Elastofibroma is a rare tumour that occurs in the subscapular space, and it typically presents in middle-aged and older individuals. The aetiology of elastofibroma remains unknown. Recent, sporadic reports have shown, immunohistologically, that <em>fibroblasts</em> in elastofibroma may produce abnormal elastic and collagen fibres through the action of transforming <em>growth</em> <em>factor</em>-beta (TGF-β), a <em>factor</em> that promotes <em>fibroblast</em> proliferation. However, that finding lacked quantitative measurements and controls. Therefore, in this study, we performed quantitative, immunohistochemical analyses of TGF-β1 and basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) in three elastofibromas, and we compared them to ten dermatofibromas and keloids, and five normal skin. In elastofibroma specimens, 16-59 % <em>fibroblasts</em> were positive for TGF-β1 in the cytoplasm, compared to 96 % in dermatofibroma, 93 % in keloid and 2 % in normal dermis specimens. Also, in elastofibroma specimens, 26-67 % of <em>fibroblasts</em> were positive for bFGF in the cytoplasm, compared to 97 % in dermatofibroma, 97 % in keloid, and <em>22</em> % in normal dermis specimens. Intriguingly, the tumour size and <em>growth</em> rate were proportional to the percentage of cells positive for bFGF. Finally, greater levels of bFGF expressions in <em>fibroblasts</em> were associated with larger sized elastofibromas. These results suggested that elastofibroma development depended on high expression of TGF-β1 and bFGF.

It has previously been shown that administration of basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF-2) to mice bearing xenografted human DLD-2 carcinomas produces significant increases in tumor <em>growth</em> rates and decreased intratumor hypoxia, effects which appear to be secondary to changes in the vasculature. In this study, we treated DLD-2 tumors with FGF-2 (ip, 0.25 mg/kg, q.i.d. x 7) beginning on day 15 after implantation, when average tumor volumes were 238 mm3. One day after cessation of administration of FGF-2 (day <em>22</em> after implantation, average tumor volume 1748.1 mm3), clamped tumors were given hyperthermia (42.5 degrees C, 60 min) by water bath heating. The slower-<em>growing</em> tumors in the control mice (sham-injected with Hanks' basic salt solution) were clamped and subjected to hyperthermia treatment at equivalent average tumor volumes (1882.7 mm3), which occurred on day 26 after implantation. Tumors in control groups were clamped but not heated. The time needed for neoplasms to grow to twice their volumes at the time of hyperthermia treatment was 68 days for the FGF-2-treated neoplasms and 47 days for the controls, while 26 and 31 days were needed for the control groups which were not treated with heat. The relative <em>growth</em> delay induced by hyperthermia is therefore 16 (47-31) days for control neoplasms and 42 (68-26) days for FGF-2-treated tumors. Therefore, tumors in the mice injected with FGF-2 were significantly more sensitive to the hyperthermia than controls, by a <em>factor</em> of about 2.6 (42/16). This result indicates that administration of <em>growth</em> <em>factors</em> such as FGF-2 to mice bearing tumors may produce an increased sensitivity of the tumors to hyperthermia.

Angiogenesis can be described as a formation of new vessels from the existing microvasculature and is a process of great importance to the tumor development. Parathyroid tissue can trigger spontaneous induction of angiogenesis in vitro and in vivo models in a vascular endothelial <em>growth</em> <em>factor</em> (VEGF)-dependent manner. Autotransplantated parathyroid tissue after thyroidectomy is able to form new vasculature and produce parathormone, maintaining calcium homeostasis. A great amount of <em>factors</em> contributes to the process of new vessel formation in primary hyperparathyroidism, such as VEGF, transforming <em>growth</em> <em>factor</em> β, and angiopoietins. Studies demonstrated that markers for angiogenesis can be useful in distinguishing between parathyroid hyperplasia and neoplasia, due to the increased angiogenesis in parathyroid proliferative lesions compared with parathyroid adenomas. These <em>factors</em> include, inter alia, VEGF, VEGFR2, CD105, and <em>fibroblast</em> <em>growth</em> <em>factor</em>-2. Although these differences appear promising in the differential diagnosis, there is an overlap between benign and malignant parathyroid lesions and there is no definite cutoff value. Loss of heterozygosity and comparative genomic hybridization studies revealed chromosomal regions frequently altered in parathyroid tumorigenesis at 9p21, 1p21-<em>22</em>, 1p35-36, and 11q13. Therefore, immunohistochemistry and genetic testing should be an additional diagnostic marker in combination with the traditional criteria. A better understanding of angiogenesis in primary hyperparathyroidism could result in more precise assessment of diagnosis and more effective treatment, especially in those cases, in which the commonly used parameters are insufficient.

