Consensus paper on postural dysfunction: recommendations for prevention, diagnosis and therapy.

Good fundamentals of posture and balance are essential for the efficient performance of both simple daily tasks and more complex movement patterns. In particular, postural balance is the ability to keep the body in equilibrium and to regain balance after the shift of body segments: postural control mechanisms of integration of the visual, vestibular and foot afferential channels contribute to this. This document provides recommendations based on scientific evidence, clinical practice, and consensus between experts concerning the prevention, diagnosis, and treatment of postural dysfunction at the three stages of life as the developmental age, adult age, and old age > 65 years and follows the "National Guidelines on Classification and Measuring of Posture and its Dysfunctions" per the Italian Ministry of Health (December 2017). The paper answers four main questions: i) "Which measures can be adopted to prevent postural dysfunctions?" ii) "What can we do in order to make a correct diagnosis of postural dysfunction?" iii) "What are the correct treatment programs for postural dysfunctions?" iv) Which professional competencies and experiences are useful for preventing, diagnosing and treating postural dysfunctions? By the Consensus of the Experts and the scientific evidence, emerge that the approach to postural dysfunctions requires a multidisciplinary and interdisciplinary team. Furthermore, rehabilitation treatment interventions must be specific to the age groups that have been indicated, to consider the integration of the main systems and subsystems of postural control that change with age.

ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget's disease of bone.

Paget's disease of bone (PDB) is a skeletal disorder whose molecular basis is not fully elucidated. However, 10% of patients show a familial PDB and 35% of them carry mutations in the SQSTM1 gene. We recently reported a founder mutation (p.Pro937Arg) in the ZNF687 gene, underlying PDB complicated by giant cell tumor (GCT/PDB) and rarely occurring in PDB patients without neoplastic degeneration. Since 80% of Italian GCT/PDB patients derive from Avellino, we hypothesized that ZNF687 mutation rate was higher in this region than elsewhere. Interestingly, our molecular analysis on 30 PDB patients showed that 33% hosted ZNF687 mutations, with the p.Pro937Arg identified in 8 familial cases. Two novel ZNF687 mutations (p.Pro665Leu and p.Gln784Glu) were detected in 2 sporadic patients. Only 2 subjects were positive for the p.Pro392Leu mutation in SQSTM1. ZNF687-mutated patients showed a severe PDB, with a remarkable number of affected sites. in vitro studies revealed that the ZNF687-mutant osteoclasts appeared as giant sized with up to 150 nuclei, never described in PDB. Finally, we also confirmed the causality of the p.Pro937Arg mutation in 4 additional GCT/PDB cases deriving from the same geographic area, indicating that PDB and GCT/PDB represent 2 sides of the same coin.

Mitotane treatment for adrenocortical carcinoma: an overview.

Adrenocortical carcinoma (ACC) is a rare aggressive endocrine neoplasm characterized by a 5-year survival of less than 50%. Due to the widespread use of imaging techniques in clinics, ACC is increasingly recognized as an incidentally discovered tumor. Mostly characterized by poor prognosis, ACC is often diagnosed at an advanced stage of disease. Early diagnosis is uncommon; when diagnosed, ACCs are usually large and have invaded adjacent organs, even if metastatic spread to distant sites can be absent. Complete surgical resection is the only potentially curative treatment for patients with localized disease; however, due to a recurrence rate of 50-70% after apparent radical surgery, there is a strong rationale for a concomitant systemic treatment. Adrenolytic therapy with mitotane (o,p>-DDD), administered alone or in combination with others antineoplastic agents, is the primary treatment for patients with advanced ACC and is increasingly used also in an adjuvant setting, even if controversy exists on this issue due to the limitations of the available literature. Despite being in use for many years, the rarity of ACC precluded the organization of randomized trials; thus, many areas of uncertainty and controversy remain regarding the role of this old drug in the clinical management of patients with ACC. The purpose of this paper is to review the current evidence on mitotane treatment in patients with advanced disease and in ACC patients after complete surgical resection as adjuvant treatment.

Cannabis use disorder and dissociation: A report from a prospective first-episode psychosis study.

BACKGROUND: Cannabis is the most used recreational drug worldwide. Its use can increase the risk of developing psychotic disorders and exacerbate their course. However, the relationship between cannabis use and dissociative symptoms has been scarcely investigated. AIMS: To examine differences in psychotic and dissociative symptoms, and in functioning in first-episode psychotic patients (FEPp) using cannabis compared with those not using cannabis. METHODS: Between January 2014 and December 2019, seventy FEPp with cannabis use disorder (N = 35) and without it (N = 35) were recruited in psychiatric inpatient facilities in the Italian regions of Lazio and Piemonte. All subjects were assessed at FEP, after 4 and 8 months, using the Positive and Negative Syndrome Scale (PANSS), the Global Assessment of Functioning (GAF) scale and the Dissociative Experiences Scale - II (DES-II). Detailed information on the pattern of cannabis and other substance use were collected. RESULTS: FEP using cannabis showed higher levels of positive symptomatology, dissociative experiences and worse functioning than their non-user counterpart, despite a comparable antipsychotic treatment. At an eight-month prospective evaluation, FEP using cannabis still showed higher levels of positive symptomatology and dissociation. Moreover, global functioning worsened over time in FEPp using cannabis, whereas it improved those not using it. DISCUSSION: Our findings suggest that a greater degree of dissociation and positive symptoms at FEPp and their persistence over time may characterise cannabis-associated psychosis. Both these factors might explain the overall functioning worsening over time that we observed in the cannabis-user group compared to the functioning improvement in the non-user group.

Electrochemical behaviour of titanium in ammine and stannous fluoride and chlorhexidine 0.2 percent mouthwashes.

Titanium (Ti) is widely used in dentistry. Fluorides at acid pH could destabilize Ti oxide and make it susceptible to corrosion. The behaviour of IV grade machined Ti disks in 5 electrolytic solutions: Fusayama artificial saliva (Fas), ammine fluoride-stannous fluoride (Am-SnF2), 0.2 percent Chlorexidine (CHX) 0.20 percent, Fas with 20 percent Am-SnF2, and Fas with 20 percent CHX, was evaluated. Open circuit potential Ecorr was determined by immersing Ti disks for 24 hours in an electrochemical cell containing the solutions, potential changes were measured until a stable value was obtained. Examination by Scanning Electronic Microscope and Energy Dispersive X-ray Analysis were then performed. One way ANOVA analysis showed a significant difference of Ecorr values regarding the 5 solutions (p less than 0.001). The highest values were observed for Fas (-37.6 mV), intermediate for Am-SnF2 (-81mV) and lowest for CHX (-87.6mV). SEM analysis of disks after polarization curve in CHX showed a marked localized corrosion, while the other solutions showed no considerable corrosive action on Ti surface. When considering corrosive potential range in oral cavity, Ti had an excellent behaviour on both antiseptics evaluated. The results obtained in this study will enable us to recommend the use of Am-SnF2 mouthwash for patients with dental implants.

Augmenting pharmacotherapy with neuromodulation techniques for the treatment of bipolar disorder: a focus on the effects of mood stabilizers on cortical excitability.

Introduction: Mood stabilizers and antipsychotics have been demonstrated to be effective in Bipolar Disorder, with lithium as the gold standard. However, the presence of adverse events and treatment-resistance is still a relevant issue. To this respect, the use of brain stimulation techniques may be considered as an augmentation strategy, with both Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS) having shown some level of efficacy in bipolar patients although clinical trials are still not sufficient to draw any conclusion. Areas covered: The authors have conducted a systematic review of the literature, in order to evaluate the role of mood stabilizers on neural activity and cortical excitability. Furthermore, the article reviews neuromodulation techniques and highlights the potential of integrating pharmacological first-line therapies with these techniques to treat BD patients. Expert opinion: The combination of neuromodulation techniques and available pharmacotherapies is a valuable opportunity which is not undermined by specific effects on cortical excitability and could improve BD patient outcome. Neurostimulation techniques may be considered safer than antidepressant treatments in BD, with a lower level of manic switches and may represent a new treatment strategy in BD depressive episodes.

Influence of amine fluoride/stannous fluoride mouthwashes with and without chlorhexidine on secretion of proinflammatory molecules by peri-implant crevicular fluid cells.

AIM: Patients with dental implants need optimal plaque control. Peri-implantitis is an inflammation of soft and hard tissues around implants characterized by bone loss mediated by proinflammatory molecules such as IL-1beta, PGE(2), vascular endothelial growth factor (VEGF). The aim of this study was to evaluate the influence of amine fluoride/stannous fluoride (AmF-SnF(2)) vs chlorhexidine 0.12% (CHX) combined with Am-SnF(2) on IL-1beta, PGE(2) and EGF secretion by cells of crevicular peri-implant fluid. METHODS: Thirty patients with dental implants were included in this study. The test group used AmF-SnF(2) rinsing for 14 days, the control group used CHX rinsing during the first 7 days and AmF-SnF(2) during the following 7 days. Crevicular samples were collected using filter paper strips and assayed for level of IL-1beta, PGE(2) and VEGF with ELISA test. Data were analyzed with paired and unpaired t test. RESULTS: IL-1beta, VEGF and PGE(2) levels were significantly lower in test compared to control group. Comparing first with second week of treatment, a greater decrease of IL-1beta and VEGF was evident in sample group during the second week. There was a lower decrease of IL-1beta and VEGF during the entire treatment in control group. Differences of PGE(2) levels after 7 days in both the groups were not significant while there was a significant difference during the second week. CONCLUSION: The following data suggest that the use of AmF-SnF(2) could decrease the production of IL-1beta, PGE(2) and VEGF by inflammatory cells.AmF-SnF(2) could be an alternative to CHX mouth rinses in plaque control of patients with implants.

Animal models in oral cancer research.

Biologically and clinically relevant animal models are essential in investigation of the progression of diseases and the elaboration of diagnostic or therapeutic protocols. The several rodent models used for in vivo evaluation for oral cancer employ chemical, transplantation and genetic (knockout and transgenic) induction methods. These models are described together with their advantages and disadvantages. Their optimization and application in future research may improve the early detection and treatment of oral cancer.

Production of casein and the presence of estrogen receptors in human breast cancer.

The relationship between the presence of estrogen receptors and casein (evaluated on a semiquantitative basis with a specific immunofluorescence method) was statistically analyzed in 50 cases of human breast carcinomas. No significant correlation was found between these two parameters, whereas a relationship was established between the production of casein and the degree of histological differentiation. The results of this study, like those of other studies, revealed a lack of correlation between the presence of estrogen receptors and the degree of histologic differentiation.

Metabolism of pentaerythritol trinitrate.

The absorption, excretion, and biotransformation of 14C-labeled pentaerythritol (PE) trinitrate was studied in man. The administration of a single sublingual dose was followed by rapid absorption and extensive biotransformation. Six drug metabolites were identified. Final excretion of the drug and its metabolites was almost totally through the kidney. Low levels of unchanged drug were present in plasma and urine. PE mononitrate was the major drug metabolite in plasma and urine. Glucuronides of PE trinitrate, dinitrate, and mononitrate were identified for the first time in man. PE trinitrate glucuronide appeared in plasma rapidly and about 8% of the dose was excreted in urine. Reversible and irreversible pathways are proposed for the formation of the metabolites. The reconversion of PE trinitrate glucuronide to PE trinitrate is postulated to explain the duration of drug activity and excretion.

Metabolism of l-bunolol.

The metabolism of l-bunolol, a new beta-blocking drug, was studied in man after single oral 3-mg doses of 3H-labeled compound. Absorption from the gut was rapid and virtually complete. Peak levels of bunolol and of dihydrobunolol, an active metabolite, were observed at 1 hr. Excretion of the administered radioactivity was mainly into the urine (78% in 4 days), with only 3% appearing in the feces. Bunolol, bunolol glucuronide, bunolol sulfate, dihydrobunolol, and dihydrobunolol glucuronide were identified and quantified in the plasma. These compounds represented 82% of the radioactivity in plasma at 30 min and 55% at 24 hr. Plasma half-lives (+/-S.D.) were estimated to be 6.1 +/- 0.3 hr for bunolol, 9.1 +/- 1.9 hr for bunolol glucuronide, 17.4 +/- 2.5 hr for bunolol sulfate, 7.1 +/- 0.5 hr for dihydrobunolol, and 7.7 +/- 0.8 hr for dihydrobunolol glucuronide.

Interference of gestagens and androgens with rat uterine oestrogen receptors.

The inhibitory effect of some gestagens and calusterone on the binding of oestradiol-17beta to its specific uterine receptors has been investigated in intact rats. Progesterone, medrogestone, clogestone, medroxyprogesterone acetate and calusterone reduce the specific oestradiol-receptor interaction in vitro; this effect is dose-dependent and does not differ significantly from one drug to the other. A more relevant decrease in the amount of oestradiol-17beta bound to specific receptors has been observed with calusterone. Progesterone, clogestone, medrogestone, medroxyprogesterone acetate and calusterone given orally induce a marked decrease (between 30 and 70% depending on the dose) in the binding capacity of oestradiol-17beta to specific uterine receptors in vivo. Results from a Scatchard plot analysis suggest that the interference with the binding of oestradiol-17beta caused by both progestogens and calusterone is due to a non-competitive interaction.

PIP: The inhibitory effect of some gestagens and calusterone on the binding of estradiol-17beta to its specific uterine receptors has been investigated in intact rats. Progesterone, medrogestone, clogestone, medroxyprogesterone acetate and calusterone reduce the specific estradiol-receptor interaction in vitro; this effect is dose-dependent and does not differ significantly from 1 drug to the other. A more relevant decrease in the amount of estradiol-17beta bound to specific receptors has been observed with calusterone. Progesterone, clogestone, medrogestone, medroxyprogesterone acetate and calusterone given orally induce a marked decrease (between 30 and 70% depending on the dose) in the binding capacity of estradiol-17beta to specific uterine receptors in vivo. Results from a Scatchard plot analysis suggest that the interference with the binding of estradiol-17beta caused by both progestogens and calusterone is due to a noncompetitive interaction.

Changes in the concentration of uterine cytoplasmic oestrogen receptors induced by doxorubicin and methotrexate.

The effects of doxorubicin and methotrexate on the oestradiol-induced depletion, replenishment and subsequent increase beyond the normal value (overshoot) in the number of uterine cytoplasmic oestrogen receptors were investigated in intact rats. Injection of doxorubicin (0.5 mg/kg, i.v.) or methotrexate (1mg/kg, i.m.) 5 min after a single i.p. injection of 10 ng oestradiol-17beta (which is able to induce a 50% depletion in the number of oestrogen receptors) caused a significant increase in the oestradiol-induced depletion. Both drugs inhibited the replenishment and the overshoot phases until 48 h after treatment, although the effect was more marked with doxorubicin. Experiments in vitro showed that both methotrexate and doxorubicin affected the capacity of oestradiol-17beta to bind to specific cytoplasmic receptors, inducing an increase in binding when used at low concentrations and a decrease at higher concentrations. The effects of doxorubicin and methotrexate on the depletion, replenishment and overshoot of oestrogen receptors seemed to be partly dependent on the inhibition of protein synthesis and partly due to direct action on the binding of oestradiol-17beta to its receptors.

Changes in the binding of oestradiol to uterine oestrogen receptors induced by some progesterone and 19-nor-testosterone derivatives.

The effects of two progesterone derivatives, namely medroxyprogesterone acetate (MPA) and chlormadinone, and two 19-nor-testosterone derivatives, namely norgestrel and norethisterone, on the binding of oestradiol to its cytoplasmic receptors in the rat uterus were compared. In experiments performed in vivo, the rats were given a single oral dose (15 mg/kg) of one of the four progestins and killed 1, 6, 24 and 48 h later. Norgestrel, norethisterone and MPA induced a prompt and remarkable decrease in oestradiol-receptor interaction 1 h after treatment. This reduction lasted almost unchanged for 24 h in rats treated with MPA or norgestrel, but was much lower in animals given norethisterone. In the hours that followed, the effect of MPA and norgestrel began to decrease, but was still detectable after 48 h, whereas the effect of norethisterone had disappeared by this time. The effect of chlormadinone was much less than that induced by both MPA and norgestrel 1, 6 and 24 h after treatment. On the other hand, this effect was less than that caused by norethisterone 1 h after administration, equal after 6 h and much greater after 24 and 48 h. In experiments performed in vitro, the different ability of the four progestins to interfere with the capacity of oestradiol to bind to its receptors was confirmed. In conclusion, all the synthetic progestins used were able to reduce the binding of oestradiol to its cytoplasmic receptors, although there was a clear difference between the progestins in the intensity and duration of this effect. This could be one of the mechanisms by which progestins modulate the activity of oestrogens in target tissues.

Effects of long-term administration of high doses of medroxyprogesterone acetate on hormone receptors and target organs in the female rat.

The changes in oestrogen, progesterone and prolactin receptor levels in target organs, and the macroscopic and microscopic modifications of uterus, ovary, adrenal and pituitary gland induced by long-term administration of high doses of medroxyprogesterone acetate (MPA) were investigated in female rats. Medroxyprogesterone acetate was injected i.m. for 30 days at daily doses of 7.5, 15 and 75 mg/kg. Oestrogen and/or progesterone-binding capacities were remarkably reduced at all doses of MPA used both in the uterus and pituitary gland. Furthermore, MPA caused a very evident reduction in the weight of pituitary glands, ovaries, adrenals and uterus. In all MPA-treated rats corpora lutea were absent from the ovaries, whereas the adrenals showed a significant reduction in the thickness of the cortex. In accordance with this, there was no evidence of ACTH-producing cells in the pituitary glands. Prolactin-producing cells were also absent, while GH-producing cells were present. Serum prolactin levels were significantly reduced at all doses of MPA used. A dramatic reduction of prolactin receptor concentrations was observed in the liver and the ovaries of MPA-treated rats. The results suggest that MPA acts as an antioestrogenic drug both by reducing the number of oestrogen receptors in target tissues and by changing the structure (and perhaps the function) of those organs (pituitary glands, ovaries and adrenals) which are, directly or indirectly, a source of oestrogens. The decreased synthesis of prolactin and the reduction of the number of prolactin receptors (which, on the contrary, are both increased by oestrogens) might be considered as additional antioestrogenic effects of MPA.

Calcyclin gene expression modulation by medroxyprogesterone acetate.

Calcyclin is a cell-cycle-related gene corresponding to a calcium-binding protein whose expression is mainly controlled by platelet-derived growth factor. This paper illustrates medroxyprogesterone acetate (MPA) inhibition of endogenous calcyclin RNA expression of both estrogen-dependent human mammary carcinoma cells and estrogen-independent hamster fibroblasts. Transfection of fragments of the calcyclin promoter driving the chloramphenicol-acetyl-transferase (CAT) gene into hamster fibroblasts was used to evaluate the hormone sensitivity of different promoter regions by considering calcyclin expression at both the RNA and protein level, as evaluated by the CAT assay. A 164 bp promoter fragment showed a good activity that was inhibited by MPA, thereby confirming the results of the observation of endogenous calcyclin gene: smaller fragments, however, required cotransfection of progestin receptor to show full activity, with MPA displaying a stimulatory effect. These findings show that progestin modulation of calcyclin gene expression may be independent of progestin receptors, and that MPA has opposite effects on different promoter regions.

Assessment of the hazards of polybrominated biphenyls.

During their peak use period, PBBs represented under 1% of the total sales of fire retardant chemicals, and very probably would have escaped intensive study if they had not been mixed accidentally with animal feed preparations. Instead, international attention was drawn to PBBs by the state-supervised killing of over 35,000 cattle which had been contaminated with PBBs. Interestingly, low doses of PBBs exert a broad spectrum of toxicological, pharmacological, and biochemical effects despite low acute toxicity. These effects and the intensive bioaccumulation of PBBs derive from their structure and their consequent resistance of biotransformation and high solubility in fat. In rodents, PBBs are teratogenic, immunosuppressive, and potentially carcinogenic. In bovine, rodent, and avian species, PBBs reduce feed intake and induce mixed function oxidases of liver microsomes. The latter effect may be responsible for steroid level changes which underline hormonal toxicities observed in cows, mink, rats, and chickens. The effects of PBBs on humans are controversial, but data suggestive of immunological, skin, and liver disorders continue to accumulate. Concern about the clinical effects of PBBs is heightened by the knowledge that these compounds readily enter the fetus by crossing the placental barrier and can be transferred to newborn children after extensive passage into breast milk.

Assessment of carcinogenic hazard of chemical mixtures through analysis of binary chemical interaction data.

Assessment of the potential health hazard of environmental complex chemical mixtures is one of the most difficult and challenging problems in toxicology. In this article, we describe the development of an innovative computerized system for ranking and predicting potential cancer hazard of chemical mixtures. We take into consideration both the additive risk of individual carcinogens present and the projected overall interaction effect of the mixture based on analyzing and integrating the possible interaction effects of all binary pairs of individual constituents of the mixture. Using this system, it can be predicted that a number of mixtures of polycyclic aromatic hydrocarbons should have a carcinogenic risk lower than that calculated by the simple additivity model, whereas the reverse is true for a number of other mixtures. The system can be very useful in hazard ranking and priority setting in dealing with mixture problems such as cleanup of hazardous waste.

Growth inhibition of DMBA-induced rat mammary carcinomas by UK 114.

A perchloric acid-soluble protein extracted from goat liver and designated as UK 114 is known to be expressed over the cell membrane of (some) human cancer cell lines. This protein is antigenic, and specific antibodies elicit complement-dependent cytolysis of neoplastic target cells. In this study we demonstrate that administration of UK 114, either pure or as a crude extract (designated UK 101), inhibits the growth of mammary carcinomas induced in female Sprague-Dawley rats by dimethylbenzanthracene (DMBA). The mechanism of the tumour inhibitory activity of UK 114 is probably related to induction of immunosurveillance.

Potentiation of medroxyprogesterone acetate antineoplastic activity by histidine in rat mammary tumours.

The antitumour activity of arginine, histidine and medroxyprogesterone acetate (MPA) was studied in female rats with dimethylbenzanthracene (DMBA)-induced mammary adenocarcinomas. After 15 days of treatment, regression was observed in 4 of 19 (21%), 3 of 18 (16.7%) and 22 of 59 (37.3%) tumours taken from rats given arginine, histidine or MPA, respectively. A total of 17 rats with tumours that had been non-responsive to MPA were then treated with MPA plus histidine for 15 more days; the growth of 3 lesions (17.6%) was arrested, and 5 tumours (29.4%) regressed markedly. The antineoplastic activity of MPA was found to be related to the oestrogen-(ER) and progesterone-receptor (PgR) concentrations measured in the tumours before the start of treatment, whereas that of arginine and histidine appeared to be independent of receptor status. A significant reduction in serum prolactin (PRL) levels occurred in rats that were responsive to MPA alone or to MPA plus histidine. In tumours taken from the same rats, the PRL receptor content was also significantly increased in comparison with that in non-responsive tumours. In contrast, serum PRL levels increased significantly in rats with tumours that were non-responsive to MPA, whereas no change in serum PRL or PRL receptor levels was observed in rats treated with arginine or histidine. Histidine showed the ability to increase the number of ERs and PgRs in responsive tumours; this could have been responsible for the unexpected potentiation of MPA antineoplastic activity. In contrast, the levels of ER and PgR in uteri taken from the same rats were not modified. Furthermore, the addition in vitro of histidine to cytosols obtained from tumours of control animals did not influence ER and PgR concentrations. These results suggest that the effect of histidine on ER and PgR levels is probably specific for tumour tissue and is not due to a direct activity.