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Biomedical subjects

M Heller

Publications and source records attributed to M Heller.

At least 19 recordsLinked to original sources

Percutaneous management of occlusive arterial disease associated with vasculitis: a single center experience.

The purpose of this study was to evaluate the safety and effectiveness of percutaneous transluminal angioplasty for occlusive arterial disease associated with vasculitis. Eleven patients (10 women, 1 man; ages 35-82 years) with the diagnosis of vasculitis of the large vessels underwent interventional treatment during intraarterial angiography. The causes included giant cell arteritis (n = 8) and Takayasu arteritis (n = 3). Thirty-three occlusive lesions (including brachiocephalic and renal arteries, and arteries of upper and lower extremities) were treated with balloon angioplasty and/or stent placement. Follow-up included clinical examination, angiography, and color duplex ultrasound. Technical success was 100% (25/25) for stenoses and 50% (4/8) for occlusive lesions, representing all lesions combined from different anatomic locations. Dissection (n = 3) and arterial rupture with retroperitoneal hematoma (n = 1) was found in three patients. During follow-up (mean 12 months), restenoses (n = 8) and re-restenoses (n = 1) occurred in 8 vascular areas. Three of these lesions were treated with repeated PTA (n = 4). The cumulative primary clinical success rate was 67.6%, cumulative secondary success rate 74.4%, and cumulative tertiary success rate 75.9%. Interventional therapy in systemic vasculitis provides promising results in technical success rates and followup. Angioplasty may result in arterial injury, but the rate of complications is low.

Adult↗

[Induction of remission with infliximab in therapy-refractory Wegener's granulomatosis - Follow-up of six patients].

UNLABELLED: BACKGROUND AND QUESTION: The prognosis of patients with Wegener's granulomatosis (WG) refractory to standard treatment for the induction of remission (cyclophosphamide and steroids) has been poor so far. We report on the results of the follow-up of six patients refractory to the standard regimen (Fauci's scheme) with progressive, imminent visual loss, pulmonary and renal involvement, respectively. How long can remissions be successfully maintained with anti-TNF-alpha-antibody infliximab? What side effects occur? PATIENTS AND METHODS: Patients received infliximab (3 mg/kg) in addition to standard therapy with cyclophosphamide and steroids. Intervals between the first two infliximab infusions were 2 weeks, thereafter 4 weeks. Based on the impression of higher efficacy patients received 5 mg/kg infliximab for subsequent infusions. RESULTS: Remission was induced after 4-6 infliximab infusions in five patients. Remission has been maintained in four patients for 16-26 months. After 12 months a pulmonary relapse occurred in one patient, who received azathioprine for the maintenance of remission. Infliximab was stopped in another patient because of a suspected infection. In the light of high cumulative cyclophosphamide doses (100 g/275 g) and cyclophosphamide induced hemorrhagic cystitis, infliximab was added to azathioprine in the two patients with a pulmonary relapse and protrusion of the eye with imminent visual loss, respectively. Remission was induced in both patients. A carcinoid of the bronchus was diagnosed in one patient after 12 months in remission. CONCLUSION: Infliximab means a new therapeutic option and offers better perspectives for a patient group with previously bad prognosis.

Adrenal Cortex Hormones↗

Gadobutrol: an alternative contrast agent for digital subtraction dacryocystography.

We report the application of gadobutrol as a contrast medium for digital subtraction dacryocystography (DS-DCG) in patients with known allergy to iodinated contrast agent. Gadobutrol has the double gadolinium concentration (1.0 mmol/ml) of other gadolinium-based contrast agents. Quality of the DS-DCG images obtained with gadobutrol was comparable to DS-DCG images obtained with iodinated contrast medium. Radiodensity measurements using a micro-CT scanner confirmed a high radiodensity of gadobutrol which was comparable to the radiodensity of iopentol with a iodine concentration of 250 mg/ml and only approximately 20% lower than the radiodensity of iopentol with a concentration of 300 mg/l. Gadobutrol is a well-suited substitute for DS-DCG in patients with allergy to iodinated contrast agents.

Aged↗

[Sport injuries of the extensor mechanism of the knee].