BACKGROUND

The best treatment for end-stage renal disease (ESRD) is kidney transplantation. Twenty-seven percent of transplantations in Norway are from living donors. Recent studies have shown an increased risk of ESRD and increased mortality in donors. The aim of this study was to determine if the levels of the new biomarkers neutrophil gelatinase-associated lipocalin (NGAL), soluble Klotho (sKlotho), and fibroblast growth factor 23 (FGF23) are changed in kidney donors with normal kidney function defined as an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 compared to patients with chronic kidney disease (CKD) stages 3-5 and healthy controls.

METHODS

This is a cross-sectional, observational, single-center study including 35 kidney donors with an eGFR ≥60 ml/min/1.73 m2 5 years after donation, 22 patients with CKD stage 3 (eGFR 30-59 ml/min/1.73 m2), 18 patients with CKD stage 4 (eGFR 15-29 ml/min/1.73 m2), 20 patients with CKD stage 5 (eGFR <15 ml/min/1.73 m2), and 35 controls comparing levels of biomarkers in long-term kidney donors with those in CKD patients and healthy controls.

RESULTS

The level of log NGAL was significantly higher in donors than in healthy controls (2.02 ± 0.10 vs. 1.89 ± 0.10 ng/ml; p < 0.001), and the level increased with declining kidney function. The log FGF23 level was nonsignificantly higher in donors than in controls, but it significantly increased with declining kidney function. The log sKlotho levels were significantly lower in patients with CKD stages 4 and 5 than in controls, but no difference was revealed between controls and donors.

CONCLUSIONS

Kidney donors have significantly higher levels of NGAL than healthy controls after a median of 15 years (range 5-38). NGAL could be a valuable diagnostic marker in the future. FGF23 and sKlotho were not significantly different between donors and controls.

In the <em>22</em> member mammalian FGF family, FGF<em>22</em> belongs to FGF7 subfamily, and its effects are largely confined to the brain and skin. To explore the functions of FGF<em>22</em> on other tissues and develop a large-scale production of recombinant human FGF<em>22</em> (rhFGF<em>22</em>) without a fusion tag, a plasmid encoding human FGF<em>22</em> (pET3a-rhFGF<em>22</em>) was used to express rhFGF<em>22</em> in E. coli BL21 (DE3) pLysS. A large amount of rhFGF<em>22</em> inclusion body protein was obtained. A two-step denaturing method successfully solubilized rhFGF<em>22</em>, and it was refolded and then purified in one step via heparin affinity chromatography. A yield of 105 mg rhFGF<em>22</em> with a purity of up to 95% was obtained from 100 g wet bacteria. It was found that the rhFGF<em>22</em> had biological activity, since it effectively attenuated H2O2-induced human hepatic L02 cell death. Analysis by qRT-PCR and Western blot demonstrated that rhFGF<em>22</em> protects L02 cells from H2O2-induced oxidative damage via suppression of mitochondrial apoptosis pathways. In conclusion, the strategy described in this paper may provide a novel means to solve the production of insoluble rhFGF<em>22</em> and shine new light on its translational potential.

We have investigated the localization of basic <em>fibroblast</em> <em>growth</em> <em>factor</em> (bFGF) binding sites during the development of the neural retina in the chick embryo. The specificity of the affinity of bFGF for its receptors was assessed by competition experiments with unlabelled <em>growth</em> <em>factor</em> or with heparin, as well as by heparitinase treatment of the samples. Two different types of binding sites were observed in the neural retina by light-microscopic autoradiography. The first type, localized mainly to basement membranes, was highly sensitive to heparitinase digestion and to competition with heparin. It was not developmentally regulated. The second type of binding site, resistant to heparin competition, appeared to be associated with retinal cells from the earliest stages studied (3-day-old embryo, stages 21-<em>22</em> of Hamburger and Hamilton). Its distribution was found to vary during embryonic development, paralleling layering of the neural retina. Binding of bFGF to the latter sites was observed throughout the retinal neuroepithelium at early stages but displayed a distinct pattern at the time when the inner and outer plexiform layers were formed. During the development of the inner plexiform layer, a banded pattern of bFGF binding was observed. These bands, lying parallel to the vitreal surface, seemed to codistribute with the synaptic bands existing in the inner plexiform layer. The presence of intra-retinal bFGF binding sites whose distribution varies with embryonic development suggests a regulatory mechanism involving differential actions of bFGF on neural retinal cells.

