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Biomedical subjects

S Karlsson

Publications and source records attributed to S Karlsson.

At least 37 records · Page 2Linked to original sources
PubMed2001

A transplantable human carcinoid as model for somatostatin receptor-mediated and amine transporter-mediated radionuclide uptake.

A human midgut carcinoid tumor was successfully transplanted into nude mice and propagated for five consecutive generations (30 months) with well-preserved phenotype. Tumor cells in nude mice expressed identical neuroendocrine markers as the original tumor, including somatostatin receptors (somatostatin receptors 1 to 5) and vesicular monoamine transporters (VMAT1 and VMAT2). Because of the expression of somatostatin receptors and VMAT1 and VMAT2 the grafted tumors could be visualized scintigraphically using the somatostatin analogue 111In-octreotide and the catecholamine analogue 123I-metaiodobenzylguanidine. The biokinetics of the somatostatin analogue 111In-octreotide in the tumors was studied and showed a high retention 7 days after administration. Cell cultures were re-established from transplanted tumors. Immunocytochemical and ultrastructural studies confirmed the neuroendocrine differentiation. The human origin of transplanted tumor cells was confirmed by cytogenetic and fluorescence it situ hybridization analyses. Spontaneous secretion of serotonin and its metabolite, 5-hydroxyindole acetic acid, from tumor cells was demonstrated. The tumor cells increased their [Ca2+]i in response to beta-adrenoceptor stimulation (isoproterenol) and K+-depolarization. All somatostatin receptor subtypes could be demonstrated in cultured cells. This human transplantable carcinoid tumor, designated GOT1, grafted to nude mice, will give unique possibilities for studies of somatostatin receptor- and VMAT-mediated radionuclide uptake as well as for studies of secretory mechanisms.

3-Iodobenzylguanidine↗
PubMed2001

Protein characterisation of salivary and plasma biofilms formed in vitro on non-corroded and corroded dental ceramic materials.

Dental ceramics are generally regarded as low-adhesive materials. Different ceramics may, however, differ in composition and physico-chemical surface properties, which may be changed after corrosion. The aim of this study was to examine the adsorption of proteins onto specimens of different ceramic materials after the incubation in saliva and plasma before and after in vitro corrosion. In addition, the topography of the biofilm was examined by AFM. Surface-bound proteins were desorbed and analysed by polyacrylamide gel electrophoresis (PAGE) and immunoblotting using antibodies to saliva and plasma proteins. Silver-stained gels indicated differences in the adsorption of proteins. Differences in surface roughness at the nanometer level did not, however, seem to be correlated to the protein adsorption. After corrosion, unchanged or increased protein staining was generally seen in the gels and Western blots. The reactions for salivary amylase and proline-rich proteins varied between the different materials. Albumin and fibrinogen were identified in samples from all materials tested. Fibronectin and in specific IgA were more sparsely seen. No saliva but all plasma proteins were identified in the alumina and yttria-stabilised zirconia samples and reduced protein reactions were obtained after corrosion.

Adsorption↗
PubMed2001

Influence of pH and storage time on the sorption and solubility behaviour of three composite resin materials.

OBJECTIVES: The aim of this study was to determine whether pH and time has any influence on the sorption and solubility behaviour of composite resin materials stored in a buffer solution. METHODS: Three hybrid composite restorative resin materials (Spectrum, Z-100 and ArtGlass) with different matrix structure and filler composition were studied. One hundred and twenty specimens of each material were produced according to ISO 4049. The materials were stored in McIlvain's buffer solution at different pH (4, 6 and 8) at 1, 7, 60 and 180 days. pH measurements were carried out before and after completed storage. RESULTS: Time had a significant influence on the sorption and solubility behaviour of the composite resin materials tested. One of the materials Z-100 showed a significant mass increase and/or decrease depending on the pH of the solution. The material Spectrum was significantly influenced by pH, resulting in different sorption depending on the pH of the solution. CONCLUSIONS: Time of storage was important for the sorption and solubility behaviour of the composite resin materials tested. Comparison of solubility for one of the materials showed twice as high values in the present study as previously reported when distilled water was used as storage medium. pH in the solution seems to have an influence on the sorption and solubility behaviour of composite resin materials. The sensitivity of the sorption and solubility behaviour to time and pH of the materials tested seems to be related to the hydrophilicity of the matrix and the chemical composition of the filler.