Injuries of the extensor mechanism of the knee occur frequently during sport activity. For a successful treatment they must be diagnosed early. Besides osseous structures the patellar tendon, the patella, the quadriceps muscle and tendon, retinacula and bursae can be affected. After initial clinical examination there are different noninvasive imaging modalities available for assessment of bone, cartilage, ligaments, tendons and soft tissue. Conventional radiographs are still the basic imaging tool for the clinician. Additional information about the osseous status is provided by computed tomography, whereas sonography plays an important role concerning diagnosis of soft tissue injuries. For the detection of cartilagenous, ligamentous or tendon lesions MRI is the superior non-invasive imaging modality.

Athletic Injuries↗

German pediatric reference data for quantitative transverse transmission ultrasound of finger phalanges.

Quantitative ultrasound (QUS) of the finger phalanges is a useful tool in the assessment of disease- or age-related deterioration of bone. For studying the impact of juvenile diseases or growth disorders affecting the skeleton, a reference database for QUS parameters is needed. The aim of this study was to establish a calibrated reference database of parameters of transverse ultrasound transmission through juvenile finger phalanges. A total of 1328 children (650 females, 678 males; ages 3-17 years) were measured in Heidelberg and Kiel in order to establish a German reference database. Highly significant gender-specific correlations (p<0.0001) were found between the QUS parameters amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) versus age, body height and body mass index (BMI). For AD-SoS the correlation coefficients were R2 = 0.64 against age in males and R2 = 0.73 in females, R2 = 0.60 against body height in males and R2 = 0.68 in females, and R2 = 0.19 against BMI in males and R2 = 0.23 in females. For BTT the correlation coefficients were R2 = 0.74 against age in males and R2 = 0.79 in females, R2 = 0.75 against body height in males and R2 = 0.77 in females, and R2 = 0.32 against BMI in males and R2 = 0.35 in females. Age and height were the strongest determinants of QUS results. Gender-specific differences were observed in AD-SoS (significant for ages 11-14 years and for 150-170 cm body height) and in BTT (significant for ages 7 and 11-17 years and for 160-170 cm body height). Tables of QUS parameters versus age and height can serve as a basis for the evaluation of the impact of skeletal diseases or growth disorders on phalangeal QUS. Depending on the type of disease or growth disorder, measurement results can be compared with age- or height- specific reference data. In this way a simple and radiation-free assessment of juvenile skeletal disorders using quantitative ultrasound might be possible in the future.

Adolescent↗

Metabolically active components of fat-free mass and resting energy expenditure in humans: recent lessons from imaging technologies.

Imaging technologies, i.e. magnetic resonance imaging (MRI), computer tomography (CT) and dual-energy X-ray absorptiometry (DEXA), are precise and accurate techniques used to study lean body mass and adipose tissue distribution. CT and MRI can also be used to assess metabolically active components of fat-free mass (FFM). (Throughout this article, metabolic activity is defined with respect to oxidative metabolism.) To date a total of 116 in vivo measurements of organ masses (OM), in combination with the measurement of resting energy expenditure (REE), have been reported. These data suggest that MRI- or CT-derived OM explains part (approximately 5-10%) of the interindividual variance in REE. The data also suggest that REE can be reconstructed from detailed body composition analysis. Calculating REE from the sum of individual OM multiplied by a constant organ tissue-respiration rate showed a high correlation between calculated and measured REE, with only small and non-significant differences of 83-96 kJ d-1. In addition to CT- and MRI-derived OM, data are available of 244 obese and non-obese subjects regarding the association between regional components of lean body mass (LBM, assessed by DEXA) and REE. These results suggest that measurement of LBM distribution also provides the opportunity to adjust for the non-linearity of REE on body mass. Assessment of metabolically active components of FFM or LBM may also add to our understanding of malnutrition-, obesity- and disease states-related variance in REE. There is need for (1) standardization of imaging technology in body composition research; (2) reference data on detailed body composition, also including more recent autopsy data; (3) reducing the number of assumptions in model-based predictions; and (4) a combination of imaging technologies with in vivo measurements of individual OM respiration.

Absorptiometry, Photon↗

Detection of changes in cartilage water content using MRI T2-mapping in vivo.