We investigated the effect of interferon-gamma (IFN-gamma) on skin equivalents. Keratinocytes from involved and uninvolved skin from psoriatic subjects and from healthy subjects were grown on preproduced dermal equivalents (DE) containing <em>fibroblasts</em> from healthy skin or psoriatic lesions. Healthy keratinocytes were added when the dermal equivalents were either <em>22</em> days (DE(<em>22</em>)) or 37 days old (DE(37)) and psoriatic keratinocytes when the dermal equivalents were 28-52 days old (DE(28-52)). The skin equivalents were cultured for 11 days in a serum-free medium, and then with or without 500 U/ml IFN-gamma for 6 days. The expression of markers associated with differentiation and proliferation were investigated by immunohistochemistry. Differentiation was assessed by computed scores for the expression of cytokeratin 16, involucrin, filaggrin and the receptor for epidermal <em>growth</em> <em>factor</em>. The differentiating effect of IFN-gamma on healthy keratinocytes grown on DE(37) was significantly stronger than on psoriatic keratinocytes grown on DE(28-52). In healthy keratinocytes, the differentiating effect of IFN-gamma was significantly stronger in skin equivalents containing DE(37) than in those containing DE(<em>22</em>). The proliferation rate, i.e. the percentage of Ki-67+ keratinocytes in the basal layer, was studied in healthy keratinocytes grown on DE(<em>22</em>). In these cultures IFN-gamma increased the proliferation rate in the presence of psoriatic <em>fibroblasts</em> but not in the presence of healthy <em>fibroblasts</em>. HLA-DR expression was induced only in healthy keratinocytes grown on DE(<em>22</em>). We conclude that the influence of IFN-gamma epidermal differentiation and proliferation is influenced by the origins of both the keratinocytes and the <em>fibroblasts</em>. These findings suggest that interactions between keratinocytes and <em>fibroblasts</em> might be involved in the pathogenesis of psoriasis.

Keratinocyte hyperproliferation has been regarded as a central event in psoriasis pathogenesis. Investigating the mechanisms of keratinocyte hyperproliferation might provide novel strategies for psoriasis treatment. we demonstrated that <em>fibroblast</em> <em>growth</em> <em>factor</em> receptor 2 (FGFR2) expression was abnormally upregulated within psoriatic lesion tissues and HaCaT cells under rIL-<em>22</em> stimulation. FGFR2 silence within HaCaT cells under rIL-<em>22</em> stimulation significantly inhibited the capacity of cells to proliferate and to migrate, reduced IL-17A and TNFα mRNA expression, and decreased the protein levels of FGFR2, keratin 6, keratin 16, MMP1, MMP9, p-PI3K, p-AKT and p-ERK. In contrast to FGFR2, the expression of miR-124-3p showed to be remarkably downregulated within psoriasis lesion tissue samples and rIL-<em>22</em>-stimulated HaCaT cells. miR-124-3p inhibited the expression of FGFR2 via direct binding to its 3'UTR. Within HaCaT cells under rIL-<em>22</em> stimulation, the overexpression of miR-124-3p also suppressed the capacity of cells to proliferate and to migrate, reduced IL-17A and TNFα mRNA expression, and decreased the protein levels of FGFR2, keratin 6, keratin 16, MMP1, MMP9 and p-PI3K, p-AKT and p-ERK. More importantly, when co-transfected to HaCaT cells, FGFR2-overexpressing vector significantly attenuated the effects of miR-124-3p mimics on HaCaT cells. In conclusion, we demonstrated an miR124-3p/FGFR2 axis that might inhibit human keratinocyte proliferation, migration, and improve the inflammatory microenvironment in psoriasis. miR124-3p/FGFR2 axis could be an underlying target for psoriasis therapy, which requires further in vivo and clinical investigation.

