Smallpox vaccination and vaccine hesitancy in the Kingdom of the Two Sicilies (1801) and the great modernity of Ferdinand IV of Bourbon: a glimpse of the past in the era of the SARS-COV-2 (COVID-19) pandemic.

OBJECTIVE: The current health emergency caused by COVID-19 disease shows several correspondences with well-known epidemics of the past. The knowledge of their management and overcoming could give us useful tools to face the present COVID-19 pandemic and future epidemics. STUDY DESIGN: On 1 March 1801, the first smallpox vaccinations were carried out in Palermo, and a few weeks later, the vaccine was also administered in Naples and the various provinces of the Kingdom. We aim to study the mass vaccination programme initiated by the Bourbon king Ferdinand IV that was the first large-scale campaign to be conducted in Italy and one of the first in Europe. METHODS: The authors searched and examined historical testimony and different aspects linked to the public health issues on vaccination. It is a topical topic in the current period with the COVID pandemic. RESULTS: Albeit with the due differences determined by the passage of time and by the scientific and cultural advances of modern society, this testimony from the past can provide us with food for thought regarding how to face the present COVID-19 pandemic and to prepare for the future. Indeed, it shows us how the terrible smallpox epidemic was handled and finally overcome, thanks to vaccination.

Medical Cannabis: A plurimillennial history of an evergreen.

The history of Cannabis goes along that of humankind, as speculated based on geographical and evolutionary models together with historic data collected to date. Its medical use is several thousand years old, as attested both by archeobotanical evidence of Cannabis remains and written records found in ancient texts from the sacred Vedic foundational texts of Ayurvedic medicine (about 800 before current era [BCE]) to the first known Pharmacopoea, the Chinese "Shen Nung Pen Ts'ao Ching" (1 century BCE). In this paper, we retrace the history of Cannabis traveling through the key stages of its diffusion among the most important ancient cultures up to our days, when we are facing a renaissance of its medical employment. We report through the centuries evidence of its use in numerous pathologic conditions especially for its anti-inflammatory, antiseptic, and anticonvulsing properties that support the requirement to direct our present research efforts into the definitive understanding of its efficacy.

Dental care and dentistry practice in the Medieval Medical School of Salerno.

Even though dental care is sometimes erroneously considered a modern practice, written records from major ancient civilisation all around the world date back to several millennia BC. In particular, in the Middle Ages, among the tenth and thirteenth centuries, the illustrious Medical School of Salerno in Italy, the most important institution in the Western world for the diffusion of medical knowledge, disseminated through its precepts the importance of oral hygiene and practiced specific dental therapies for tooth decay, gingivitis, paradentosis and halitosis among others. Interestingly, several of the officinal plants and natural ingredients proposed for oral care by the school's most famous physicians recipes, notably those of the legendary Trotula De Ruggiero, considered the first female physician in history, are still in vogue in the twenty-first century.

Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene (c.1824C>T) leading to the production of a toxic form of the prelamin A protein called progerin. Because farnesylation process had been shown to control progerin toxicity, in this study we have developed a screening method permitting to identify new pharmacological inhibitors of farnesylation. For this, we have used the unique potential of pluripotent stem cells to have access to an unlimited and relevant biological resource and test 21,608 small molecules. This study identified several compounds, called monoaminopyrimidines, which target two key enzymes of the farnesylation process, farnesyl pyrophosphate synthase and farnesyl transferase, and rescue in vitro phenotypes associated with HGPS. Our results opens up new therapeutic possibilities for the treatment of HGPS by identifying a new family of protein farnesylation inhibitors, and which may also be applicable to cancers and diseases associated with mutations that involve farnesylated proteins.

p53 regulates the mevalonate pathway in human glioblastoma multiforme.