OBJECTIVES: Osteoarthritis (OA) is the most prevalent chronic disease in the elderly, and it is generally diagnosed at an advanced state when treatment is difficult if not impossible. The early form of OA is characterized by an elevated water content in the cartilage tissue. The purpose of this study was to verify in vivo if changes in the water content of patellar cartilage typically occurring in early OA can be detected using T(2) mapping MRI methods. DESIGN: Twenty healthy volunteers performed 60 knee bends in order to compress their patellar cartilage thereby reducing its water content. MR images of the patellar cartilage were acquired immediately following exercise and after 45 min of rest. Patellar cartilage thickness and T(2) maps were determined and their difference between the time points evaluated. RESULTS: Cartilage thickness increased by 5.4+/-1.5% from 2.94+/-0.15 mm to 3.10+/-0.15 mm (P< 0.001) following 45 min of rest, while T(2) increased by 2.6+/-1.0% from 23.1+/-0.5 ms to 23.7+/-0.6 ms (P< 0.05). CONCLUSION: Small, physiologic changes in the water content of patellar cartilage and the concomitant change in proteoglycan and collagen density following exercise can be detected using MRI. The proposed T(2)-mapping method, together with other non-invasive MR cartilage imaging techniques, could aid in the early diagnosis of OA.

Adult↗

[Early results with a monorail-stent-balloon device for endovascular treatment of renal artery stenosis].

OBJECTIVE: To evaluate the technical feasibility of a new monorail-stent-balloon device for treatment of renal artery stenosis (RAS). PATIENTS AND METHODS: During a study period of 18 months, 38 patients with proven RAS in 41 cases (hypertension n = 36, renal insufficiency n = 13) and indication for stenting (calicified ostial lesions n = 35, insufficient PTA n = 4, dissection n = 2) were enrolled into this prospective evaluation. Pre-mounted stents (Rx-Herculink(TM) 5 mm = 13, 6 mm = 34, 7 mm = 1) were implanted a transfemoral (n = 35) or transbrachial approach (n = 6). Mean grade and lengths of stenosis measured were 88 % plus minus 10 and 9 mm plus minus 5. RESULTS: Renal stent implantation was technically successful in all cases (100 %). In 7 cases a second stent had to be implanted to cover the entire lesion. The transstenotic pressure drop decreased from 88 mmHg plus minus 10 before to 1 mmHg plus minus 1.8 after the procedure. Remaining stenosis measured 0.7 % plus minus 4.2. Serum creatine levels decreased from 1.9 mm/dl to 1.5 mg/dl (n. s.), blood pressure decreased from 178/94 mmHg to 148/79 mmHg (p < 0.0001) after the intervention. Primary and secondary patency rates at 6 months were 72 % (Standard Error 9.8 %) and 77 (% (Standard Error 9.2 %), respectively. CONCLUSION: With the used monorail-stend-balloon device a technically easy, secure and exact renal stent placement is guaranteed, patency rates are similar to those described in the current literature.

Adult↗

[Alar ligaments: radiological aspects in the diagnosis of patients with whiplash injuries].

Post-traumatic changes of the alar ligaments have been proposed to be the cause of chronic pain in patients after whiplash injury of the cervical spine. In addition to an asymmetric dens position, widening of the atlantodental distance to more than 12 mm can be an indirect sign of an alar ligament rupture. CT is recommended for detection of a avulsion fracture of the occipital condyle. Isolated ruptures of the alar ligaments are best visualized on MRI. In patients with chronic impairments after whiplash injuries changes of the alar ligaments on MRI must be differentiated from normal variants in healthy individuals.

Adult↗

[High-resolution computed tomography of the lungs in pediatric patients].

Since the introduction of the high-resolution technique more than ten years ago, HRCT has become an established modality for diagnosing diseases of the respiratory system. This is especially true for the diagnosis of lung diseases in adults. Experience in HRCT of the lungs is limited in pediatric patients. This review gives an overview of frequent and less frequent HRCT findings in pulmonary diseases in childhood. A purely reticular pattern is rarely observed in infants. Pulmonary diseases associated with overinflation are relatively frequent. Paired inspiratory-expiratory scans combine morphological analysis with functional information and have improved the diagnosis of air trapping, e. g. in post-infectious bronchiolitis obliterans or bronchopulmonary dysplasia. Especially in children the high radiation exposure is a problem. Even when applying a low-dose protocol the radiation dose of HRCT will still exceed the dose of a chest X-ray by 100 times. The indication for pediatric pulmonary HRCT is limited to selected cases and it should be decided in agreement with the pediatric radiologists and the pediatric pulmonologists.

