Factors Associated with Increased Caregiver Burden of Informal Caregivers during the COVID-19 Pandemic in Japan.

This study's objective was to explore the association between various factors and the increased caregiver burden of informal caregivers during the COVID-19 pandemic. On February, 2021, 700 informal caregivers completed an online survey. We assessed the change in caregiver burden during the COVID-19 pandemic. Among all caregiver participants, 287 (41.0%) complained of an increased caregiver burden due to the COVID-19 pandemic. The factors associated with increased caregiver burden were depressive symptoms in caregivers [odds ratio (OR), 2.20; 95% confidence interval (CI), 1.50-3.23], dementia (OR, 2.48; 95%CI, 1.07-5.73) and low Barthel Index scores (OR, 2.01; 95%CI, 1.39-2.90) in care receivers, care days (OR, 1.09; 95%CI, 1.01-1.17) and times (OR, 1.06; 95%CI, 1.01-1.10), and use of home care service (OR, 1.46; 95%CI, 1.01-2.10) and visiting care service (OR, 1.71; 95%CI, 1.20-2.45). These findings suggest we need to pay attention to the physical and mental health of both the care receivers and caregivers.

Diagnostic performance of MR imaging of three major salivary glands for Sjögren's syndrome.

OBJECTIVE: We analyzed the diagnostic performance of the MR imaging findings of the parotid, submandibular, and sublingual glands to discriminate between patients with and without Sjögren's syndrome. METHODS: We retrospectively analyzed the correlation between the MR imaging and histopathological findings obtained from 69 patients with clinically suspected Sjögren's syndrome. We evaluated the heterogeneous signal intensity distribution on T1- and T2-weighted images, the multiple high-signal-intensity spots on MR sialograms, and the volume of the parotid, submandibular, and sublingual salivary glands. RESULTS: The multiple high-signal-intensity spots in the parotid gland showed the highest sensitivity and diagnostic accuracy (82% and 83%, respectively). In addition, the multiple high-signal-intensity spots and the heterogeneous signal intensity distribution in the submandibular gland showed high specificity (100% and 88%, respectively). The volume of the submandibular gland, but not that of the parotid or sublingual gland, was smaller in patients with Sjögren's syndrome. CONCLUSIONS: The presence of multiple high-signal-intensity spots on an MR sialogram in the parotid gland should be considered the best diagnostic indicator for Sjögren's syndrome. The presence of spots, heterogeneity, and the change to smaller volumes in the submandibular gland were also helpful because of their high specificity, particularly in advanced cases.

Diagnostic value of capsule-like rim enhancement on magnetic resonance imaging for distinguishing malignant from benign parotid tumours.

The purpose of this study was to clarify the diagnostic value of capsule-like rim enhancement (CLRE) on magnetic resonance imaging (MRI) for distinguishing malignant from benign tumours of the parotid gland. We retrospectively evaluated contrast-enhanced T1-weighted images of 100 patients with malignant and benign parotid tumours for the presence, completeness, and irregularity of CLRE and its maximum thickness. We investigated any correlation of imaging and histopathological findings for 51 cases showing CLRE with available histology. The presence and completeness of CLRE did not differ significantly between benign and malignant tumours. Malignant tumours had more irregular CLRE than benign tumours (P<0.05). The mean CLRE thickness was significantly greater for malignant (2.4 mm) than benign tumours (1.4 mm) (P<0.0001). The two types of tumour were most accurately distinguished using a cut-off value of 1.5 mm thickness. Histopathology demonstrated the general correspondence of thick CLRE on MRI in malignant tumours with thick but sparse fibrous tissue and infiltration of tumour cells and lymphocytes, whereas thin CLRE in benign tumours typically represented dense fibrous tissue without infiltration of tumour cells. CLRE was more irregular and thicker in malignant tumours than in benign tumours, which may be of help in differentiating them.

Safety evaluation of 1,4-alpha-glucan branching enzymes from Bacillus stearothermophilus and Aquifex aeolicus expressed in Bacillus subtilis.