<AbstractText>This study examined the usefulness of basic <em>fibroblast</em> <em>growth</em> <em>factor</em> impregnated collagen-gelatin sponge (bFGF-CGS) in reconstructive surgery for various acute skin defects including deep dermal burns, facial full-thickness skin defects, and finger amputations as the first clinical application.</AbstractText><p><div><b>Methods</b></div>Reconstructive surgery was performed in two stages with bFGF-CGS in 8 male subjects, ranging in age from 6 to 84 years, with acute full-thickness skin defects. Following the adequate debridement of the defect, surgeons prepared a bFGF-CGS with bFGF solution at a dose of 7-14 mg/cm² approximately 10 min just before application and then secured the bFGF-CGS in place with non-absorbable sutures. Second-stage wound closure was performed with autologous skin grafting following adequate dermis-like tissue regeneration at the site postoperatively. Follow-up was continued for 6 months.</p><AbstractText>Of the 8 subjects, the mean duration from the adequate vascularization of the dermis-like tissue until the second-stage autologous skin graft was <em>22</em> ± 4 days. Wound closure was achieved in all cases; the mean duration until wound closure was 32 ± 8 days. During the 6-month follow-up period, no wound infection, recurrent skin ulceration, and no exposure of tendon, bone, and cartilage were observed, and there were no cases of indirectly restricted range of motion from postoperative scar contracture and none with disfiguring scars.</AbstractText><AbstractText>The authors achieved favorable outcomes following reconstructive surgery with a hybrid artificial dermis impregnated with bFGF for treating acute full-thickness skin defects. bFGF-CGS serves as a convenient regenerative device requiring no specialized medical facilities.</AbstractText>

OBJECTIVE

To study the adhesion-preventing effect of basic fibroblast growth factor (bFGF) combined slow-releasing degradable membrane.

METHODS

The bFGF combined slow-releasing degradable membrane was made from bFGF and the reagent which could promote fibrinogen synthesize. Sixty-six SD rats were divided into groups A, B, C randomly (22 rats each group). In group A, sutured achilles tendon were encapsulated with bFGF combined slow-releasing degradable membrane; in group B, sutured achilles tendon were encapsulated with degradable membrane without any drug; in group C, achilles tendon were only sutured. Ninety days later, light-microscope, electron-microscopoe, figure-analysing, hydroxyproline content, extent of peritendon adhesion and biomechanic test were evaluated.

RESULTS

1. The amount of fibroblast and fibrinogen inside the sutured tendon in group A was larger than that in its peripheral connective tissue and in groups B and C (P < 0.05). The content of hydroxyproline and the ultimate tensile strength in group A was higher than those in groups B and C (P < 0.01). 2. The peripheral tissue in group A almost remains the formal loose connective tissue, but it became dense connective tissue in groups B and C and grew into the tendon. Moreover, the extent of adhesion in group A was lesser than that in groups B, C according to the mensuration of peritendon adhesion.

CONCLUSIONS

The bFGF combined slow-releasing degradable membrane can make the intrinsic healing of tendon faster than peripheral connective tissue proliferation, so it can prevent the formation of adhesion.

Transforming <em>growth</em> <em>factor</em>-β1 (TGFβ1)-stimulated clone <em>22</em> (TSC-<em>22</em>) is a primary response gene isolated by subtractive screening of genes expressed in murine osteoblastic cells treated with TGFβ1, which is one of the cytokines abundantly stored in bone. <em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) is also stored in bone matrix and acts as a potent autocrine/paracrine modulator of osteoblastic function. In this report, we investigated FGF effects on the expression of TSC-<em>22</em> gene in a murine osteoblast-like cell line, MC3T3E-1. Treatment with recombinant basic FGF enhanced TSC-<em>22</em> mRNA level in these cells within 1 h. This effect peaked at 2 h with several fold enhancement, after which the mRNA abundance returned to the basal level by 24 h. The FGF effect was dose-dependent, starting at 0.2 ng/ml, peaking at 2 ng/ml, and then declining at 20 ng/ml. The FGF effect on TSC-<em>22</em> mRNA was blocked by actinomycin D, indicating the involvement of transcriptional events. The FGF enhancement of TSC-<em>22</em> mRNA expression was partially blocked by genistein. Additive effect was observed upon contreatment with saturating concentrations of FGF and TGFβ, suggesting the presence of at least two independent pathways for the two cytokines in the regulation of TSC-<em>22</em> gene expression. These results indicate that the TSC-<em>22</em> gene is one of the targets of FGF action in osteoblasts.

OBJECTIVE

To explore the in vitro differentiation of the rat mesenchymal stem cells (MSCs) into the skeletal muscle cells induced by the myoblast differentiation factor (MyoD) and 5-azacytidine.

METHODS

The MSCs were taken from the rat bone marrow and the suspension of MSCs was made and cultured in the homeothermia incubator which contained 5% CO2 at 37 degrees C. The cells were observed under the inverted phase contrast microscope daily. The cells spreading all the bottom of the culture bottle were defined as one passage. The differentiation of the 3rd passage of MSCs was induced by the combination of 5-azacytidine, MyoD, transforming growth factor beta1, and the insulin-like growth factor 1. Nine days after the induction, the induced MSCs were collected, which were analyzed with the MTT chromatometry, the flow cytometry, and the immunohistochemistry.

