Effects of tramadol and its enantiomers on Concanavalin-A induced-proliferation and NK activity of mouse splenocytes: involvement of serotonin

The centrally acting analgesic drug tramadol is a 1:1 racemic mixture of two enantiomers, with different pharmacological properties. The (-)-tramadol preferentially inhibits noradrenaline uptake, whereas the (+)-tramadol inhibits serotonin uptake and binds to opioid receptors. Since tramadol has been shown to stimulate some immune responses in mice, in the present work we analyzed the effects of its enantiomers on the same parameters, with the aim to better characterize the mechanisms involved in such action of tramadol. The acute administration of 20 and 40 mg/kg of racemic tramadol and of 10 and 20 mg/kg of (+)-tramadol induced a significant and comparable stimulation of Concanavalin-A (Con-A) induced proliferation and of Natural Killer (NK) activity of splenocytes. On the contrary, the (-)-tramadol was devoid of any effect. The pretreatment with the serotoninergic antagonist metergoline (3.0 mg/kg) completely blocked the effects of both tramadol and (+)-tramadol. We suggest that the enhancement of the serotoninergic tone could be at the basis of the stimulatory effects exerted by tramadol on Con-A induced lymphoproliferation and NK activity.     

Plaque‐like myofibroblastic tumor,a rare entity of childhood: Possible pitfalls in differential diagnosis

Plaque‐like myofibroblastic tumor is a rare and benign pediatric soft tissue tumor. It presents as a slowly growing plaque reaching several centimeters in diameter, made up of multiple nodules. The clinical and histological features of this benign entity are similar to other fibrohistiocytic or myofibroblastic tumors occurring in childhood, so the diagnosis can be difficult. The correlation between clinical data, histopathology, and immunohistochemistry is necessary for the correct diagnosis.     

SCAI stage reclassification at 24 h predicts outcome of cardiogenic shock: Insights from the Altshock-2 registry

Background

Cardiogenic shock (CS) includes several phenotypes with heterogenous hemodynamic features. Timely prognostication is warranted to identify patients requiring treatment escalation. We explored the association of the updated Society for Cardiovascular Angiography and Interventions (SCAI) stages classification with in-hospital mortality using a prospective national registry.

Methods

Between March 2020 and February 2022 the Altshock-2 Registry has included 237 patients with CS of all etiologies at 11 Italian Centers. Patients were classified according to their admission SCAI stage (assigned prospectively and independently updated according to the recently released version). In-hospital mortality was evaluated for association with both admission and 24-h SCAI stages.

Results

The overall in-hospital mortality was 38%. Of the 237 patients included and staged according to the updated SCAI classification, 20 (8%) had SCAI shock stage B, 131 (55%) SCAI stage C, 61 (26%) SCAI stage D and 25 (11%) SCAI stage E. In-hospital mortality stratified according to the SCAI classification at 24 h was 18% for patients in SCAI stage B, 27% for SCAI stage C, 63% for SCAI stage D and 100% for SCAI stage E. Both the revised SCAI stages on admission and at 24 h were associated with in-hospital mortality, but the classification potential slightly increased at 24-h. After adjusting for age, sex, lactate level, eGFR, CVP, inotropic score and mechanical circulatory support [MCS], SCAI classification at 24 h was an independent predictor of in-hospital mortality.

Conclusions

In the Altshock-2 registry the utility of SCAI shock stages to identify risk of in-hospital mortality increased at 24 h after admission. Escalation of treatment (either pharmacological or with MCS) should be tailored to achieve prompt clinical improvement within the first 24 h after admission. Registration:  http://www.clinicaltrials.gov ; Unique identifier: NCT04295252.     

Alcohol consumption and risk of type 2 diabetes in European men and women: influence of beverage type and body sizeThe EPIC-InterAct study