Absorption↗
PubMed2001

Mean frequency and signal amplitude of the surface EMG of the quadriceps muscles increase with increasing torque--a study using the continuous wavelet transform.

The continuous wavelet transform (CWT), a time-frequency method, was used when calculating mean frequency of the power spectrum (MNF) and signal amplitude (RMS) of the surface EMG to investigate their relationships to force during a gradually increasing knee extension (ramp). Based upon the CWT, MNF was redefined to include time dependence on the EMG signal frequency contents, the short-time MNF (STMNF). Surface EMG was recorded from vastus lateralis, rectus femoris and vastus medialis in 21 clinically healthy subjects during a brief, gradually increasing contraction up to 100% of a maximum voluntary contraction (MVC), with a duration of approximately 10 s. The relationships between the EMG variables and force using linear regression were determined for each subject. For vastus lateralis, we also investigated if certain aspects of the muscle morphology (i.e., proportions and areas of different fibre types) influenced the EMG-force relationship. For the majority of subjects (17-18 out of 21 subjects) there were significant positive correlations between STMNF and force in the three muscles. No sex differences were found in intercepts or regression coefficients of STMNF. The muscle morphology had a significant influence on the STMNF-force intercept and the regression coefficient. Positive and highly significant linear correlations between RMS and force were found for all subjects and all three muscles.In conclusion, time frequency methods can be applied when investigating EMG during brief contractions associated with non-stationarity. In a great majority of the subjects, and in the three muscles, significant linear force dependencies were found for STMNF. Thus, when evaluating muscle fatigue, e.g., in ergonomic situations, it is important to consider the force level as one factor that can influence the results. Morphological variables (fibre proportions and fibre areas) influenced the STMNF-force relationship in vastus lateralis.

Adult↗
PubMed2001

Protective gloves in Swedish dentistry: use and side-effects.

BACKGROUND: During the 1980s routine wearing of gloves in dentistry was recommended by health authorities in several countries. However, prolonged glove use is associated with side-effects of irritant and allergic origin. OBJECTIVES: To investigate the extent of glove use and self-reported glove intolerance reactions among Swedish dentists, and to examine how far IgE-mediated allergy to natural rubber latex (NRL) occurs in subjects who report rapid itching when in contact with protective gloves. SUBJECTS/METHODS: A postal questionnaire was answered by 3083 of 3500 licensed dentists, a response rate of 88%. Of the dentists who reported rapidly occurring itching of the hands from gloves, 131 of 170 attended a clinical examination including a skin prick test (SPT) and a serological examination (RAST) for IgE-mediated allergy. RESULTS: Seventy-three per cent of the dentists reported daily glove use of more than 2 h, 48% more than 6 h a day, and 6% reported no use. NRL gloves were used most frequently (P < 0.001) and were the main material that elicited symptoms (P < 0.001). Female dentists reported more frequent glove use than males, as did young dentists (P < 0.001) compared with older ones. Females also preferred vinyl gloves. Glove intolerance reactions were reported by 723 (23%) dentists, [females 28%, males 21% (P < 0.001)] and were more common in younger dentists. Of the 417 dentists with reported hand eczema during the previous year, 54% reported glove intolerance, compared with 20% of the dentists without hand eczema (P < 0.001). A logistic regression analysis including hand eczema, age, sex and atopy showed that all these factors contributed significantly to the risk of glove intolerance, and that hand eczema was a stronger factor than atopy. In 15 of 131 (11%) dentists examined for reported glove-related itch, latex allergy was verified by SPT and/or RAST. Glove-related conjunctivitis, rhinitis and asthma, in contrast to skin symptoms, showed a significant association with IgE-mediated allergy to NRL. CONCLUSIONS: Swedish dentists show good compliance with the recommendations for routine glove use. Intolerance reactions are frequently reported, especially by dentists with hand eczema, which emphasizes the need for preventive skin care programmes. Glove-related symptoms from mucous membranes showed a higher association with IgE-mediated allergy to NRL than reported itching of the skin, a fact that should be considered when composing screening questionnaires for NRL sensitization

Adult↗
PubMed2001

Eating difficulties, need for assisted eating, nutritional status and pressure ulcers in patients admitted for stroke rehabilitation.