RESULTS

The primarily cultured MSCs grew as a colony on the walls of the culture bottle; after the culture for 5-7 days, the cells were shaped like the fibroblasts, the big flat polygonal cells, the medium-sized polygonal cells, and the small triangle cells; after the culture for 12 days, the cells were found to be fused, spreading all over the bottle bottom, but MSCs were unchanged too much in shape. After the induction by 5-azacytidine, some of the cells died, and the cells grew slowly. However, after the culture for 7 days, the cells grew remarkably, the cell volume increased gradually in a form of ellipse, fusiform or irregularity. After the culture for 14 days, the proliferated fusiform cells began to increase in a great amount. After the culture for 18-22 days, the myotubes increased in number and volume, with the nucleus increased in number, and the newly-formed myotubes and the fusiform myoblst grew parallelly and separately. The immunohistochemistry for MSCs revealed that CD44 was positive in reaction, with the cytoplasm in a form of brown granules. And the nucleus had an obvious border, and CD34 was negative. The induced MSCs were found to be positive for desmin and specific myoglobulin of the skeletal muscle. The flow cytometry showed that most of the MSCs and the induced MSCs were in the stages of G0/G1, accounting for 79.4% and 62.9%, respectively; however, the cells in the stages of G2/S accounted for 20.6% and 36.1%. The growth curve was drawn based on MTT,which showed that MSCs were greater in the growth speed than the induced MSCs. The two kinds of cells did not reach the platform stage,having a tendency to continuously proliferate.

CONCLUSIONS

In vitro, the rat MSCs can be differentiated into the skeletal muscle cells with an induction by MyoD and 5-azacytidine, with a positive reaction for the desmin and the myoglobulin of the skeletal muscle. After the induction, the proliferation stage of MSCs can be increased, with a higher degree of the differentiation into the skeletal muscle.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Hypophosphatemia was demonstrated in adult patients with preserved renal function, together with high fibroblast growth factor 23 (FGF23) and low soluble Klotho levels. The latter explained the relative FGF23 hyporesponsiveness in this cohort.

Evaluating phosphate and bone mineral metabolism in children with ADPKD compared with what is known in adult ADPKD patients.

Observational cross-sectional study.

Multicenter study via ambulatory care in tertiary centers.

Ninety-two children with ADPKD (52 males; mean ± standard deviation age, 10.2 ± 5.0 years) and 22 healthy controls (HCs, 10 males; mean ± standard deviation age, 10.3 ± 4.1 years).

The predictor was early ADPKD stage. Bone mineral metabolism and renal phosphate handling were the main outcome measures. Performed measurements were serum phosphate, tubular maximum phosphorus reabsorption per glomerular filtration rate, FGF23, soluble Klotho, sclerostin, and bone alkaline phosphatase.

ADPKD children had significantly lower serum phosphate levels compared with HC. Low tubular maximum phosphorus reabsorption per glomerular filtration rate was observed in 24% of patients, although not significantly different from HC. Serum FGF23 and soluble Klotho levels were comparable between patients and HC. In addition, we showed decreased bone alkaline phosphatase levels in ADPKD children, suggesting suppressed bone formation.

This report demonstrates hypophosphatemia and suppressed bone formation in a pediatric ADPKD cohort, with preserved renal function, compared with HC. Although FGF23 levels were not different from controls, they should be considered inappropriate, given the concomitant hypophosphatemia. Further studies are required to elucidate underlying pathophysiology and potential clinical consequences.

Clinical examination and biochemical studies revealed hepatic functional disorders in 30 (93.75 +/- 4.28%) of 32 patients with metabolic syndrome (MS) and chronic non-calculous cholecystitis (NCC) and only in 3 (13.63 +/- 7.32%) of <em>22</em> patients with CC without MS. Most patients with CC and MS had elevated levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) and endothelial <em>growth</em> <em>factor</em> (EGF) suggesting activation of fibrotic processes. They were not significantly different from normal values in patients with CC without MS. Pair correlation analysis revealed the relationship between enhanced activity of the pathological process in the hepatobiliary system and increased FGF and EGS levels. It was confirmed by direct correlation between FGF. EGS levels and ALT, AST activities. Also, FGF and EGS levels were related to leptin and triglyceride levels as well as to HOMA-IR index.

BACKGROUND

Fibroblast growth factor 21 (FGF21) is an important metabolic regulator that has multiple beneficial effects on glucose homeostasis and lipid metabolism. Although circulating levels of FGF21 are mainly derived from liver, FGF21 is also found in other tissues and fluids including the cerebrospinal fluid (CSF). The aim of the present study was to investigate the relationships of CSF and/or plasma FGF21 levels with metabolic parameters in a normal-weight Chinese population.