Abstract. Beulens JWJ, van der Schouw YT, Bergmann MM, Rohrmann S, B Schulze M, Buijsse B, Grobbee DE, Arriola L, Cauchi S, Tormo M‐J, Allen NE, van der A DL, Balkau B, Boeing H, Clavel‐Chapelon F, de Lauzon‐Guillan B, Franks P, Froguel P, Gonzales C, Halkjær J, Huerta JM, Kaaks R, Key TJ, Khaw KT, Krogh V, Molina‐Montes E, Nilsson P, Overvad K, Palli D, Panico S, Ramón Quirós J, Ronaldsson O, Romieu I, Romaguera D, Sacerdote C, Sánchez M‐J, Spijkerman AMW, Teucher B, Tjonneland A, Tumino R, Sharp S, Forouhi NG, Langenberg C, Feskens EJM, Riboli E, Wareham NJ (University Medical Center Utrecht, The Netherlands; German Institute of Human Nutrition, Potsdam‐Rehbrücke, Germany; German Cancer Research Centre, Heidelberg, Germany; Basque Government, San Sebastian, CIBERESP, Spain; Institut de Biologie de Lille, Lille, France; Murcia Regional Health Council, Murcia, Spain; CIBER Epidemiologia y Salud Publica (CIBERESP), Spain; University of Oxford, Oxford, UK; National Institute of Public Health and the Environment, Bilthoven, The Netherlands; Inserm, CESP Centre for Research in Epidemiology and Population Health, Villejuif Cedex, France; Lund University, Malmö, Sweden; Imperial College, London, UK; Department of Epidemiology, Barcelona, Spain; Danish Cancer Society, Copenhagen, Denmark; University of Cambridge, Cambridge, UK; Fondazione IRCCS Istituto Nazionale Tumori Milan, Milan, Italy; Andalusian School of Public Health, Granada, Spain; School of Public Health, Aarhus, Denmark; Cancer Research and Prevention Institute (ISPO), Florence, Italy; Università Federico II, Napoli, Italy; Consejeria de Salud y Servicios Sanitarios, Oviedo‐Asturias, Spain; Umea University, Umea, Sweden; International Agency for Research of Cancer, Lyon, France; Center for Cancer Prevention (CPO‐Piemonte), Torino, Italy; “Civile ‐ M.P. Arezzo” Hospital, Ragusa, Italy; Addenbrooke’s Hospital, Cambridge, UK; and Wageningen University, Wageningen, The Netherlands). Alcohol consumption and risk of type 2 diabetes in European men and women: influence of beverage type and body size. The EPIC–InterAct study. J Intern Med 2012; 272: 358–370. Objective: To investigate the association between alcohol consumption and type 2 diabetes, and determine whether this is modified by sex, body mass index (BMI) and beverage type. Design: Multicentre prospective case–cohort study. Setting: Eight countries from the European Prospective Investigation into Cancer and Nutrition cohort. Subjects: A representative baseline sample of 16 154 participants and 12 403 incident cases of type 2 diabetes. Interventions: Alcohol consumption assessed using validated dietary questionnaires. Main outcome measures: Occurrence of type 2 diabetes based on multiple sources (mainly self‐reports), verified against medical information. Results: Amongst men, moderate alcohol consumption was nonsignificantly associated with a lower incidence of diabetes with a hazard ratio (HR) of 0.90 (95% CI: 0.78–1.05) for 6.1–12.0 versus 0.1–6.0 g day^?1, adjusted for dietary and diabetes risk factors. However, the lowest risk was observed at higher intakes of 24.1–96.0 g day^?1 with an HR of 0.86 (95% CI: 0.75–0.98). Amongst women, moderate alcohol consumption was associated with a lower incidence of diabetes with a hazard ratio of 0.82 (95% CI: 0.72–0.92) for 6.1–12.0 g day^?1 (P interaction gender <0.01). The inverse association between alcohol consumption and diabetes was more pronounced amongst overweight (BMI ≥ 25 kg m^?2) than normal‐weight men and women (P interaction < 0.05). Adjusting for waist and hip circumference did not alter the results for men, but attenuated the association for women (HR=0.90, 95% CI: 0.79–1.03 for 6.1–12.0 g day^?1). Wine consumption for men and fortified wine consumption for women were most strongly associated with a reduced risk of diabetes. Conclusions: The results of this study show that moderate alcohol consumption is associated with a lower risk of type 2 diabetes amongst women only. However, this risk reduction is in part explained by fat distribution. The relation between alcohol consumption and type 2 diabetes was stronger for overweight than normal‐weight women and men.     

Clinical and histological features of gingival lesions: A 17-year retrospective analysis in a northern Italian population

