Altered sensorimotor integration in multiple sclerosis: A combined neurophysiological and functional MRI study.

OBJECTIVE: To explore whether abnormal thalamic resting-state functional connectivity (rsFC) contributes to altered sensorimotor integration and hand dexterity impairment in multiple sclerosis (MS). METHODS: To evaluate sensorimotor integration, we recorded kinematic features of index finger abductions during somatosensory temporal discrimination threshold (STDT) testing in 36 patients with relapsing-remitting MS and 39 healthy controls (HC). Participants underwent a multimodal 3T structural and functional MRI protocol. RESULTS: Patients had lower index finger abduction velocity during STDT testing compared to HC. Thalamic rsFC with the precentral and postcentral gyri, supplementary motor area (SMA), insula, and basal ganglia was higher in patients than HC. Intrathalamic rsFC and thalamic rsFC with caudate and insula bilaterally was lower in patients than HC. Finger movement velocity positively correlated with intrathalamic rsFC and negatively correlated with thalamic rsFC with the precentral and postcentral gyri, SMA, and putamen. CONCLUSIONS: Abnormal thalamic rsFC is a possible substrate for altered sensorimotor integration in MS, with high intrathalamic rsFC facilitating finger movements and increased thalamic rsFC with the basal ganglia and sensorimotor cortex contributing to motor performance deterioration. SIGNIFICANCE: The combined study of thalamic functional connectivity and upper limb sensorimotor integration may be useful in identifying patients who can benefit from early rehabilitation to prevent upper limb motor impairment.

Ethnobotany of dye plants in Southern Italy, Mediterranean Basin: floristic catalog and two centuries of analysis of traditional botanical knowledge heritage.

BACKGROUND: Since ancient times, man has learned to use plants to obtain natural dyes, but this traditional botanical knowledge (TBK) is eroding. In the late, during, and the early 1800s, there was an increase in research related to dye species, and this allowed the development of industry and economy in rural contexts of Southern Italy. Today, dyes are mainly obtained from synthetic products, and this leads to risks for human health related to pollution. METHODS: Starting from the literature, three catalogs of the dyeing species (plants, algae, fungi, and lichens) used in the Mediterranean Basin and mainly in Southern Italy have been created. Percentages of parts used and colors extracted from species have been recorded and analyzed. The plant species present in the catalogs have been verified in the territories of Southern Italy, and the data have been registered. An ethnobotanical survey was conducted, in the region of Southern Italy, to verify the erosion level of traditional botanical knowledge, linked to the ethnobotanical dyeing, over time. RESULTS: A total of 524 species were recorded among plants, algae, fungi, and lichens, and related parts used and extracted pigments. Most uses concern the stems and leaves, and the most frequent color is yellow. From the on-field survey operations, 283 plant species have been verified. These represent 64.31% of the species reported in the flora of the dye plants produced. The results, from the ethnobotanical survey, show that only 8.6% of TBK remained in the collective memory. CONCLUSIONS: This catalog is among the largest in this sector and is the basis for studies related to the restoration of an eco-sustainable economy which would allow the development of marginal areas present throughout Southern Italy.

Tyr1068-phosphorylated epidermal growth factor receptor (EGFR) predicts cancer stem cell targeting by erlotinib in preclinical models of wild-type EGFR lung cancer.

Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFRtyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.

Muscle phosphorus magnetic resonance spectroscopy oxidative indices correlate with physical activity.

The purpose of this study was to assess the effect of physical deconditioning on skeletal muscle's oxidative metabolism as evaluated by phosphorus-31 magnetic resonance spectroscopy ((31)P MRS). Twenty-seven subjects without muscle disease, representing a wide range of fitness levels, were evaluated with (31)P MRS. Spectra were obtained at rest and during recovery from in-magnet exercise. The data show a significant correlation between maximum resting metabolic equivalent (MET) score and the following (31)P MRS recovery indices: adenosine diphosphate and phosphocreatine recovery half-time; initial phosphocreatine resynthesis rate; calculated estimation of mitochondrial capacity; pH at end of exercise; and phosphocreatine depletion. In addition, significant differences between the deconditioned and conditioned group were found for all of the aforementioned recovery indices. At rest, only the inorganic phosphate concentration was significantly different between the two groups. These data indicate that physical activity level should be taken into account when assessing patients' oxidative metabolism with (31)P MRS.

Immobilization stress rapidly decreases hypothalamic corticotropin-releasing hormone secretion in vitro in the male 344/N Fischer rat.