The mevalonate (MVA) pathway is an important metabolic pathway implicated in multiple aspects of tumorigenesis. In this study, we provided evidence that p53 induces the expression of a group of enzymes of the MVA pathway including 3'-hydroxy-3'-methylglutaryl-coenzyme A reductase, MVA kinase, farnesyl diphosphate synthase and farnesyl diphosphate farnesyl transferase 1, in the human glioblastoma multiforme cell line, U343 cells, and in normal human astrocytes, NHAs. Genetic and pharmacologic perturbation of p53 directly influences the expression of these genes. Furthermore, p53 is recruited to the gene promoters in designated p53-responsive elements, thereby increasing their transcription. Such effect was abolished by site-directed mutagenesis in the p53-responsive element of promoter of the genes. These findings highlight another aspect of p53 functions unrelated to tumor suppression and suggest p53 as a novel regulator of the MVA pathway providing insight into the role of this pathway in cancer progression.

Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism.

Gemcitabine (GEM, 2',2'-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl-L-cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells.

Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability in human sperm.

BACKGROUND AND PURPOSE: The endocannabinoid system and the cannabinoid CB(1) receptor have been identified in human sperm, and it is well known that endocannabinoids have pronounced adverse effects on male and female reproduction. In order to elucidate further the pathophysiological role of the endocannabinoid system in male fertility, we investigated the activity of the CB(1) receptor antagonist rimonabant (SR141716) on the fertilizing ability of human sperm. EXPERIMENTAL APPROACH: We evaluated in vitro the effects of rimonabant on motility, survival, capacitation, acrosin activity and metabolism of human sperm. Particularly, capacitation was studied by using three different approaches: intracellular free Ca(2+) content assay, cholesterol efflux assay and protein tyrosine phosphorylation analysis. KEY RESULTS: Rimonabant significantly increased sperm motility and viability through the induction of pAkt and pBcl2, key proteins of cell survival and metabolism, and it induced acrosome reaction and capacitation as well. Rimonabant reduced the triglyceride content of sperm, while enhancing lipase and acyl-CoA dehydrogenase activities, implying an overall lipolytic action in these cells. Rimonabant also affected sperm glucose metabolism by decreasing phosphorylation of glycogen synthase kinase 3 and increasing glucose-6-phosphate dehydrogenase activity, suggesting a role in inducing sperm energy expenditure. Intriguingly, agonism at the CB(1) receptor, with an anandamide analogue or a selective inhibitor of fatty acid amide hydrolase, produced opposing effects on human sperm functions. CONCLUSIONS AND IMPLICATIONS: Our data suggest that blockade of the CB(1) receptor by rimonabant induces the acquisition of fertilizing ability and stimulates energy expenditure in human sperm.

Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.

Endocannabinoids modulate eating behavior; hence, endocannabinoid genes may contribute to the biological vulnerability to eating disorders. The rs1049353 (1359 G/A) single nucleotide polymorphism (SNP) of the gene coding the endocannabinoid CB1 receptor (CNR1) and the rs324420 (cDNA 385C to A) SNP of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, have been suggested to have functional effects on mature proteins. Therefore, we explored the possibility that those SNPs were associated to anorexia nervosa and/or bulimia nervosa. The distributions of the CNR1 1359 G/A SNP and of the FAAH cDNA 385C to A SNP were investigated in 134 patients with anorexia nervosa, 180 patients with bulimia nervosa and 148 normal weight healthy controls. Additive effects of the two SNPs in the genetic susceptibility to anorexia nervosa and bulimia nervosa were also tested. As compared to healthy controls, anorexic and bulimic patients showed significantly higher frequencies of the AG genotype and the A allele of the CNR1 1359 G/A SNP. Similarly, the AC genotype and the A allele of the FAAH cDNA 385C to A SNP were significantly more frequent in anorexic and bulimic individuals. A synergistic effect of the two SNPs was evident in anorexia nervosa but not in bulimia nervosa. Present findings show for the first time that the CNR1 1359 G/A SNP and the FAAH cDNA 385C to A SNP are significantly associated to anorexia nervosa and bulimia nervosa, and demonstrate a synergistic effect of the two SNPs in anorexia nervosa.