The aim of this study was to describe the types and extent of eating difficulties, the need for assistance when eating, the nutritional status and pressure ulcers in consecutive patients (n = 162) admitted for stroke rehabilitation over a period of 1 year. Structured observations and assessments of eating, nutritional status (subjective global assessment of nutritional status), pressure ulcers and activities in daily living (Katz ADL-index) were performed by a nurse who also trained the staff to perform these assessments. Difficulties in eating were found in 80%, and 52.5% were unable to eat without assistance. Eating difficulties were: 'eats three-quarters or less of served food' (60%), difficulties in 'manipulating food on the plate' (56%), 'transportation of food to the mouth' (46%), 'sitting position' (29%), 'aberrant eating speed' (slow or forced) (26%), 'manipulating food in the mouth' (leakage, hoarding, chewing difficulties) (24%), 'swallowing difficulties' (18%), 'opening and/or closing the mouth' (16%), and 'alertness' (9%). Thirty-two percent were undernourished (49% of patients needing assisted eating and 13% of those not needing assistance, P < 0.0005). Among patients who were dependent in one or more functions according to the Katz ADL-index, 15% had pressure ulcers. The strongest eating variables for predicting nutritional status were 'alertness', 'swallowing difficulties', 'eats three-quarters or less of served food', and 'aberrant eating speed'. Nutritional status could in turn significantly predict pressure ulcers. Eating difficulties among patients with stroke are complex and the patient's situation before stroke adds to this complexity, especially among those dependent on assisted eating. As difficulties occur both among patients needing and not needing assisted eating, all patients with stroke admitted for rehabilitation need to be systematically assessed for eating difficulties and action needs to be taken to facilitate eating, especially as patients with eating difficulties risk becoming undernourished and in turn developing pressure ulcers.

Activities of Daily Living↗
PubMed2001

Lentiviral-mediated gene transfer into haematopoietic stem cells.

OBJECTIVES: Lentiviral vectors can transduce nondividing cells. As most haematopoietic stem cells (HSCs) are nondividing in vivo, lentiviral vectors are promising viral vectors to transfer genes into HSCs. DESIGN AND SETTING: We have used HIV-1 based lentiviral vectors containing the green fluorescent protein (GFP) gene to transduce umbilical cord blood CD34+ and CD34+/CD38- cells prior to transplantation into NOD/SCID mice. RESULTS: High level engraftment of human cells was obtained and transgene expression was seen in both myeloid and lymphoid lineages. Bone marrow from the primary transplant recipients mice was transplanted into secondary recipients. GFP expression was seen in both lymphoid and myeloid cells in the secondary recipients 6 weeks posttransplantation. Human haematopoietic progenitor colonies were grown from both primary and secondary recipients. Over 50% of the haematopoietic colonies in these recipients were positive for the GFP transgene by PCR. Following inverse PCR, amplified fragments were sequenced and integration of the vector into human genomic DNA was demonstrated. Several vectors containing different internal promoters were tested in NOD/SCID mice that had been transplanted with transduced CD34+ and CD34+/CD38- cells. The elongation factor-1alpha (EF-1alpha) promoter gave the highest level of expression, both in the myeloid and lymphoid progeny of the engrafting cells. CONCLUSIONS: These data collectively indicate that candidate human HSCs can be efficiently transduced with lentiviral vectors and that the transgene is highly expressed in their progeny cells.

Animals↗
PubMed2001

Water sorption and solubility of dental composites and identification of monomers released in an aqueous environment.

Water sorption and solubility of six proprietary composite resin materials were assessed, and monomers eluted from the organic matrix during water storage identified. Water sorption and solubility tests were carried out with the following storage times: 4 h, 24 h and 7, 60 and 180 days. After storage, water sorption and solubility were determined. Eluted monomers were analysed by high performance liquid chromatography (HPLC). Correlation between the retention time of the registered peak and the reference peak was observed, and UV-spectra confirmed the identity. The results showed an increase in water sorption until equilibrium for all materials with one exception. The solubility behaviour of the composite resin materials tested revealed variations, with both mass decrease and increase. The resin composition influences the water sorption and solubility behaviour of composite resin materials. The HPLC analysis of eluted components revealed that triethyleneglycol dimethacrylate (TEGDMA) was the main monomer released. Maximal monomer concentration in the eluate was observed after 7 days. During the test period, quantifiable quantities of urethanedimethacrylate (UEDMA) monomer were observed, whereas 2,2-bis[4-(2-hydroxy-3-methacryloyloxypropoxy)-phenyl]propane (Bis-GMA) was only found in detectable quantities. No detectable quantities of bisphenol-A were observed during the test period.

Analysis of Variance↗
PubMed2001

Factors relating to the use of physical restraints in geriatric care settings.

Physical restraints are commonly used on older persons living in geriatric care settings. The aim of this study was to investigate the influence of environmental and organizational variations and resident and staff characteristics on restraint prevalence. In this cross-sectional study of 33 nursing home wards and 12 group living units for old persons with dementia in two municipalities in northern Sweden, 540 residents (mean age 82) and 529 staff members were evaluated for resident and staff characteristics and organizational and environmental variables. The proportion of residents with impaired mobility function, the number of behavioral disturbances, and nursing staff's attitudes towards use of restraints were the strongest discriminators between restraint-free wards and wards that used restraints. A classification function analysis showed that these three variables could correctly classify the wards as restraint-free, low-use, and high-use wards in 63.6% of the cases, with the highest figures for restraint-free wards (91%). This study has shown that the use of physical restraints is strongly connected with residents' functional status and nursing staffs' attitudes toward their use.

Aged↗
PubMed2001

Work-related skin and airway symptoms among Swedish dentists rarely cause sick leave or change of professional career.

Dentistry usually is 'wet work' with risk of damage to the skin barrier, and the hands may be exposed to skin irritants and contact-sensitizing substances used in dental materials or gloves. Airway irritants may also be present. This study assessed the consequences of work-related skin and airway symptoms among dentists in terms of contact with health authorities, sick leave, or changes in the professional career. A questionnaire on these factors was answered by more than 3000 Swedish dentists. Only 6% of the respondents had consulted a physician, although 22% had noted work-related skin symptoms. In 2% the skin symptoms had caused sick leave, and about 2% had reported their skin symptoms as an occupational disease. Two per cent had consulted a physician owing to work-related airway symptoms, which is a minor part of the 13% who had experienced such symptoms when in contact with dental materials. Twenty-five dentists (<1%) had been on sick leave because of work-related airway symptoms. Only 1 dentists reported change of activities or occupation owing to work-related skin or airway symptoms, and in most cases these symptoms only contributed to their decision. In summary, whereas sick leave in dentists because of musculoskeletal problems may be common, the present study shows that this is not the case for work-related skin or airway symptoms, and such symptoms seldom affect the dentists' professional career.

Adult↗
PubMed2001

Beta cell adaptation to dexamethasone-induced insulin resistance in rats involves increased glucose responsiveness but not glucose effectiveness.