Corticotropin-Releasing-Hormone (CRH) is the principal secretagogue for plasma ACTH and corticosterone secretion and plays an important role in coordinating a variety of physiological and behavioral responses to stress. To explore whether there is a rapid change in the secretory response of the hypothalamic CRH neuron during acute stress, we report here a study of the effects of KCl and norepinephrine (NE) on CRH release in vitro from rat hypothalami explanted after 5, 30, 60, and 120 minutes of immobilization. We also measured the plasma levels of ACTH, beta-endorphin, corticosterone, prolactin, GH, and TSH at these intervals. As the duration of immobilization increased, KCl and NE-induced CRH release in vitro progressively fell. After reaching a maximal rise after 30 minutes of immobilization, plasma ACTH, beta-endorphin, and prolactin progressively fell in plasma, whereas corticosterone remained elevated up to 120 minutes; TSH and GH secretion rapidly declined and remained suppressed. Taken together, these data suggest that during immobilization stress, the responsiveness of the hypothalamic CRH neuron rapidly falls, owing either to CRH depletion and/or desensitization to NE, and this is paralleled by a concomitant decrease in pituitary-adrenal responsiveness.

Recovery of the rat hypothalamic-pituitary-adrenal axis after discontinuation of prolonged treatment with the synthetic glucocorticoid agonist dexamethasone.

To evaluate the recovery of the hypothalamic-pituitary-adrenal (HPA) axis after discontinuation of prolonged exposure to glucocorticoids, we employed adult male Sprague-Dawley rats which were implanted sc with osmotic minipumps filled with saline (vehicle) or dexamethasone (DEX), 100 micrograms/day, for 7 days. At the end of the glucocorticoid treatment period, the minipumps were removed and both saline- and DEX-treated rats were randomly assigned to five different groups tested at 1, 3, 7, 14, and 21 days after removal of the minipumps. Each group was divided into two subgroups receiving either arecoline (ARE), or ovine CRH (oCRH) stimulation tests. ARE was chosen because it has been shown to selectively stimulate the hypothalamic CRH neuron, whereas oCRH was selected as a probe of the pituitary component of the HPA axis. ARE (0.2 mg/kg) and oCRH (10 micrograms/kg) were injected iv to catheterized, freely moving rats and serial blood samples for plasma ACTH and corticosterone determinations were drawn from the catheter before, and 5, 15, 30, and 60 min after the injection. The day after the tests were performed, the rats were killed by decapitation, and body, adrenal and thymus weights, as well as hypothalamic CRH and pituitary ACTH content were determined. On the day of the stimulation tests, basal plasma levels of ACTH and corticosterone were not different between saline- and DEX-treated rats at any time-point after discontinuation of treatment. The ACTH response to ARE, on the other hand, was suppressed one day after, but became normal 3 days after discontinuation of DEX treatment. ACTH response to oCRH normalized later, after 7 days. Interestingly, corticosterone responses to both ARE and oCRH normalized 7 days after discontinuation of glucocorticoid administration. Body, adrenal and thymus weights were significantly reduced by DEX treatment. They recovered slowly and only after 22 days there was no difference between DEX- and saline-treated rats in body and adrenal weight. In contrast, thymus weight was still low on day 8, began to increase after 15 days, and by day 22 did not reach the values recorded in saline-treated rats. Hypothalamic immunoreactive CRH content was not different between DEX- and saline-treated rats, whereas the content of ACTH in the pituitary gland was lower in the DEX-treated rats the second day after discontinuation of GC treatment, normalized after 4 days and increased significantly after 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

The muscarinic cholinergic agonist arecoline stimulates the rat hypothalamic-pituitary-adrenal axis through a centrally-mediated corticotropin-releasing hormone-dependent mechanism.

Several lines of experimental evidence suggest that acetylcholine and other cholinergic agonists are excitatory to the hypothalamic-pituitary-adrenal (HPA) axis. To examine the site on the HPA axis that is stimulated by cholinergic agents, we evaluated the in vivo and in vitro effects of the muscarinic cholinergic agonist arecoline in intact and pituitary stalk-transected rats as well as on isolated rat hypothalami, dispersed anterior pituicytes, and adrenocortical cells in culture. Arecoline, injected iv to catheterized, freely moving male Sprague-Dawley rats, stimulated plasma ACTH and corticosterone release in a dose-dependent fashion. The muscarinic cholinergic antagonist atropine significantly blunted the ACTH response to arecoline. Pituitary stalk transection led to diminished plasma ACTH and corticosterone responses to arecoline. Similarly, previous administration of anti-CRH serum significantly blunted these responses. These findings suggest that arecoline stimulates the HPA axis centrally, mainly via secretion of CRH. This hypothesis was confirmed by the dose-dependent ability of arecoline to cause hypothalamic CRH secretion in vitro, an effect antagonized by atropine, and its failure to elicit ACTH and corticosterone secretion by dispersed anterior pituicytes and adrenocortical cells in culture, respectively. These data suggest that the muscarinic cholinergic agonist arecoline stimulates the HPA axis in the rat and that this effect is mediated mainly by the release of endogenous CRH. Arecoline, therefore, appears to be a compound suitable to selectively evaluate the responsiveness of the central component of the HPA axis.