1,4-alpha-Glucan branching enzyme (BE; EC 2.4.1.18) is a key biocatalyst in the synthesis of polysaccharides, and is therefore useful in the production of food ingredients. The BEs evaluated in this study (BE-01 and BE-02) are obtained by fermentation of Bacillus subtilis expressing the BE gene from either Bacillus stearothermophilus strain TRBE14 or Aquifex aeolicus strain VF5. The safety of BE-01 and BE-02 have not been previously evaluated, and therefore, both were subjected to standard toxicological testing. In a battery of standard Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) and in Escherichia coli WP2uvrA, both with and without metabolic activation, neither BE-01 nor BE-02 exhibited mutagenic activity. Similarly, neither was associated with clastogenic properties in Chinese hamster ovary cells in an in vitro chromosomal aberration assay. In rats, oral administration of BE-01 or BE-02 at doses of up to 15 mL/kg body weight/day (approximately 870 and 900 mg/kg body weight/day, respectively) for 13 weeks did not produce compound-related clinical signs or toxicity, changes in body weight gain, food consumption, hematology, clinical chemistry, urinalysis, organ weights, or in any gross and microscopic findings. The results of this study support the safety of BE-01 and BE-02 in food production.

High serum levels of IGF-I contribute to promotion of endochondral ossification in mandibular condyle and cause its specific elongation in acromegaly-like rats.

Mandibular protrusion accompanies acromegaly or acrogigantism. To clarify the detailed mechanisms, we used an acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I). Human recombinant IGF-I (640 microg/day) continuously was infused subcutaneously to 10-week-old male rats (n=12) for four weeks. Control, sham-operated animals (n=12) were injected with saline alone. Twelve rats (six from each group) were killed immediately after ending administration at age 14 weeks. Another 12 rats (six from each group) were housed for an additional four weeks after treatment ended. Mandibular condylar length increased significantly in the IGF-I rats compared with the control rats, but no significant intergroup difference was found in the lengths of the coronoid and angular processes. Cartilaginous layer width, bone matrix volume, and the number of osteoblasts in the mandibular condyle increased significantly in the IGF-I group. These histopathological changes in the condyle disappeared after IGF-I administration was discontinued; however, the morphological change in condylar length remained. These findings suggest that mandibular protrusion in patients with acromegaly or acrogigantism may be evoked by superfluous elongation of the mandibular condyle and that such elongation can be induced by endochondral ossification caused by high IGF-I serum levels.

A case of masticatory disturbance incidental to trigeminal schwannoma: changes in occlusal force and masticatory sensation before and after radiosurgery.

We report here a case of masticatory disturbance evoked by trigeminal schwannoma, in which we have evaluated the changes in occlusal force and masticatory sensation before and after treatment for the tumour. The patient was a 43-year-old woman and her chief complaint was a loss of masticatory sensation on her left side. MR imaging revealed an enhanced tumour in the left cavernous sinus/Meckel's cave. The left masseter muscle function and occlusal force showed remarkable decreases before treatment; however, the sensory thresholds of her facial skin and dental pulp were not significantly different from the control side, indicating that her loss of masticatory sensation was not due to sensory disturbance but to occlusal force weakness. Gamma-knife radiosurgery resulted in a significant improvement in masticatory sensation following an increase in occlusal force.

Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells.

Chronic proteinuria appears to be a key factor in tubulointerstitial damage. Recent studies have emphasized a pathogenic role of endoplasmic reticulum (ER) stress which is induced by the accumulation of misfolded proteins in ER, extracellular stress, etc. In the present study, we investigated ER stress and ER stress-induced apoptosis in proximal tubular cells (PTCs). Immortalized rat PTCs (IRPTCs) were cultured with bovine serum albumin (BSA). The viability of IRPTCs decreased proportionately with BSA overload in a time-dependent manner. Quantitative real-time polymerase chain reaction analysis revealed that 40 mg/ml BSA increases mRNA of ER stress markers by 7.7- and 4.6-fold (glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150), respectively) as compared to control. The increased expression of ORP150 and GRP78 in IRPTCs with albumin overload was detected by Western blot and immunofluorescence study. These in vitro observations were supported by in vivo studies, which demonstrated that ER stress proteins were upregulated at PTCs in experimental proteinuric rats. Furthermore, increased ER stress-induced apoptosis and activation of caspase-12 were observed in IRPTCs with albumin overload and kidneys of experimental proteinuric rats. We confirmed that apoptotic cell death was attenuated by co-incubation with caspase-3 inhibitor or calpain inhibitors. These results indicate that the ER stress-induced apoptosis pathway contributed to the insult of tubular cells by proteinuria. In conclusion, renal tubular cells exposed to high protein load suffer from ER stress. ER stress may subsequently lead to tubular damage by activation of caspase-12.