Bovine serum amine oxidase and spm potentiate docetaxel and interferon-alpha effects in inducing apoptosis on human cancer cells through the generation of oxidative stress.

It was previously demonstrated that bovine serum amine-oxidase (BSAO) and SPM (SPM) addition to cancer cells induces cell growth inhibition and over-run the multi-drug resistance (MDR) phenotype through the oxidative stress caused by polyamine metabolites. In this study, it is reported that BSAO/SPM enzymatic system antagonizes the survival pathway induced by either docetaxel (DTX) or interferon alpha (IFNalpha) in human epidermoid cancer KB cells. The combination of BSAO/SPM with either DTX or IFNalpha had a synergistic effect on cell growth inhibition through apoptosis in both human epidermoid KB and breast cancer MCF-7 cell lines. The effects of the BSAO/SPM-DTX combination on apoptosis were caspase 3 and 9-dependent and were paralleled by the enhancement of intracellular O(2-), nitric oxide levels and of lipo-oxidation. The scavenger moiety N-acetyl-cysteine antagonized the effects on apoptosis and cell growth inhibition induced by the combination suggesting a role of the oxidative products of SPM. These effects occurred together with a decrease of the physiological scavenger MnSOD and an increase of both p38 kinase activity and DNA damage. The results suggest that DTX and IFNalpha could sensitize tumour cells to the oxidative stress and apoptosis induced by BSAO/SPM through the induction of a survival ras-dependent pathway and the consequent elevation of the intracellular polyamine pool. These data allow the design of new therapeutic strategy based on the use of this combination in human neoplasms.

The first cosmetic treatise of history. A female point of view.

The Schola Medica Salernitana was an early medieval medical school in the south Italian city of Salerno and the most important native source of medical knowledge in Europe at the time. The school achieved its splendour between the 10th and 13th centuries, during the final decades of Longobard kingdom. In the school, women were involved as both teachers and students for medical learning. Among these women, there was Trotula de Ruggiero (11th century), a teacher whose main interest was to alleviate suffering of women. She was the author of many medical works, the most notable being De Passionibus Mulierum Curandarum (about women's diseases), also known as Trotula Major. Another important work she wrote was De Ornatu Mulierum (about women's cosmetics), also known as Trotula Minor, in which she teaches women to conserve and improve their beauty and treat skin diseases through a series of precepts, advices and natural remedies. She gives lessons about make-up, suggests the way to be unwrinkled, remove puffiness from face and eyes, remove unwanted hair from the body, lighten the skin, hide blemishes and freckles, wash teeth and take away bad breath, dying hair, wax, treat lips and gums chaps.

Rimonabant (SR141716) exerts anti-proliferative and immunomodulatory effects in human peripheral blood mononuclear cells.

BACKGROUND AND PURPOSE: Rimonabant (SR141716) is the first selective cannabinoid receptor CB(1) antagonist described. Along with its anti-obesity action, emerging findings show potential anti-proliferative and anti-inflammatory action of SR141716 in several in vitro and in vivo models. In this study we have investigated the anti-proliferative and immunomodulatory effects of SR141716 in human peripheral blood mononuclear cells (PBMCs). EXPERIMENTAL APPROACH: We have evaluated in vitro the effect of SR141716 in human PBMCs stimulated with different mitogens. Cell proliferation was assessed by (3)H-thymidine incorporation. Cell cycle, cell death and apoptosis were analysed by flow cytometry. Protein expression was investigated by Western blot. KEY RESULTS: SR141716 significantly inhibited the proliferative response of PBMCs and this effect was accompanied by block of G(1)/S phase of the cell cycle without induction of apoptosis and cell death. SR141716 used in combination with 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA), a stable analogue of the endogenous cannabinoid anandamide, showed synergism rather than antagonism of the inhibition of cell proliferation. The immunomodulatory effects of SR141716 were associated with increased expression of IkappaB, phosphorylated AKT (p-AKT) and decreased expression of NF-kappaB, p-IkappaB, p-ERK, COX-2 and iNOS. CONCLUSIONS AND IMPLICATIONS: Our findings suggest SR141716 is a novel immunomodulatory drug with anti-inflammatory properties.

