The vitamin D receptor (VDR) gene rs11568820 variant is associated with type 2 diabetes and impaired insulin secretion in Italian adult subjects, and associates with increased cardio-metabolic risk in children.

BACKGROUND AND AIMS: 1α,25-dihydroxyvitamin-D3, the biologically active vitamin D, plays a central role in several metabolic pathways through the binding to the vitamin D receptor (VDR). VDR has been shown to be involved in cardiovascular diseases, cancer, autoimmunity and type 2 diabetes mellitus (T2DM). Several polymorphisms in the VDR gene have been described. Among these, the rs11568820 G-to-A nucleotide substitution was found to be functional, modulating the transcription of the VDR gene. Objective of this study was to perform an association study between rs11568820 polymorphism and T2DM in a cohort of Italian adults with T2DM and in non-diabetic controls. To add further insight into the role of VDR gene we explored whether this association begins early in life in overweight/obese children, or becomes manifest only in adulthood. METHODS AND RESULTS: As many as 1788 adults and 878 children were genotyped for the rs11568820 polymorphism. All participants underwent oral glucose tolerance tests (OGTT), with measurement of glucose and insulin levels. Indices of insulin-resistance and secretion were also calculated. The AA genotype was significantly more frequent in adults with T2DM compared to controls (7.5% vs. 4.6%, P = 0.037), and conferred a higher risk of T2DM (ORHom = 1.69C.I. = [1.13-2.53], P = 0.011). In the adult cohort, rs11568820 was also associated with reduced indices of ß-cell insulin secretion. In children, the AA genotype was associated with 2 h high-normal glucose, a marker of cardio-metabolic risk. CONCLUSIONS: Our study demonstrates for the first time that VDR gene AA carriers have higher risk of T2DM and impaired insulin secretion. In children, the association between AA homozygous and high-normal 2h glucose suggests that mild alterations associated with this genotype may appear early in life.

HIV-1 coreceptor usage in paired plasma RNA and proviral DNA from patients with acute and chronic infection never treated with antiretroviral therapy.

Although an independent evolution of viral quasispecies in different body sites might determine a differential compartmentalization of viral variants, the aim of this paper was to establish whether sequences from peripheral blood mononuclear cells (PBMCs) and plasma provide different or complementary information on HIV tropism in patients with acute or chronic infection. Tropism was predicted using genotypic testing combined with geno2pheno (coreceptor) analysis at a 10% false positive rate in paired RNA and DNA samples from 75 antiretroviral-naïve patients (divided on the basis of avidity index into patients with a recent or long-lasting infection). A high prevalence of R5 HIV strains (97%) was observed in both compartments (plasma and PBMCs) in patients infected recently. By contrast, patients with a long-lasting infection showed a quite different situation in the two compartments, revealing more (46%) X4/DM in PBMCs than patients infected recently (3%) (P = 0.008). As- a knowledge of viral strains in different biological compartments might be crucial to establish a therapeutic protocol, it could be extremely useful to detect not only viral strains in plasma, but also viruses hidden or archived in different cell compartments to better understand disease evolution and treatment efficacy in patients infected with HIV.

Immunohistochemical expression of VDR is associated with reduced integrity of tight junction complex in psoriatic skin.

BACKGROUND: Cell junctions are crucial for the formation and maintenance of the paracellular barrier and for cell polarity in simple epithelia and endothelia. Altered localization and formation of tissue junction proteins in the epidermis have been described in plaque-type psoriasis. Vitamin D receptor (VDR) is a nuclear hormone involved in anti-proliferative and pro-differentiation pathways in keratinocytes. However, still to date, vitamin D/VDR signalling involved in tissue barrier related to psoriasis remains largely unknown. OBJECTIVE: To study the expression of VDR and tight junctions (TJ) proteins (claudin 1, ZO-1 and occludin) in psoriatic skin, and to correlate the expression of VDR with that of the junctional proteins claudin- 1, occludin and ZO- 1. METHODS: A total of 20 psoriatic tissue samples were included in the analysis. Immunohistochemical studies for VDR, claudin-1, occludin and ZO-1 were performed. RESULTS: We observed a reduction of VDR, claudin-1 and ZO-1 expression in psoriatic skin if compared to normal skin, and the statistical analysis showed a significant correlation between a downgrading of VDR expression and that of claudin-1 (P < 0.005) and ZO-1(P < 0.005). CONCLUSIONS: Our results suggest a new role of VDR in the maintenance of the homeostasis skin barrier. Although the exiguity of our cohort, VDR status appears to be associated with the expression level and functions of TJ proteins, suggesting multiple and different cellular functions of the VDR.

Monkeypox (Mpox): Evolution of Transmission and Comprehensive Review.