Objectives: Only few studies on gingival lesions considered large enough populations and contemporary literature does not provide a valid report regarding the epidemiology of gingival lesions within the Italian population. The histopathological and clinical appearance of 538 gingival lesions from northern Italians are described and discussed here.Study Design: The case records of patients referred for the diagnosis and management of gingival lesions, from October 1993 to October 2009, were reviewed. Data regarding the histological type of lesion were also obtained from the biopsy register for each case, and blindly re-examined.Results: We reported a greater frequency of benign lesions (reactive and/or inflammatory) in non-plaque/non-calculus induced gingival disorders. We confirmed an unambiguous prevalence of oral squamous cell carcinoma above all other malignant neoplasia, and a prevalence of neoplastic malignant lesions in the maxilla, with a slight increase in females and a drift of the incidence peak from the seventh to the eighth decade. There was a prevalence of precancerous gingival lesions in the maxilla, with a higher incidence in females and with a drift from the sixth to the seventh decade. We also reported a prevalence of oral lichen planus and lichenoid lesions as major manifestations of desquamative gingivitis.Conclusions: The high frequency of gingival involvement of such different diseases emphasizes the importance of histological characterization and differential diagnosis for periodontists, but more prospective studies are needed to better describe the true incidence of the non-plaque related gingival diseases. Key words:Gingival lesions, clinical appearance, histological analysis.     

Trans-Epithelial Transport,Metabolism, and Biological Activity Assessment of the Multi-Target Lupin Peptide LILPKHSDAD (P5) and Its Metabolite LPKHSDAD (P5-Met)

P5 (LILPKHSDAD) is a hypocholesterolemic peptide from lupin protein with a multi-target activity, since it inhibits both 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) and proprotein convertase subtilisin/kexin type-9 (PCSK9). This work shows that, during epithelial transport experiments, the metabolic transformation mediated by intestinal peptidases produces two main detected peptides, ILPKHSDAD (P5-frag) and LPKHSDAD (P5-met), and that both P5 and P5-met are linearly absorbed by differentiated human intestinal Caco-2 cells. Extensive comparative structural, biochemical, and cellular characterizations of P5-met and the parent peptide P5 demonstrate that both peptides have unique characteristics and share the same mechanisms of action. In fact, they exert an intrinsically multi-target behavior being able to regulate cholesterol metabolism by modulating different pathways. The results of this study also highlight the dynamic nature of bioactive peptides that may be modulated by the biological systems they get in contact with.     

Cerebellar degeneration and hearing loss in a patient with idiopathic myenteric ganglionitis

A 35-year-old male with an 11-year history of intestinal pseudo-obstruction associated with an idiopathic inflammatory insult of the myenteric plexus and the presence of circulating anti-Hu antibodies developed a neurological syndrome characterized by bilateral hearing loss, deteriorating balance, an unsteady gait and difficulty in estimating distances. A similar neurological syndrome has previously been described in older patients among the paraneoplasic syndromes associated with small-cell lung carcinoma and the presence of circulating anti-Hu antibodies, but never in the rare cancer-free patients with anti-Hu-associated chronic idiopathic intestinal pseudo-obstruction. The patient underwent a steroid treatment. No further episodes of functional intestinal obstruction were observed and, after an initial improvement, the neurological symptoms stabilized, leaving a permanent reduction in hearing function and an unsteady gait. The case shows that an idiopathic inflammatory insult of the myenteric plexus may precede (and perhaps lead to) central nervous system impairment in patients with anti-Hu-associated chronic idiopathic intestinal pseudo-obstruction.     

Different Mechanisms Lead to the Angiogenic Process Induced by Three Adenocarcinoma Cell Lines

Neoangiogenesis is essential for tumor and metastasis growth, but this complex process does not follow the same activation pathway, at least in tumor cell lines originated from different murine mammary adenocarcinomas. LMM3 cells were the most potent to stimulate new blood vessel formation. This response was significantly reduced by preincubating cells with indomethacin and NS-398, non-selective cyclooxygenase (COX) and COX-2 selective inhibitors, respectively. COX-1 and COX-2 isoenzymes were both highly expressed in LMM3 cells, and we observed that indomethacin was more effective than NS-398 to inhibit prostaglandin E2 (PGE2) synthesis. In addition, nitric oxide synthase (NOS) inhibitors, Nomega monomethyl L-arginine and aminoguanidine, also reduced LMM3-induced angiogenesis and nitric oxide (NO) synthesis as well. NOS2 > NOS3 proteins and arginase II isoform were detected in LMM3 cells by Western blot. The latter enzyme was also involved in the LMM3 neovascular response, since the arginase inhibitor, Nomega hydroxy L-arginine reduced the angiogenic cascade. On the other hand, parental LM3 cells were able to stimulate neovascularization via COX-1 and arginase products since only indomethacin and Nomega hydroxy L-arginine, which diminished PGE2 and urea synthesis, respectively, also reduced angiogenesis. In turn, LM2 cells angiogenic response could be due in fact to PGE2-induced VEGF liberation that stimulated neoangiogenesis at very low levels of NO.     

Opioids and the immune system

Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid's profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent micro-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity.