How do systemic sclerosis manifestations influence patients' lives? Results from a survey on patients and caregivers.

OBJECTIVE: To investigate the patient- and caregiver-reported impact of systemic sclerosis (SSc) manifestations (hand/feet/joint involvement and pulmonary complications) on the diagnostic and therapeutic journey, working productivity, and social life. METHODS: Two questionnaires (one for the patients, n = 260 and one for the caregivers, n = 47) were designed in collaboration with the patients' association Gruppo Italiano per la Lotta alla Sclerodermia (GILS). Validated questionnaires were combined with specific questions relevant to the Italian scenario. RESULTS: Pulmonary fibrosis and hand/feet/joint involvement have a major impact on patient's working status: (85.3% of patients with pulmonary fibrosis and 72.6% with hand/feet/joint involvement report loss of job/job change due to SSc. Productivity was affected as well: 60.6% of the patients (75% of those with fibrosis) reported that working productivity in the previous 4 weeks was restricted by physical limitations. The disease has a significant impact on patients' life, limiting the ability to conduct common activities, especially those related to movement, such as object manipulation (61.1%), doing small manual jobs (44.0%), writing (38.9%), and an increased impact in case of pulmonary fibrosis and hands/feet/joints involvement. Half of the patients also present some difficulties in eating-related activities a Patients also experience poorer social life, personal relationships, and sexual life. Caregivers are also deeply influenced by the manifestations of SSc. Pulmonary fibrosis and hand/feet/joint involvement represent an additional challenge. CONCLUSION: Pulmonary fibrosis and hand/feet/joint involvement are extremely burdensome complications for both SSc patients and caregivers, decreasing work productivity, limiting relationship and social life, and impacting psychological status and everyday activities.

The use of medical cannabis in pediatric palliative care: a case series.

BACKGROUND: Medical cannabis may be a useful tool for managing treatment-resistant epilepsy and chronic pain, which affect many patients in pediatric palliative care (PPC); however, little evidence is available in this setting. CASE PRESENTATION: We aimed to describe a clinical experience in a setting where high-level evidence may not be obtained. We report our clinical experience in a pediatric palliative care department in Italy. Caregivers reported changes in intensity and frequency of pain and epilepsy events. Six patients received a titrated plant extract of cannabis sativa for 1 year. Only mild and transient adverse events occurred: drowsiness, euphoria, restlessness and tachycardia; the resolution was either spontaneous or obtained by modifying the administration schedule. Treatment was never discontinued. No overdoses occurred. All patients experienced seizures during the pre-treatment observation period, and obtained a reduction in seizure frequency, although with variable extent while receiving cannabis. In addition, a benefit on pain was observed, based on the caregiver's evaluation, and a reduction of analgesic use. CONCLUSION: Our experience suggests that a titrated plant extract preparation of medical cannabis may be useful to control treatment-resistant pain and epilepsy in PPC patients.

Therapeutic Opportunities for Food Supplements in Neurodegenerative Disease and Depression.

Emerging evidence is showing nutrition as a crucial factor in the high prevalence and incidence of neurodegenerative mental disorders. Preventive interventions on neuroinflammation seem to be able to interfere with neurodegeneration. Supplementation of essential nutrients, such as long-chain-polyunsaturated fatty acids, vitamin E and mineral elements, may minimize inflammation, enhancing antioxidative defense, and lowering the risk and incidence of age-related diseases, such as cardiovascular diseases and neurodegenerative diseases. This manuscript reviews the current evidence on the role of neuroinflammation in the pathophysiology of neurodegenerative and mental disorders, and preventive strategies for food supplementation in these neuropsychiatric diseases. Dietary supplementation-based strategies have been demonstrated to be effective in subjects with mild cognitive impairment, while weaker results have been obtained in patients with advance neurodegenerative disease. Adjunctive supplementation has also been demonstrated to improve depression, this being of marked benefit considering the comorbidity between cognitive impairment/dementia and depression. Further research is needed to improve the prescriptive precision of supplementation in patients, and to better understand potential interactions with clinical and pharmacokinetic factors.