METHODS

Forty-five subjects (22 males and 23 females) were recruited from a patient population undergoing surgery for lower extremity injuries due to ligament damage or bone fractures below the knee in the Beijing Jishuitan Hospital. The levels of FGF21 in CSF and plasma were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively.

RESULTS

No significant differences were detected in the levels of FGF21 in CSF and plasma between males (CSF: 158.01 ± 12.10 pg/mL; plasma: 206.19 ± 7.22 pg/mL) and females (CSF: 159.27 ± 17.85 pg/mL; plasma: 203.10 ± 7.53 pg/mL). The level of FGF21 in CSF was about 75% of that in plasma. The FGF21 level in CSF was positively correlated with triglyceride level, whereas plasma FGF21 level was negatively correlated with alanine aminotransferase in women but not in men. The CSF/plasma FGF21 ratio was positively correlated with CSF FGF21 in both genders and with peripheral glucose, triglyceride, and gamma-glutamyl transferase levels in female Chinese patients.

CONCLUSIONS

These results have important implications regarding the potential central actions of FGF21.

Debilitating rickets-like lower limb deformities are common in children throughout the world, particularly in Malawi, Africa where the causes are unknown. We have identified that Blount disease and calcium deficiency rickets are the likely causes of these deformities and propose calcium supplementation as a potential treatment of Malawian rickets.

Surgical correction of rickets-like lower limb deformities is the most common paediatric operation performed at Beit Cure Orthopaedic Hospital, Malawi. The aim of this study was to investigate the aetiology of these deformities.

Children with a tibio-femoral angle of deformity >20° were enrolled (n = 42, 3.0-15.0 years). Anthropometric and early life and well-being data were collected. Early morning serum and urine samples were collected on the morning of the operation for markers of calcium and phosphate homeostasis. Knee radiographs were obtained, and the children were diagnosed with either Blount (BD, n = <em>22</em>) or evidence of rickets disease (RD, n = 20). As BD is a mechanical rather than metabolic disease, BD were assumed to be biochemically representative of the local population and thus used as a local reference for RD.

There were no differences in anthropometry or early life experiences between BD and RD. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, total alkaline phosphatase and urinary phosphate were significantly higher and serum phosphate, 25-hydroxyvitamin D (25OHD) and tubular maximal reabsorption of phosphate significantly lower in RD than BD. There was no difference in serum calcium, fibroblast growth factor 23 or markers of iron status between groups. All children had 25OHD>> 25 nmol/L.

Vitamin D deficiency is not implicated in the aetiology of RD or BD in Malawian children. The cause of RD in Malawi is likely to be dietary calcium deficiency leading to elevated PTH resulting in increased losses of phosphate from the bone and glomerular filtrate. The causes of BD remain unclear; there was no evidence in support of previously suggested risk factors such as being overweight or starting to walk early. Prior to surgical intervention, supplementation with calcium should be considered for children with RD.

Tyrosine autophosphorylation plays a crucial regulatory role in the kinase activities of <em>fibroblast</em> <em>growth</em> <em>factor</em> receptors (FGFRs), and in the recruitment and activation of downstream intracellular signaling pathways. Biophysical and biochemical investigations of FGFR kinase domains in membrane environments offer key insights into phosphorylation mechanisms. Hence, we constructed nickel chelating nanodiscs based on a <em>22</em>-residue peptide. The spontaneous anchoring of N-terminal His₆-tagged FGFR1c kinase domain (FGFR1K) onto peptide nanodiscs grants FGFR1K orientations occurring on native plasma membranes. Following membrane incorporation, the autophosphorylation of FGFR1K, as exemplified by Y653 and Y654 in the A-loop and the total tyrosine phosphorylation, increase significantly. This in vitro reconstitution system may be applicable to studies of other membrane associated phenomena.

A number of peptide <em>growth</em> <em>factors</em> have been shown to induce the secretion of type I collagenase into the medium of human <em>fibroblast</em> cultures (Chua et al., 1985). In this study the ability of eye-derived <em>growth</em> <em>factor</em>, lectin and tumor-promoting agents on collagenase induction in human <em>fibroblast</em> cells were examined. These agents were found to be able to induce collagenase production to a similar extent as epidermal <em>growth</em> <em>factor</em>. Dexamethasone at 10-100 nM was found to suppress collagenase induction in human <em>fibroblast</em> cells. The cell-type specificity of this enzyme induction by <em>growth</em> <em>factors</em> was studied by using a human epidermoid carcinoma cell line, A-431. An Mr 55,000 band appeared in the medium of A-431 cells upon <em>22</em> h exposure to EGF. Two-dimensional peptide pattern of the Mr 55,000 band in A-431 cells was identical to the counterpart in HF cells. Our results indicated that the induction of collagenase was not unique to human <em>fibroblast</em> cultures.