Adolescent↗

[Sensitivity of MRI in detecting alveolar Infiltrates: Experimental studies].

PURPOSE: An experimental study using porcine lung explants and a dedicated chest phantom to evaluate the signal intensity of artificial alveolar infiltrates with T 1 - and T 2 -weighted MRI sequences. MATERIAL AND METHODS: 10 porcine lung explants were intubated, transferred into the cavity of a MRI-compatible chest phantom and inflated by continuous evacuation of the artificial pleural space. All lungs were examined with MRI at 1.5 T before and after intra-tracheal instillation of either 100 or 200 ml gelatine-stabilised liquid to simulate alveolar infiltrates. MR-examination comprised gradient echo (2D- and 3D-GRE) and fast spin echo sequences (T 2 -TSE and T 2 -HASTE). The signal intensity of lung parenchyma was evaluated at representative cross sections using a standardised scheme. Control studies were acquired with helical CT. RESULTS: The instilled liquid caused patchy confluent alveolar infiltrates resembling the findings in patients with pneumonia or ARDS. CT revealed typical ground-glass opacities. Before the application of the liquid, only T 2 -HASTE and T 2 -TSE displayed lung parenchyma signals with a signal/noise ratio of 3.62 and 1.39, respectively. After application of the liquid, both T 2 -weighted sequences showed clearly visible infiltrates with an increase in signal intensity of approx. 30 % at 100 ml (p < 0.01) and 60 % at 200 ml (p < 0.01). With 2D- and 3D-GRE the infiltrates were not visible, although the lung parenchyma signal increase was statistically significant. On 2D-GRE the increase in signal intensity reached 0.74 % (p = 0.32) after 100 ml and 5.6 % (p < 0.01) after 200 ml (for 3D-GRE: 2.2 % [p = 0.02] at 100 ml and 4.4 % at 200 ml [p < 0.01]). The CT controls revealed a significant increase of lung density of 17 H.E. at 100 ml (p = 0.02) and 75 H.E. at 200 ml (p < 0.01). CONCLUSIONS: MRI with T 2 -weighted sequences detects artificial alveolar infiltrates with high signal intensity and may be a highly sensitive tool to detect pneumonia in patients.

Animals↗

[Radiological assessment of small bowel obstructions: Value of conventional enteroclysis and dynamic MR-enteroclysis].

PURPOSE: To compare small bowel lesions, especially stenoses, with conventional enteroclysis, static MRI and dynamic MR-enteroclysis. MATERIALS AND METHODS: Forty-two patients with Crohn's disease or other suspected small bowel lesions were examined. MRI was performed in a static and a dynamic way either within one hour after conventional enteroclysis (n = 30) or a few days afterwards (n = 12). In order to monitor bowel filling and to characterize stenoses in a dynamic fashion, 4 series of coronal T2w HASTE breath hold sequences were used, first without additional bowel opacification and then during administration of 1,5 l methyl cellulose via a naso-intestinal tube in the MR unit. Intravenously applied Buscopan was used to reduce bowel movement. RESULTS: In 4 out of 42 Patients, application of methylcellulose was limited to 1000 ml because of gastrointestinal complaints or visible gastral reflux. All patients could be evaluated. Static MRI performed within one hour after conventional enteroclysis and no additional bowel opacification showed insufficient bowel distension. Distension was still better than in MRI without prior application of contrast medium. On the contrary, dynamic MR - enteroclysis lead to controlled and complete bowel distension which allowed for significantly better evaluation of normal bowel anatomy and pathological alterations of the gut. Because of a better bowel distension and dynamic evaluation, MR-enteroclysis revealed significantly more stenoses (n = 42) than MRI obtained with less distension (n = 27, p < 0.001), and characterization of lesions was comparable to conventional enteroclysis (p < 0.001). Fixed and non-fixed stenoses could be differentiated by dynamic MR-enteroclysis. Furthermore, extraluminal complication of Crohn's disease such as abscesses and fistulae or large bowel manifestation of disease were shown in 13 patients. CONCLUSIONS: Dynamic MR-enteroclysis is feasible in routine diagnostic work-up of the small bowel. It is superior in depicting intra- and extraluminal manifestation of small bowel lesions and enables characterization of stenoses comparable to conventional enteroclysis.