ICS/formoterol in the management of asthma in the clinical practice of pulmonologists: an international survey on GINA strategy.

BACKGROUND: The treatment with short-acting beta-2 agonists (SABA) alone is no longer recommended due to safety issues. Instead, the current Global Initiative for Asthma (GINA) Report recommends the use of the combination of inhaled corticosteroids (ICS) with the rapid/long-acting beta-2 agonist formoterol, although the use in steps 1 and 2 is still off-label in the EU and in many countries. It is important to understand clinicians' knowledge and opinions on the issue with the ultimate goal to encourage the implementation of the new approach in clinical practice. METHODS: We performed an international survey, directed to pulmonologists interested in the management of patients with asthma. RESULTS: Most participants reported that SABA alone should not be used in GINA Step 1 asthma treatment. As-needed low-dose ICS/formoterol combination to patients in step 1, and as-needed low-dose ICS/formoterol as reliever therapy in any step were found to be of current use prescribed in their real-life settings. SABA alone was still prescribed to a proportion of patients, although the pulmonologists' opinion was that it should no longer be used. CONCLUSIONS: Most specialists are up to date and understand the relevance of the changes in GINA reports from 2019. Nevertheless, dissemination and implementation of GINA novel management strategy is still needed.

Placenta growth factor in diabetic wound healing: altered expression and therapeutic potential.

Reduced microcirculation and diminished expression of growth factors contribute to wound healing impairment in diabetes. Placenta growth factor (PlGF), an angiogenic mediator promoting pathophysiological neovascularization, is expressed during cutaneous wound healing and improves wound closure by enhancing angiogenesis. By using streptozotocin-induced diabetic mice, we here demonstrate that PlGF induction is strongly reduced in diabetic wounds. Diabetic transgenic mice overexpressing PlGF in the skin displayed accelerated wound closure compared with diabetic wild-type littermates. Moreover, diabetic wound treatment with an adenovirus vector expressing the human PlGF gene (AdCMV.PlGF) significantly accelerated the healing process compared with wounds treated with a control vector. The analysis of treated wounds showed that PlGF gene transfer improved granulation tissue formation, maturation, and vascularization, as well as monocytes/macrophages local recruitment. Platelet-derived growth factor, fibroblast growth factor-2, and vascular endothelial growth factor mRNA levels were increased in AdCMV.PlGF-treated wounds, possibly enhancing PlGF-mediated effects. Finally, PlGF treatment stimulated cultured dermal fibroblast migration, pointing to a direct role of PlGF in accelerating granulation tissue maturation. In conclusion, our data indicate that reduced PlGF expression contributes to impaired wound healing in diabetes and that PlGF gene transfer to diabetic wounds exerts therapeutic activity by promoting different aspects of the repair process.

Endogenous VEGF-A is responsible for mitogenic effects of MCP-1 on vascular smooth muscle cells.

Vessel wall remodeling is a complex phenomenon in which the loss of differentiation of vascular smooth muscle cells (VSMCs) occurs. We investigated the role of rat macrophage chemoattractant protein (MCP)-1 on rat VSMC proliferation and migration to identify the mechanism(s) involved in this kind of activity. Exposure to very low concentrations (1-100 pg/ml) of rat MCP-1 induced a significant proliferation of cultured rat VSMCs assessed as cell duplication by the counting of total cells after exposure to test substances. MCP-1 stimulated VSMC proliferation and migration in a two-dimensional lateral sheet migration of adherent cells in culture. Endogenous vascular endothelial growth factor-A (VEGF-A) was responsible for the mitogenic activity of MCP-1, because neutralizing anti-VEGF-A antibody inhibited cell proliferation in response to MCP-1. On the contrary, neutralizing anti-fibroblast growth factor-2 and anti-platelet-derived growth factor-bb antibodies did not affect VSMC proliferation induced by MCP-1. RT-PCR and Western blot analyses showed an increased expression of either mRNA or VEGF-A protein after MCP-1 activation (10-100 pg/ml), whereas no fms-like tyrosine kinase (Flt)-1 receptor upregulation was observed. Because we have previously demonstrated that hypoxia (3% O2) can enhance VSMC proliferation induced by VEGF-A through Flt-1 receptor upregulation, the effects of hypoxia on the response of VSMCs to MCP-1 were investigated. Severe hypoxia (3% O2) potentiated the growth-promoting effect of MCP-1, which was able to significantly induce cell proliferation even at a concentration as low as 0.1 pg/ml. These findings demonstrate that low concentrations of rat MCP-1 can directly promote rat VSMC proliferation and migration through the autocrine production of VEGF-A.