Metabolically labile cannabinoid esters: a 'soft drug' approach for the development of cannabinoid-based therapeutic drugs.

Biphenylic ester derivatives, designed by using a 'soft-drug' approach, proved to possess good binding properties toward cannabinoid CB(1) and CB(2) receptors and, at the same time, their metabolically labile ester portion would promote a rapid systemic inactivation. This may constitute a possible solution to the psychotropic side effects encountered when cannabinoids are therapeutically employed as local analgesic or antiglaucoma agents.

Association between cannabinoid type-1 receptor polymorphism and body mass index in a southern Italian population.

CONTEXT: Endocannabinoids control food intake via both central and peripheral mechanisms, and cannabinoid type-1 receptor (CB1) modulates lipogenesis in primary adipocyte cell cultures and in animal models of obesity. OBJECTIVES: We aimed to evaluate, at the population level, the frequency of a genetic polymorphism of CB1 and to study its correlation with body mass index. DESIGN, SETTING AND PARTICIPANTS: Healthy subjects from a population survey carried out in southern Italy examined in 1992-1993 and older than 65 years (n=419, M=237, F=182) were divided into quintiles by body mass index (BMI). Two hundred and ten subjects were randomly sampled from the first, third and fifth quintile of BMI (BMI, respectively: 16.2-23.8=normal, 26.7-28.4=overweight, 31.6-49.7=obese) to reach a total of 70 per quintile. Their serum and white cells from the biological bank were used to measure the genotype and the blood variables for the study. MEASUREMENTS: Anthropometric parameters, blood pressure, serum glucose and lipid levels were measured with standard methods; genotyping for the CB1 1359G/A polymorphism was performed using multiplex PCR. Statistical methods included chi2 for trend, binomial and multinomial multiple logistic regression to model BMI on the genotype, controlling for potential confounders. RESULTS: We found a clear trend of increasing relative frequency of the CB1 wild-type genotype with the increase of BMI (P=0.03) and, using a multiple logistic regression model, wild-type genotype, female gender, age, glycaemia and triglycerides were directly associated with both overweight (third quintile of BMI) and obesity (fifth quintile of BMI). CONCLUSIONS: Although performed in a limited number of subjects, our results show that the presence of the CB1 polymorphic allele was significantly associated with a lower BMI.

Increased farnesyltransferase activity in human colorectal cancer: relationship with clinicopathological features and K-ras mutation.

BACKGROUND: The enzyme farnesyltransferase has emerged as an important target for anti-cancer therapies. Farnesyltransferase inhibitors have been introduced in clinical trials of subjects with colorectal cancer. We investigated Farnesyltransferase activity, beta-subunit Farnesyltransferase protein expression and its mRNA in patients with colorectal cancer and its relationship with clinicopathological features and K-ras mutation. METHODS: Farnesyltransferase activity was determined by Farnesyltransferase [3H] SPA enzyme assay. Beta-subunit Farnesyltransferase protein expression was investigated by Western blotting and its mRNA by reverse transcriptase-polymerase chain reaction. K-ras mutation was detected by polymerase chain reaction amplification and restriction enzyme analysis. Multiple linear regression analysis was used to analyse relationships among age, sex, site of tumour, Dukes' stage, histological differentiation, K-ras mutation and Farnesyltransferase activity in normal mucosa and cancer. RESULTS: The levels of Farnesyltransferase activity and beta-subunit Farnesyltransferase protein expression were significantly higher in cancer than in normal mucosa. Moreover, tumours located on the right side, with mucinous histological differentiation and with K-ras mutation showed higher levels of Farnesyltransferase activity. CONCLUSIONS: Our findings suggest that Farnesyltransferase activity may be a potential marker of tumourigenicity. The differences in Farnesyltransferase activity in relation to histological grading, tumour location and K-ras mutation described here may constitute a starting point for investigating the causes of this variation within the large bowel.