The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between <em>fibroblast</em> <em>growth</em> <em>factor</em> 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level ≥150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (1<em>22</em> pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484); P = 0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia -23 pg/mL (-43, <em>22</em>); central diabetes insipidus 17 pg/mL (-76, 88); healthy volunteers -6 pg/mL (-68, <em>22</em>); P = 0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients.

<AbstractText>Levels of <em>fibroblast</em> <em>growth</em> <em>factor</em> 23 (FGF23) have been positively associated with measures of adiposity, cardiovascular disease and mortality. It is unclear whether the relationship of FGF23 with cardiovascular disease and mortality is confounded by obesity. We aimed to determine whether FGF23 concentrations decline following a reduction in adiposity after sleeve gastrectomy (SG).</AbstractText><AbstractText>The effect of SG on FGF23 was evaluated in <em>22</em> obese adults (59% male) with type 2 diabetes. Fat mass, weight, BMI, plasma intact FGF23, parathyroid hormone (PTH) and leptin were determined at baseline and at 12 months following SG.</AbstractText><p><div><b>RESULTS</b></div>At baseline, median (IQR) age was 51 (43-54) years, fat mass 47.8 (41.0-59.4) kg, BMI 40.9 (36.9-46.9) kg/m² and FGF23 66.2 (55.3-82.9) pg/mL. Significant changes in median BMI (-10.8 kg/m² , 95% CI: -12.9 to -7.2, P < 0.0001), fat mass (-20.0 kg, 95% CI: -26.7 to -12.4, P < 0.0001) and weight (-34.7 kg, 95% CI -40.0 to -23.1, P < 0.0001) were observed after SG. FGF23 (-12.4 pg/mL, 95% CI: -19.5 to 2.0, P = 0.005), PTH (-1.1 pmol/L, 95% CI: -1.7 to 0.2, P = 0.009) and leptin (-1687 pg/mL, 95% CI -4524 to -563, P = 0.01) declined following SG. Change in FGF23 was not significantly associated with change in measures of adiposity, PTH or leptin.</p><AbstractText>FGF23 concentrations decline in the setting of significant weight loss following SG, implying that increased FGF23 concentrations are a downstream consequence of obesity, which may confound its association with cardiometabolic dysfunction. Mediators of the relationship between adiposity and FGF23 require further elucidation.</AbstractText>

The processes of spontaneous and asbestos-induced transformation of rat mesothelium were studied using cell cultures obtained in the laboratory. The same changes in cell properties were established in both spontaneous and asbestos-induced transformation: change in epidermal <em>growth</em> <em>factor</em> (EGF) response, in some cases appearance of <em>fibroblast</em>-like cells instead of polygonal ones, appearance of multilayer cell <em>growth</em> foci, and ability to grow in semisolid agar. The response to <em>fibroblast</em> <em>growth</em> <em>factor</em>, insulin-like <em>growth</em> <em>factor</em> 1, and insulin did not change during transformation as well as the P450 system activity measured by benz(a)pyrene (BP) and 7,12-dimethylbenzanthracene (DMBA) cytotoxicity. The asbestos-induced transformation began earlier than the spontaneous one. EGF began to stimulate mesothelium proliferation instead of its inhibition at 6-7 passages in the case of asbestos-induced transformation, whereas during spontaneous transformation this change began at 9-10 passages. Elongated rather than polygonal cells appeared at 10-11 instead of 17-18 passages (this morphological change did not take place at all lines studied). The ability to grow in semisolid agar was found at 14-16 passages with asbestos and at <em>22</em>-24 passages without it. The results allow us to propose the necessity of a positive EGF response for mesothelial cell transformation and the similarity of mechanisms of spontaneous and asbestos-induced transformation.