Morphological and histopathological changes in tongues of experimentally developed acromegaly-like rats.

An acromegaly-like rat model recently developed by exogenous administration of insulin-like growth factor I (IGF-I) was used to investigate morphological and histopathological tongue changes and clarify whether the changes were reversible. Human recombinant IGF-I (640 microg/day) was continuously subcutaneously infused into ten-week-old male rats for four weeks (IGF-I group; n = 6). Control sham-operated animals were injected saline alone (control group; n = 6). Rats were sacrificed immediately on ending administration at the age of fourteen weeks. Another 12 rats (6 from each group) were housed for an additional four weeks after administration ended. Total IGF-I (human + rat) increased significantly during administration, returning to control levels afterwards. Tongue weights significantly increased with histopathological changes present (increases in the muscle-bundle width, spaces between muscle-bundles and epithelium thickness) in the IGF-I group compared to control rats. Tongue size returned to control levels after discontinuation of IGF-I administration. These findings suggest that the characteristic tongue enlargement was developed experimentally in our acromegaly-like rat model, and that such morphological and histopathological tongue changes are reversible on normalization of circulating IGF-I levels.

Insulin-like growth factor-I stimulates acromegaly-like specific mandibular enlargement in rats.

To help us investigate the time course of mandibular enlargement in acromegaly or acrogiantism to determine the most suitable period for occlusal treatment in this disease, our aim was to develop a rat model of acromegaly (acrogiantism). In this study, prominent mandibular enlargement was induced by continuous subcutaneous infusion of human recombinant insulin-like growth factor-I (IGF-I) (640 microg/day) in 10-week-old male rats for 4 weeks (n = 6); the control sham-operated group was injected with saline alone (n = 6). Circulating human IGF-I was clearly detectable in the IGF-I group during the four-week administration period, while endogenous rat IGF-I levels decreased. Total IGF-I (human + rat) increased significantly during administration, returning to control levels afterwards. The length of every bone examined (mandible, maxilla, and femur) showed a significant increase compared to control rats, especially the mandible. Although the mandible did not continue to grow after discontinuation of IGF-I administration, it did not return to control size, unlike the maxilla and femur, and disharmonious jaw size (between maxilla and mandible) persisted even after circulating IGF-I levels normalized. These findings in our rat model suggest that mandibular occlusal treatment should only be considered for acromegalic (acrogiantic) patients after serum IGF-I levels have normalized and bone growth has ceased.

Induction of insulin production in rat pancreatic acinar carcinoma cells by conophylline.

We set up a screening system to detect low-molecular-weight compounds that induce insulin expression in pancreatic acinar carcinoma AR42J cells. They can differentiate into insulin-producing cells with neuron-like morphological change when treated with activin A. We employed this morphological change for the screening of beta-cell inducers among various signal transduction inhibitors. As a result, a vinca alkaloid, conophylline, induced neurite formation at 0.1 approximately 0.3 microg/ml in 72 h, like activin A. Conophylline-treated cells were found to express insulin as measured at both mRNA and protein levels. By RT-PCR analysis, conophylline-treated cells were shown to express neurogenin3 strongly. They also expressed Beta2/NeuroD and Nkx2.2, but not Pax4 and PP. Although activin A induces nuclear translocation of Smad2, conophylline did not. But the latter induced p38 activation, like activin A, as detected by phosphorylation. Pretreatment with a p38-specific inhibitor, SB203580, lowered the conophylline-induced insulin production. Therefore, p38 activation would be involved in the differentiation of AR42J cells into insulin-producing cells. Studies on structure-activity relationship with conophyllidine, conofoline, conophyllinine, and related monomer alkaloids showed that the dimeric aspidosperma structure with the dihydrofuran unit in its center was essential for the differentiation-inducing activity.

Intracellular and extracellular pHs of Streptococcus mutans after addition of acids: loading and efflux of a fluorescent pH indicator in streptococcal cells.