Islet beta cell adaptation to dexamethasone-induced insulin resistance was characterized with respect to glucose-stimulated insulin secretion and islet innervation. Male Sprague-Dawley rats were injected daily with dexamethasone (2 mg/kg for 12 days), which resulted in hyperinsulinemia and hyperglycemia compared with controls (which were injected with sodium chloride). Insulin secretion was characterized in collagenase-isolated islets. Islet innervation was examined by immunocytochemical analysis of tyrosine hydroxylase, neuropeptide Y (sympathetic nerves), and vasoactive intestinal polypeptide (cholinergic nerves). In islets isolated from the insulin-resistant animals, the insulin response to 3.3 or 8.3 mM glucose was three times greater during perifusion compared with controls (p < 0.001). Incubation of islets at 0 to 20 mM glucose revealed a marked leftward shift of the glucose dose-response relation after dexamethasone treatment (potency ratio, 1.78; p < 0.01), with no difference at 0 or 20 mM glucose. Thus, the potency but not the efficacy of glucose was increased. The number of islet nerves did not differ between dexamethasone-treated rats and controls. Dexamethasone-induced insulin resistance leads to adaptively increased glucose responsiveness of the islet beta cells, with increased potency, but not increased efficacy, of glucose to stimulate insulin secretion without any evidence of altered islet innervation.

Adaptation, Physiological↗
PubMed2001

Carbachol restores insulin release in diabetic GK rat islets by mechanisms largely involving hydrolysis of diacylglycerol and direct interaction with the exocytotic machinery.

In several models of insulin resistance, cholinergically induced insulin secretion is augmented. We studied here whether this also is present in the spontaneously diabetic GK (Goto-Kakizaki) rat pancreas. Using carbachol (50 micromol/L), enhanced insulin release was elicited in perfused pancreas under normal or depolarized conditions in GK compared with control rats at 3.3 mmol/L glucose (p < 0.03). Carbachol fully normalized insulin secretion in GK rats at 16.7 mmol/L glucose through an effect abolished by atropine. Similarly, direct stimulation of protein kinase C (PKC) with the DAG-permeable compound 1-oleoyl-2-acetyl-sn-glycerol (OAG, 300 micromol/L) induced more pronounced insulin release in GK islets than in control islets. The diacylglycerol (DAG) lipase inhibitor RHC-80267 (35 micromol/L) significantly reduced carbachol effects in control and GK islets, but had no effect on OAG-induced insulin release. The enhanced insulinotropic effects of carbachol in GK islets was not accompanied by increased cyclic adenosine monophosphate (cAMP) or arachidonic acid (AA) formation in GK when compared with control islets. In conclusion, cholinergic stimulation induced enhanced insulin release in diabetic GK islets. This is largely mediated through mechanisms involving hydrolysis of DAG to AA and interaction with exocytotic steps of insulin release.

Animals↗
PubMed2000

Lentiviral gene transfer into primary and secondary NOD/SCID repopulating cells.

The ability of lentiviral vectors to transfer genes into human hematopoietic stem cells was studied, using a human immunodeficiency virus 1 (HIV-1)-derived vector expressing the green fluorescence protein (GFP) downstream of the phosphoglycerate kinase (PGK) promoter and pseudotyped with the G protein of vesicular stomatitis virus (VSV). High-efficiency transduction of human cord blood CD34(+) cells was achieved after overnight incubation with vector particles. Sixteen to 28 percent of individual colony-forming units granulocyte-macrophage (CFU-GM) colonies derived from cord blood CD34(+) cells were positive by polymerase chain reaction (PCR) for the GFP gene. The transduction efficiency of SCID-repopulating cells (SRC) within the cord blood CD34(+) population was assessed by serial transplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. When 400,000 cord blood CD34(+) cells were transplanted into primary recipients, all primary and secondary recipients contained and expressed the transgene. Over 50% of CFU-GM colonies derived from the bone marrow of these primary and secondary recipients contained the vector on average as determined by PCR. Transplantation of transduced cells in limiting dilution generated GFP(+) lymphoid and myeloid progeny cells that may have arisen from a single SRC. Inverse PCR analysis was used to amplify vector-chromosomal junctional fragments in colonies derived from SRC and confirmed that the vector was integrated. These results show that lentiviral vectors can efficiently transduce very primitive human hematopoietic progenitor and stem cells. (Blood. 2000;96:3725-3733)

Animals↗
PubMed2000

Efficient adenoviral vector transduction of human hematopoietic SCID-repopulating and long-term culture-initiating cells.