The aim of this study was to determine the expression of <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>22</em> (FGF<em>22</em>) in the bovine corpus luteum (CL) and to investigate the effects of in vivo total or partial cloprostenol-induced luteolysis on the mRNA abundance of FGF<em>22</em> and its receptor, FGFR1B. Corpora lutea at different stages of development were then dissected from abattoir ovaries (n = 10/stage); a portion of the tissue samples was fixed in paraformaldehyde and the remaining samples were homogenized and subjected to total RNA extraction. To assess mRNA abundance of target genes during induced luteolysis, nineteen cows were synchronized and then randomly assigned to a Latin square design as follows: Control; 2 administrations of prostaglandin F2α (PGF2α, total luteolysis; 2 × 250 μg of cloprostenol sodium) and 1/6PGF2α (partial luteolysis; 83.33 μg of cloprostenol sodium). FGF<em>22</em> and FGFR1B expression levels were measured by RT-qPCR, and FGF<em>22</em> protein expression was detected by immunohistochemistry. In summary, FGF<em>22</em> mRNA was detected at all stages of CL development, and FGF<em>22</em> protein was also detected in luteal tissue. FGF<em>22</em> mRNA expression was lower at stage IV than at stage III (P < 0.05), and the same pattern was observed in luteal immunoreactivity. Furthermore, cloprostenol-induced luteolysis, both total and partial, increased FGFR1B mRNA abundance in luteal tissue (P < 0.05), but did not affect FGF<em>22</em> mRNA abundance. In conclusion, these data suggest a potential role for the FGF<em>22</em>-FGFR1B system during development and regression of bovine CL.

Background: Elevated renal flow pulsatility may contribute to the pathogenesis of chronic kidney disease (CKD). The purpose of this study was to investigate the associations among age, renal flow pulsatility, and CKD biomarkers in non-CKD adults and CKD patients.

<strong class="sub-title"> Methods: </strong> Non-CKD adults (n = 415) and CKD patients (n = 136) aged between <em>22</em> and 83 years underwent the renal blood flow measurement using duplex ultrasonography. Pulsatility index (PI) and resistive index (RI) were calculated to assess renal flow pulsatility. The CKD biomarkers such as urinary liver-type fatty acid-binding protein (L-FABP) and serum <em>fibroblast</em> <em>growth</em> <em>factor</em> 23 (FGF23) were measured from each participant. Aortic hemodynamic parameters were measured by applanation tonometry.

Results: In non-CKD adults, advancing age was associated with elevations of renal PI and RI which slowly increased during middle-aged (PI: β = 0.14, RI: β = 0.17) and accelerated in older adults (PI: β = 0.34, RI: β = 0.33). In CKD patients, age-related increases in renal PI and RI were observed only in the middle age group (PI: β = 0.23, RI: β = 0.26). Multivariate analysis demonstrated that renal PI and RI were independently associated with CKD biomarkers, including urinary L-FABP and serum FGF23, and aortic pulse pressure.

Conclusions: Advancing age is associated with a progressive elevation of renal flow pulsatility which manifests during middle age and accelerates in later life. Moreover, elevated renal flow pulsatility is associated with the presence of CKD in each age group and also with biomarker levels that reflect CKD progression.

Keywords: CKD biomarker; Duplex ultrasonography; Linear spline model; Pulsatility index; Renal aging; Renal flow pulsatility; Resistive index.

We recently described that epidermal and <em>fibroblast</em> <em>growth</em> <em>factors</em> (EGF and FGF) regulate the IGF-I signaling pathway at the level of IRS-1 through the cooperative action of two independent signaling pathways; one dependent on phosphatidylinositol 3-kinase (PI 3-kinase) and the other on protein kinase D1 (PKD1) (Karam et al. [<em>22</em>]). To determine whether this mechanism could be generalized to another tyrosine kinase receptor-dependent <em>growth</em> <em>factor</em>, the effect of platelet-derived <em>growth</em> <em>factor</em> (PDGF) on the IGF-I signaling pathway was studied. PDGF inhibited IGF-I-stimulated IRS-1 tyrosine phosphorylation and subsequent IGF-I-induced PI 3-kinase activity, and stimulated IRS-1 serine 307 phosphorylation. These effects were mediated through a PI 3-kinase-dependent but extracellular signal-regulated kinase (ERK)-independent signaling pathway. However, PDGF-induced IRS-1 serine 307 phosphorylation was not sufficient per se to inhibit the IGF-I signaling but required another independent pathway. Noteworthy, although acutely stimulated by PDGF, and contrary to what we previously described (Karam et al. [<em>22</em>]), PKD1 did not associate with IRS-1and did not inhibit the IGF-I signaling in response to PDGF. However, we identified PKCβI as a new regulatory partner of PI 3-kinase for PDGF-induced inhibition of the IGF-I signaling pathway. Therefore, our results reinforce the idea that a coordinated action of two independent pathways seems absolutely necessary to negatively regulate IRS-1. Moreover, they also demonstrated that, depending of the cross-talk considered, subtle and specific regulatory mechanisms occur at the level of IRS-1 and that a unique regulatory model is not conceivable.