particles were administrated in the muscle. However, the pure form of the radionuclides were rapidly cleared from the blood and accumulated in the liver when injected i.v.. Although (153)Sm-HA is already available for nuclear medicine procedures and clinical studies with (90)Y-HA have been developed, (177)Lu-labeled RSV agents will be economically more viable and has not been studied yet. Its favorable characteristics contribute to follow, to predict and asses the success of RSV by bone scintigraphy studies.

Post-cardiotomy circulatory support with the Terumo Baby-Rx oxygenator in a newborn.

Some patients with severe post-cardiotomy ventricular dysfunction are unable to be separated from cardiopulmonary bypass (CPB). In this setting, extracorporeal circulatory support (ECS) should be instituted to obtain eventual myocardial recovery. We present a newborn in whom an ECS was established with the oxygenator used for the surgical correction.

Novel cysteine proteinase in Trypanosoma cruzi metacyclogenesis.

With the aim to study proteinases released to the culture medium during Trypanosoma cruzi metacyclogenesis, the presence of cysteine proteinases (CPs) was analysed in culture supernatants obtained throughout the differentiation induced by stimulation of epimastigotes with Triatoma infestans hindgut homogenate. In SDS-gelatin containing gels, an important endopeptidase activity with apparent molecular weight range between 97 and 116 kDa was encountered at pH 6, which was abolished by the specific cysteine proteinase inhibitor E-64 and TLCK, but not by pepstatin, 1,10 phenantroline or PMSF. This novel CP, named TcCPmet, showed affinity to cystatin-Sepharose, denoting its thiol-proteinase character as well as to ConA-Sepharose, indicating it contains N-linked oligosaccharides. However, it presented a different elution pattern on ConA-Sepharose than cruzipain and, in addition, it was not recognized by anti-cruzipain serum, facts that strongly suggest the different nature of both CPs. Moroever, evidence is presented indicating that TcCPmet was able to hydrolyse the same chromogenic peptides as cruzipain at optimal alkaline pH values, although with a different order of effectiveness. Our results indicate the presence of a novel CP secreted by metacyclic trypomastigotes and reinforces the important role of these enzymes in metacyclogenesis.

Continuous cephalosporin C purification: dynamic modelling and parameter validation.

A mathematical kinetic model for the adsorption and desorption of cephalosporin C on Amberlite XAD-2 resin is proposed. The model can represent Langmuir, Freundlich or linear isotherms at equilibrium. The intrinsic kinetic parameters and adsorption isotherms as well as physical parameters such as the effective diffusivity and the external mass transfer coefficient were obtained at different temperatures and ethanol concentrations. An unfavourable cephalosporin C adsorption occurred when ethanol was present in the solution. It has been shown that at 25 degrees C the ethanol, at concentrations from 1.5% to 2.5%, decreases the cephalosporin C adsorption. However, this behaviour was not observed at 10 degrees C. The kinetic model fitted the experimental data well under different conditions. The model was validated in a continuous process of cephalosporin C purification using the same resin. The model with the validated parameters is able to predict the behaviour of the reactor system. The continuous process is composed of two stirred tank reactors with adsorber recycle. The adsorption occurs in the first stage, and elution of the product takes place in the second stage with ethanol as eluent. The dynamic behaviour of the process was described using the following parameters: hydraulic residence time for the first (theta(h1)) and second stage (theta(h2)), solid residence time (theta(s)), initial concentration of CPC (C(0)), inlet ethanol concentration (C(ET0)) and kinetics parameters.

[Early release of the antiinflammatory cytokine IL-10 in traumatic brain injury]. / Liberación precoz de la citokina antiinflamatoria IL10 en el trauma severo de cráneo.

It has been reported that upwards of 50% of patients who survive an initial brain traumatic insult subsequently die due to infection and multiple organ failure. A paralysis of cell-mediated immunity following trauma, partially induced by anti-inflammatory cytokine release, appears to be responsible for the increased susceptibility to infections. We determined the plasma levels of the anti-inflammatory cytokine IL-10 and the pro-inflammatory TNF-alpha in 15 patients admitted with severe traumatic brain injury (TBI). None of the patients had received glucocorticoid or catecholamine treatment. Thirteen volunteers served as controls. At study entry the IL-10 plasma levels were significantly higher than in controls: 41.8 (17.3-265.4) pg/mL vs. 2.2 (1.4-2.7) pg/mL, p < 0.001 (Mann-Whitney test). There was no difference between the first (at study entry) and second sample (4 hours later) (Wilcoxon test). TNF-alpha plasma levels were similar in patients and controls at study entry and 4 hours later. We conclude that severe TBI patients present an early response, with a significant increase of IL-10 plasma levels. These results could partially explain the immunodepression following TBI.

Antibodies recognizing CD24 LAP epitope on human T cells enhance CD28 and IL-2 T cell proliferation.

Membrane expression of the CD24 molecule on activated T lymphocytes is not elucidated fully. We previously described the intracellular and cell-surface expression of the CD24 sialic acid-dependent epitope(s) on phytohemagglutinin-activated peripheral blood mononuclear cells. However, the CD24 core protein was not detected previously on human T cells. This study reinvestigated the expression and role of CD24 in T cell subsets. We analyzed binding of anti-CD24 monoclonal antibodies (mAbs) to sialic and leucine-alanine-proline (LAP) epitopes in resting and activated, normal T lymphocytes. CD24 LAP and CD24 sialic epitopes were detected on activated CD4- and CD8-positive cells. Although expression of CD24 sialic epitopes remained stably expressed in interleukin (IL)-2-dependent cultures, T cell expression of the LAP epitope was transient. Anti-LAP antibodies strongly enhanced the response of T cells to a combination of anti-CD3/CD28 mAbs and enhanced proliferative response induced by recombinant IL-2. We found similarities in the tissue distribution and function of the human CD24 LAP molecule and the murine, heat-stable antigen, which suggests that CD24 might function as a signaling molecule on human T cells.

Kinetic studies of clavulanic acid recovery by ion exchange chromatography.

Clavulanic acid (CA) is a beta-lactamase inhibitor produced by strains of Streptomyces clavuligerus. Nowadays, the combination of CA with amoxycillin is the most successful example of the use of a beta-lactam antibiotic sensitive to beta-lactamases together with an inhibitor of these enzymes. Clavulanic acid is purified from fermentation broth by a series of steps consisting mainly of two-phase separation processes such as liquid-liquid extraction, adsorption or ion-exchange chromatography, among others. Amberlite IRA 400, a strong anion-exchange resin, has a very high adsorption capacity for CA (Mayer et al. 1997). This resin can be pre-treated with NaCl (chloride cycle), to remove selectively only those anions, which are able to displace chloride from the resin or with NaOH (hydroxyl cycle), to remove all species of anions. In order to decide the best operating conditions for CA recovery by ion-exchange resins and then to construct a model of this separation process, batch experiments were conducted using Amberlite IRA 400 in the chloride cycle. These runs were carried out in a 200 ml stirred tank, at two different initial solution pH, 6.2 and 4.0; the temperature was maintained at 10 degrees C and 20 degrees C during adsorption and 30 degrees C during the desorption step. It was possible, on the basis of these batch results, to model the separation process, including the adsorption kinetics, equilibrium data and mass transfer limitations.