This article presents our studies on the adenoviral transduction efficiency, level of transgene expression, cell cycle status, and multilineage reconstitution ability of human CD34+ hematopoietic cells transduced under proliferating and survival growth conditions. Bone marrow and umbilical cord blood CD34+ cells were cultured in serum-free medium under survival conditions with thrombopoietin (Tpo) alone, or under proliferating conditions with Tpo, c-Kit ligand (KL), and Flt3 ligand (FL). Adenoviral vectors carrying the enhanced green fluorescent protein (EGFP) gene under the control of the PGK-1 promoter were used to transduce CD34+ cells. Approximately 10% of CD34+ cells were EGFP+ under both culture conditions. In contrast, up to 50% of CD34+CD38- cells were EGFP+, whereas a maximum of 8% of CD34+CD38(high) cells were EGFP+ (p < 0.001). Both colony-forming unit cells (CFU-C) and 5-week long-term culture-initiating cells (LTC-ICs) were efficiently transduced. Under survival conditions, a substantial fraction of transduced CD34+ cells remained quiescent. The nondividing CD34+EGFP+ cells contained LTC-ICs capable of reconstituting longterm culture for as long as 10 weeks. CD34+EGFP+ cells also retained the ability to engraft and multilineage-reconstitute NOD/SCID mice. These observations demonstrate that primitive human hematopoietic progenitor cells can be efficiently transduced by adenoviral vectors.

ADP-ribosyl Cyclase↗
PubMed2000

Islet phospholipase A(2) activation is potentiated in insulin resistant mice.

Insulin resistance is followed by an islet adaptation resulting in a compensating increase in insulin secretion and hyperinsulinemia. The mechanism underlying this increased insulin secretion is not established. We studied whether islet phospholipase A(2) (PLA(2)) contributes by using C57BL/6J mice fed a high-fat diet, since we previously showed that the insulin responses to the two PLA(2)-activating insulin secretagogues carbachol and cholecystokinin (CCK) are enhanced in this model. CCK (100 nM) and carbachol (100 microM) stimulated [(3)H]AA efflux, reflecting PLA(2) activation, both in islets from mice after 12 weeks on high-fat diet and in controls. The efflux increase was more pronounced in islets from high-fat diet-fed mice during both CCK (by 93 +/- 46%; P = 0. 034) and carbachol (by 64 +/- 22%; P = 0.009) stimulation. Also a direct PLA(2) activation by mellitin (2 microg/ml) elicited a potentiated efflux in islets from the insulin-resistant mice (by 361 +/- 107%; P = 0.002). The results suggest that exaggerated non-glucose-induced PLA(2) activation contributes to the islet compensation in insulin resistance.

Animals↗
PubMed2000

Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells.

Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase-signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3- and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Ctheta was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.

Animals↗
PubMed2000

The cyclic AMP-protein kinase A pathway restrains islet phospholipase A(2) activation.

Although phospholipase A(2) (PLA(2)) is of importance for insulin secretion, it is not established how it relates to other signalling mechanisms. This study examined the crosstalk between PLA(2) and the cyclic AMP (cAMP)-protein kinase A (PKA) pathway in isolated rat islets. Forskolin, IBMX, and dbcAMP reduced [(3)H]arachidonic acid ([(3)H]AA) efflux from prelabelled islets during PLA(2) activation by mellitin or cholecystokinin (CCK-8), while efflux induced by carbachol was unaffected. The PKA inhibitor myrPKI(14-22) prevented this reduction of CCK-8-induced efflux. Glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and vasoactive intestinal polypeptide (VIP) diminished CCK-8-induced efflux. Also in the absence of Ca(2+), forskolin/IBMX and dbcAMP reduced CCK-8-induced efflux. In parallel with effects on [(3)H]AA, the expected additive insulin secretion induced by mellitin or CCK-8 in combination with forskolin or GLP-1, respectively, was reduced. In conclusion, the cAMP-PKA pathway restrains both Ca(2+)-dependent and Ca(2+)-independent PLA(2) activation, indicating a regulating crosstalk between these two pathways.

1-Methyl-3-isobutylxanthine↗