Adolescent↗

Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener's granulomatosis.

OBJECTIVE: To study the effect of the chimeric monoclonal anti-tumour necrosis factor alpha (TNF-alpha) antibody infliximab in the induction of remission in six patients refractory to standard treatment with cyclophosphamide and corticosteroids. In four patients, other measures for treating refractory Wegener's granulomatosis (WG) that have been advocated previously, i.e. intensified cyclophosphamide therapy and additional intravenous immunoglobulin, were ineffective. METHODS: Patients received infliximab (3 mg/kg in two patients and 5 mg/kg in four patients) with a 2-week interval after the first administration and 4-week intervals between infusions until remission, in addition to cyclophosphamide and corticosteroids. Vasculitis activity was assessed with the Birmingham Vasculitis Activity Score (BVAS). A standardized interdisciplinary approach was used for the follow-up of specific organ involvement. RESULTS: Remission was induced in five patients and corticosteroid doses could be tapered. Acute-phase responses (e.g. C-reactive protein) normalized. Titres of c-ANCA (cytoplasmic pattern antineutrophil cytoplasmic antibodies) were no longer detectable. The BVAS was reduced to zero. The higher dose of infliximab (5 mg/kg) seemed more effective in inducing remission. One patient was withdrawn because of suspected systemic infection. Five patients remained in remission for 6-24 months of follow-up. CONCLUSION: The data suggest that infliximab may provide an effective and more specific therapeutic option in the treatment of active WG refractory to standard treatment.

Antibodies, Monoclonal↗

[In vitro studies into the influence of ochratoxin A on the production of tumor necrosis factor alpha by the human monocytic cell line THP-1].

The influence of pure OTA and an Aspergillus-ochraceus crude toxin on the intracellular expression and the secretion of tumor necrosis factor (TNF) alpha by the monocytic cell line THP-1 was studied in vitro. After 4 hours exposure, the secretion of TNF alpha was inhibited to 50% by pure OTA in a concentration of 400 ng/ml and by crude toxin in a concentration of 100 ng/ml. The same concentrations of mycotoxins impaired the mitochondrial activity of THP-1 cells only marginally. The intracellular expression of TNF alpha was not disturbed by pure OTA in the concentrations tested, whereas crude toxin showed an inhibitory effect. The possible reasons for these findings are discussed.

Calcium Channel Blockers↗

Cytokine mRNA expression in experimental porcine pneumonia.

A porcine Pasteurella multocida (P. m.) infection model was established to study the spatial distribution of cytokine mRNA-expressing cells in lung tissue during acute pneumonia. The mRNA detection was performed by non-radioactive, formamide-free in situ hybridization (ISH) using oligonucleotides against the porcine interleukins (IL): IL-1 beta, IL-2, IL-4, IL-6, IL-8, TNF alpha and TGF beta. Cytokine mRNA-expressing macrophages were demonstrated by a double staining procedure combining immunohistochemistry (IH) using the primary antibody 2G6 with IL-1 beta, IL-6 and TGF beta ISH. With the exception of some stained TNF alpha-expressing cells, no IL mRNA was detectable in the lung of unaffected animals. The experimental P. m. pneumonia was characterized by a predominant, exudative and an additional proliferative interstitial component as well as abscess formation in the lung. Many cells of the region between the abscess membrane and the affected lung area showed high IL-6, IL-1 beta, IL-4 as well as TGF beta and few cells low IL-8 mRNA expression with characteristic distribution patterns. The ISH/IH double staining procedure revealed that at least some of the IL-6 or TGF beta-producing cells belonged to the 2G6-positive macrophages.

Animals↗

Analysis of artefacts and detail resolution of lung MRI with breath-hold T1-weighted gradient-echo and T2-weighted fast spin-echo sequences with respiratory triggering.