A pH-sensitive fluorescent dye, 2', 7'-bis-(2-carboxyethyl)-5 and 6-carboxyfluorescein (BCECF), was used to determine intracellular pH (pH(in)). The efflux of BCECF loaded into oral streptococcal cells was determined after incubation of the cells at 35 degrees C for 20 min in the presence and absence of glucose. In the absence of glucose, the fluorescence of intracellular BCECF in Streptococcus mutans, Streptococcus sanguis, Streptococcus salivarius and Streptococcus sobrinus decreased only very slightly, indicating that the dye could be useful for pH(in) determination. In the presence of glucose, however, the fluorescence decreased by 57%. Thus, the pH(in) of S. mutans cells was measured by the BCECF method in the absence of glucose at various acidic pH levels by adding lactic, acetic and hydrochloric acids to the cell suspensions. The pH(in) was almost equal to the extracellular pH (pH(out)) for pH(out) values of between 8 and 5, indicating that protons permeated easily across the S. mutans cell membrane. For pH(out) between 5 and 4, pH(in) was constant at around 5, suggesting that the cell membrane was impermeable to protons, or that a cytoplasmic buffering system functioned. pH(in) decreased at pH(out) values of < 4. The constant pH(in) at acidic pH(out) levels could protect intracellular components, such as proteins, against acidification by sugar fermentation.

The neuropeptide head activator induces activation and translocation of the growth-factor-regulated Ca(2+)-permeable channel GRC.

The neuropeptide head activator stimulates cell proliferation of neuronal precursor and neuroendocrine cells. The mitogenic signaling cascade requires Ca(2+) influx for which, as we show in this paper, the growth-factor-regulated Ca(2+)-permeable cation channel, GRC, is responsible. GRC is a member of the transient receptor potential channel family. In uninduced cells only low amounts of GRC are present on the plasma membrane but, upon stimulation with head activator, GRC translocates from an intracellular compartment to the cell surface. Head activator functions as an inducer of GRC translocation in neuronal and neuroendocrine cells, which express GRC endogenously, and also in COS-7 cells after transfection with GRC. Head activator is no direct ligand for GRC, but its action requires the presence of a receptor coupled to a pertussis-toxin inhibitable G-protein. Heterologously expressed GRC becomes activated by head activator, which results in opening of the channel and Ca(2+) influx. SK&F 96365, an inhibitor specific for TRP-like channels, blocks Ca(2+) entry and, consequently, translocation of GRC is prevented. Head activator-induced GRC activation and translocation are also inhibited by wortmannin and KN-93, blockers of the phosphatidylinositol 3-kinase and of the Ca(2+)/calmodulin-dependent kinase, respectively, which implies a role for both kinases in head-activator signaling to GRC.

Promotion of beta-cell regeneration by betacellulin in ninety percent-pancreatectomized rats.

Betacellulin is thought to promote growth and differentiation of pancreatic beta-cells. We investigated the effect of betacellulin on regeneration of pancreatic beta-cells in 90%-pancreatectomized rats. Ninety percent pancreatectomy was performed in male Wistar rats and betacellulin (0.5 microg/g body weight) or saline was administered daily for 10 d starting immediately after pancreatectomy. In pancreatectomized rats, the morning-fed plasma glucose was significantly lower and the plasma insulin concentration was significantly higher in betacellulin-treated rats than those in control rats for up to 4 wk. Thirty days after pancreatectomy, a glucose tolerance test was performed. Betacellulin reduced the plasma glucose response to ip glucose loading. In control rats, the plasma insulin concentration was significantly lower and did not respond to glucose. In contrast, the plasma insulin concentration increased slightly but significantly in betacellulin-treated rats. Thirty days after pancreatectomy, the beta-cell mass was greater and the insulin content was significantly higher in betacellulin-treated rats than those in control rats. The numbers of islet cell-like cluster and bromodeoxy uridine/insulin double- positive cells in both islet cell-like cluster and islets were significantly higher in betacellulin-treated rats. These results indicate that administration of betacellulin improves glucose metabolism by promoting beta-cell regeneration in 90%-pancreatectomized rats.

Transforming growth factor beta and activin tonically inhibit DNA synthesis in the rat liver.