Effect of hypoxia and endothelial loss on vascular smooth muscle cell responsiveness to VEGF-A: role of flt-1/VEGF-receptor-1.

OBJECTIVE: The influence of hypoxia and endothelial loss on the responsiveness of vascular smooth muscle cells (VSMCs) to vascular endothelial growth factor (VEGF-A) was tested. METHODS AND RESULTS: Exposure to hypoxia induced a potentiation of cultured cell proliferation in response to either the agonist for the VEGF receptor 1 (flt-1) placental growth factor (PlGF-1) or to VEGF-A. This effect was mediated by the mitogen activated protein kinase (MAPK) cascade, since it was inhibited by the MAPK kinase inhibitor PD98059 and by the farnesyl transferase inhibitor II. Accordingly, PlGF-1 activated extracellular signal-regulated kinase(1/2). In rat aortic rings deprived of endothelium and cultured in three-dimensional fibrin gels, an increased sprouting of tubular structures in response to VEGF-A was observed only under hypoxia. Studies on rat aorta preparations revealed an endothelium-dependent vasorelaxation in response to either VEGF-A or PlGF1, which was reversed to a contractile response in endothelium-deprived preparations exposed to hypoxia. Western blot and immunohistochemistry of endothelium-deprived preparations exposed to hypoxia showed flt-1 receptor expression in all medial cells. Conversely, flt-1 mRNA, of endothelium-deprived aortic preparations and of tubular structures, was unchanged by hypoxia. CONCLUSION: These findings demonstrate that experimental conditions mimicking pathological vascular injury can make VSMCs responsive to VEGF-A through the induction of functional flt-1 receptors.

Inhibition of vascular smooth muscle cell growth by angiotensin type 2 receptor stimulation for in vitro organ culture model.

Recent data suggest that AT2 receptors in smooth muscle cells (VSMCs) of adult vessels may counterbalance AT1 receptor activity by inhibiting cell growth. The role of AT2 receptors in VSMC proliferation was investigated by using an in vitro organ culture model in which the sprouting of tubular structures was assessed. In preparations with endothelium, tubular growth was unaffected by angiotensin II (Ang II) but was inhibited by 50 +/- 9% by losartan and was increased by 110 +/- 15% by the AT2 antagonist PD123177. In endothelium-deprived preparations, growth inhibition (-49.1 +/- 0.5%) was observed when angiotensin II was added together with losartan 1 microM, whereas stimulation (59.8 +/- 14%) was induced by angiotensin II with 1 microM PD123177. In cultured VSMCs angiotensin II slightly promoted growth that was inhibited by losartan but was unaffected by PD123177. AT1a, AT1b, and AT2 mRNA expression was demonstrated in cells isolated from tubular structures grown from intact and endothelium-deprived rings, but only AT1a and AT1b mRNA was detected in cultured VSMCs. In conclusion, this paper proposes an in vitro organ culture model in which the expression of AT2 receptors in VSMCs is preserved and demonstrates AT2 receptor-mediated inhibition of VSMC proliferation in adult vessels.