The aim of this study was to evaluate feasibility and limitations of two MR sequences for imaging of the lung using a semi-quantitative rating scale. Ten healthy volunteers were assessed with a breath-hold T1-weighted gradient-recalled-echo (TR/TE=129/2.2 ms, matrix 173 x 256) and a T2-weighted turbo spin-echo (TSE) sequence with respiratory triggering (TR/TE=3000-5000/120 ms, matrix 270 x 512) in axial 6-mm slices. The T1-weighted GRE protocol included a pre-saturation pulse over the mediastinal structures. Artefacts and resolution of vessel/airway structures in each lung segment were evaluated by two observers (10 volunteers, 180 segments). Cardiac and vessel pulsation artefacts predominated on T1-weighted GRE, respiration artefacts on T2-weighted TSE (lingula and middle lobe). Pre-saturation of the mediastinum reduced pulsation artefacts on T1-weighted GRE. T1-weighted GRE images were improved by bright flow signal of vessels, whereas image quality of T2-weighted TSE was reduced by black-blood effects in central parts of the lung. Delineation of lung periphery and the mediastinum was superior with T2-weighted TSE. Segmental/sub-segmental vessels (up to fourth/fifth order) and bronchi (up to third order) were identified. All 180 lung segments were imaged in diagnostic quality with at least one of the two sequences (T1-weighted GRE not diagnostic in 9 of 180, T2-weighted TSE in 4 of 180). Both sequences were found to be complementary: superior identification of gross lung anatomy with T1-weighted GRE and higher detail resolution in the periphery and the mediastinum with T2--weighted TSE.

Adult↗

In vivo changes in the neuroforaminal size at flexion-extension and axial rotation of the cervical spine in healthy persons examined using kinematic magnetic resonance imaging.

STUDY DESIGN: In vivo flexion-extension and axial rotation magnetic resonance imaging (MRI) studies of the cervical spine were performed inside a positioning device. OBJECTIVE: To determine the functional changes of neuroforaminal size that occur during flexion-extension and axial rotation of the cervical spine in healthy persons. SUMMARY OF BACKGROUND DATA: Kinematic MRI studies of the cervical spine were performed to obtain detailed information about the functional changes that occur in neuroforaminal size during flexion-extention and axial rotation. The results were compared with published data of in vitro functional flexion-extension and axial rotation studies of the cervical spine. METHODS: Inside a positioning device, the cervical spines of 30 healthy persons were examined in a whole-body magnetic resonance scanner from 40 degrees of flexion to 30 degrees of extension at nine different angle positions. In addition, axial rotation was performed at neutral position (0 degrees ) and at 20 degrees and 40 degrees of axial rotation to both sides. The images were analyzed with respect to the neuroforaminal size at each position using a reformatted 3D-FISP sequence. RESULTS: At flexion, widening of the neuroforaminal size of up to 31% (compared with neutral position, 0 degrees ) was observed. Conversely, at extension a decrease in the size of the neuroforamen of up to 20% was recognized. At 20 degrees and 40 degrees of ipsilateral rotation of the head, a reduction in the neuroforaminal size of up to 15% and 23%, respectively, compared with the neutral position was noted. In contrast, a widening of the foraminal size was recognized on the contralateral side of 9% and 20% at 20 degrees and 40 degrees rotation. Statistically significant differences (p <== 0.05) were found in the neuroforaminal size between different degrees of flexion and extension and in addition for axial rotation compared to neutral position (0 degrees ). CONCLUSION: Compared with the results of previous biomechanical studies of human cadaver cervical spines, kinematic MRI provides additional noninvasive data concerning the physiological changes of the neuroforaminal size during flexion-extension and axial rotation in healthy individuals.

Adult↗

CD28 stimulation regulates its association with N-ethylmaleimide-sensitive fusion protein and other proteins involved in vesicle sorting.

CD28 delivers a co-stimulatory signal for T cell antigen receptor induced activation of T cells through a mechanism which remains mostly elusive to date. In order to try and gain insight into CD28 function, we therefore applied state-of-the-art mass spectrometric protein identification technology to the analysis of CD28 immunoprecipitates prepared from Jurkat T cells. We found that N-ethylmaleimide-sensitive fusion protein (NSF) and other proteins with sequence similarities to proteins part of or implicated in vesicular protein sorting pathways, were associated with CD28 in a CD28 stimulation-dependent manner. Furthermore, N-ethylmaleimide treatment abolished the NSF/CD28 interaction completely, and blocked CD28 association with a tyrosine phosphorylated 103 kDa protein in the activated cells. These results are suggestive of a potential model for CD28 co-stimulation regulated by an NSF-catalyzed mechanism.

Amino Acid Sequence↗