The present study was conducted to assess the role of transforming growth factor beta (TGF-beta) and activin(s) in the regulation of the mass of the liver. To this end, we eliminated TGF-beta or activin signaling in intact rat liver by adenovirus-mediated transfer of the gene encoding truncated type II TGF-beta receptor (AdextTR) or truncated type II activin receptor (AdextAR). In intact rat liver that received a single application of either AdextTR or AdextAR via the portal vein, DNA synthesis as assessed by bromodeoxy uridine (BrdU) labeling was induced. In AdextTR- or AdextAR-treated rats, nuclear labeling was significantly higher than that in AdexLacZ, adenovirus vector encoding Escherichia coli beta-galactosidase gene, or saline-treated rats at 3, 5, 7, and 9 days of infusion. The peak of the BrdU labeling was observed after 7 days of infusion and the labeling decreased thereafter. Apoptosis of hepatocytes, assessed by the terminal deoxynucleotidyl transferase (TdT)-mediated, dUTP-biotin nick-end labeling method was detected after 9 days of infusion. Immunoreactivity of TGF-beta and activin A increased in the liver after the blockade of the activin or TGF-beta signaling. TGF-beta and activin A may have been up-regulated when the action of these ligands was blocked. These results indicate that blockade of the action of either TGF-beta or activin leads to the initiation of DNA synthesis in intact liver. TGF-beta and activin tonically inhibit hepatocyte growth even in intact liver and may play a critical role in the maintenance of constant liver mass.

The role of the activin-follistatin system in the developmental and regeneration processes of the kidney.

Regeneration processes in many tissues are modulated by various factors, which are involved in their organogenesis. Activin A, a member of the TGF-beta superfamily, inhibits branching tubulogenesis of the kidney in organ culture system as well as in in vitro tubulogenesis model. On the other hand, follistatin, an antagonist activin A, reverses the effect of activin A on kidney development, induces branching tubulogenesis, and also promotes tubular regeneration after ischemia/reperfusion injury by blocking the action of endogenous activin A. The activin-follistatin system is one of the important regulatory systems modulating developmental and regeneration processes of the kidneys.

Orthodontic bracket bonding with a plasma-arc light and resin-reinforced glass ionomer cement.

Developments in light-curing technology have led to the introduction of a plasma-arc light-curing unit that delivers high-intensity output for faster curing. The purposes of this study were to determine the shear bond strengths of light-cured resin-reinforced glass ionomer cement cured with a plasma-arc light-curing unit and to evaluate the durability of the resultant bond strength with thermal cycling. Comparisons were made between light-cured resin-reinforced glass ionomer cement and light-cured composite resin. Two light-curing units were used in this study: a plasma-arc light-curing unit and a conventional light-curing unit. The mean shear bond strengths of light-cured resin-reinforced glass ionomer cement with the plasma-arc and the conventional light-curing units were 20.3 MPa and 26.0 MPa, respectively. An analysis of variance showed no statistically significant differences between the plasma-arc and the conventional light-curing units. Light-cured resin-reinforced glass ionomer cement and light-cured composite resin demonstrated similar bond strengths and exhibited no statistical differences. There was no statistical difference in bond strength between the teeth that were thermal cycled and those that were not. Failure sites for the brackets bonded with light-cured resin-reinforced glass ionomer cement appeared to be predominantly at the bracket-adhesive interface. The SDs of light-cured composite resin were high for both light-curing units. Whereas the coefficients of variation for light-cured resin-reinforced glass ionomer cement ranged from 20% to 30%, those of light-cured composite resin ranged from 40% to 60%. The bond strength of light-cured resin-reinforced glass ionomer cement cured with either a conventional light-curing unit or a plasma-arc light-curing unit surpassed the clinically required threshold. The plasma-arc light-curing unit may be an advantageous alternative to the conventional light-curing unit for orthodontic bracket bonding with both light-cured resin-reinforced glass ionomer cement and light-cured composite resin.

Role of the activin-follistatin system in the morphogenesis and regeneration of the renal tubules.

Activin A inhibits branching tubulogenesis of the kidney during development. Activin A also inhibits branching tubulogenesis in MDCK cells, an in vitro tubulogenesis model. On the other hand, follistatin, an antagonist of activin A, reverses the effect of activin A and induces branching tubulogenesis. Follistatin also promotes tubular regeneration after ischemia/reperfusion injury. The activin/follistatin system is one of the important regulatory systems modulating developmental and regeneration processes of the kidney.

Caspase-independent apoptosis induced by differentiation-inducing factor of Dicytostelium discoideum in INS-1 cells.

Differentiation-inducing factor (DIF) is a lipophilic hormone of Dicytostelium discoideum and has been shown to exert diverse effects in mammalian cells. We investigated the effect of DIF on cell viability in insulin-secreting INS-1 cells. DIF induced cell death in a dose-dependent manner. In DIF-treated cells, nuclear condensation and shrinkage of the cell body were observed. After 6 h of DIF treatment, cells became Tdt-mediated dUTP-biotin nick end-labeling-positive, and DNA ladder formation was detected, indicating that DIF induced apoptosis in these cells. DIF did not activate caspase-3, a key enzyme mediating apoptotic signals generated by various agents. Furthermore, DIF-induced cell death was not affected by Z-asp-2, 6-dichlorobenzoyloxymethylketone, a broad inhibitor of the caspases. As is the case in other types of cells, DIF increased cytoplasmic free calcium concentration in INS-1 cells. However, DIF-induced cell death was not affected by chelating intracellular free calcium by 1, 2-bis(2-aminoophenoxy)ethane-N, N, N, N-tetra acetic acid (BAPTA). These results indicate that DIF induces apoptosis in INS-1 cells by a mechanism independent of caspase-3. DIF-induced elevation of cytoplasmic calcium does not mediate the effect of DIF on cell death.

Differential localization and colocalization of two neuron-types of sodium-dependent inorganic phosphate cotransporters in rat forebrain.

We studied by immunohistochemistry the distribution of differentiation-associated sodium-dependent inorganic phosphate (Pi) cotransporter (DNPI) in the rat forebrain, in comparison with brain-specific cotransporter (BNPI). DNPI-staining was principally seen in axonal synaptic terminals which showed a widespread but discrete pattern of distribution different from that of the BNPI-staining. In the diencephalon, marked DNPI-staining was seen in the dorsal lateral geniculate, medial geniculate, ventral posterolateral, ventral posteromedial, anterior, and reticular thalamic nuclei without the colocalization with BNPI-staining. DNPI-staining showed a strong mosaical pattern and overlapped well the BNPI-staining in the medial habenular nucleus. DNPI-staining was moderate over the hypothalamus and notably localized in neurosecretory terminals containing corticotropin-releasing hormone in the median eminence. In contrast, the BNPI-staining was region-related and strong in the ventromedial and mammillary nuclei. In the telencephalon, laminar DNPI-staining was seen over the neocortex, corresponding to the thalamocortical termination, and also found in the retrosplenial cortex and the striatum, with the highest intensity in the accumbens nucleus shell. The present results suggest that DNPI serves as a dominant Pi transport system in synaptic terminals of diencephalic neurons including thalamocortical and thalamostriatal pathways as well as the hypothalamic neuroendocrine system in the rat forebrain.

Upregulatory expression of furin and transforming growth factor-beta by fluid shear stress in vascular endothelial cells.

Furin, a yeast Kex2-family endoprotease, converts many vasoregulatory propeptides, including pro-transforming growth factor (TGF)-beta to their mature forms. We examined whether furin expression is regulated by shear stress in vivo and in vitro. When an arteriovenous shunt was placed between the carotid artery and external jugular vein in rabbits, furin and TGF-beta were highly expressed in shear stress-loaded endothelial cells. Exposure of bovine aortic endothelial cells in culture to shear stress induced furin and TGF-beta expression in a similar manner. Molecular analysis of furin expression in bovine aortic endothelial cells revealed that shear stress increases the furin gene expression at transcriptional levels. Furthermore, TGF-beta itself increased the furin mRNA levels. Shear-mediated furin expression was partly mediated by TGF-beta because shear-induced furin mRNA levels were considerably decreased by overexpression of the truncated form of the TGF-beta type II receptor. Likewise, blockade of furin activity by a furin inhibitor significantly decreased the endothelial production of mature TGF-beta. Taken together, the results indicate that furin expression is induced and maintained by a coordination of shear stress and TGF-beta. Increased furin expression may facilitate the formation of mature TGF-beta, resulting in the enhanced effects of TGF-beta on endothelial cells and vascular smooth muscle cells in the vasculature.