The human monkeypox (mpox) virus is an orthopox virus that can be transmitted to humans. Though the disease has been endemic in Africa, the recent mpox outbreak since May 2022. We attempted to examine differences between the endemic form of mpox and the current outbreak. Review of electronic medical database with relevant keywords. The current outbreak of mpox has disproportionately impacted the gay, bisexual and other men who have sex with men (MSM) community. This is also the first time that widespread semen testing has turned up evidence of mpox viral deoxyribonucleic acid (DNA). Cases in the present outbreak are more likely to affect adults, involve the genitalia, and have no prodrome. Close diagnostic differentials include varicella and hand-foot-mouth disease. The disease is usually self-limiting; though secondary infections, anorectal pain, pharyngitis, ocular lesions and rarely, renal injury and myocarditis may occur. This review focuses primarily on the novel clinical characteristics and emerging sexual transmission route of the mpox virus, which, although unconfirmed, appears extremely likely as the route of spread. Dermatologists have an important role in this health emergency, as early diagnosis can cause a significant reduction in disease transmission.

Promyelocytic leukemia (PML) gene expression is a prognostic factor in ampullary cancer patients.

BACKGROUND: Promyelocytic leukemia (PML) tumor suppressor gene plays a key role in acute PML pathogenesis but its involvement in pathogenesis and prognosis of solid cancers has not been defined yet. PATIENTS AND METHODS: In all, 62 ampullary adenocarcinoma patients who underwent curative surgery between 1996 and 2005 were included. Expression analysis of PML was carried out by immunohistochemical staining and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: In 24 tumor specimens (38.7%), PML was classified as absent, in 16 (25.8%) as focally expressed and in 22 (35.5%) as diffusely expressed. By univariate analysis, DFS was significantly influenced by pathological T stage (P=0.03), lymph nodal involvement (P=0.002), and PML expression (P=0.001). DFS in patients without PML expression was 28.0 months versus 45.1 and 75.5 for patients with focal and diffuse expression, respectively. OS in the group of patients without PML expression, with focal expression, and with diffuse expression was 40, 48, and 77 months, respectively (P=0.002). By a multivariate analysis, PML expression was the strongest prognostic factor for DFS (P=0.003) and the only statically significant prognostic factor for OS (P=0.009). CONCLUSIONS: Our preliminary data suggest PML as a novel prognostic tool for ampullary cancer patients.

Characteristics at haematoxylin and eosin staining of ruptures of the long head of the biceps tendon.

OBJECTIVE: To examine the relative prevalence of histological changes that have been found to be associated with the process of tendinopathy in lesions of the tendon of the long head of the biceps brachii and to evaluate the reliability of histopathological evaluation of tendon tissue in lesions of the tendon of the long head of the biceps. DESIGN: Tendon samples were taken from 51 patients (31 men, 20 women; mean age 63.2 years) who underwent arthroscopic release of the long head of the biceps tendon because of refractory biceps tendinopathy and from 5 male patients who died of cardiovascular events (mean age 69.6 years). Histological examination was performed using haematoxylin and eosin staining of sections, which were interpreted using a semiquantitative grading scale assessing fibre structure and arrangement, rounding of the nuclei, regional variations in cellularity, increased vascularity, decreased collagen staining and hyalinisation. RESULTS: The mean (SD) pathological sum score of ruptured tendons was greater than that of control tendons (15.76 (3.11) vs 3.4 (1.9), p<0.001). Within each specific category of tendon abnormalities, the chi(2) test showed significant differences between the control and ruptured tendons; all the variables were significantly different (Mann-Whitney U test 0.05, p<0.001). Using the kappa statistic, the agreement between the two readings ranged from 0.53 to 0.85. CONCLUSIONS: Unruptured tendons of the long head of the biceps, even at an advanced age and ruptured tendons of the long head of the biceps are clearly part of two distinct populations.

Human equilibrative nucleoside transporter 1 (hENT1) protein is associated with short survival in resected ampullary cancer.

BACKGROUND: Gemcitabine is an acceptable alternative to best supportive care in the treatment of advanced biliary tract cancers. The human equilibrative nucleoside transporter 1 (hENT1) is a ubiquitous protein and is the major means by which gemcitabine enters human cells. Moreover, recent reports indicate a significant correlation between immunohistochemical variations of hENT1 in tumor samples and survival after gemcitabine therapy in patients with solid tumors. MATERIALS AND METHODS: We used immunohistochemistry to assess the abundance and distribution of hENT1 in tumor samples from radically resected cancer of the ampulla, and sought correlations between immunohistochemical results and clinical parameters including disease outcomes. RESULTS: In the 41 individual tumors studied, 12 (29.3%) had uniformly high hENT1 immunostaining. Statistical analysis showed a significant correlation between hENT1 and Ki-67 (P = 0.04). No statistical significant differences were found between immunohistochemical findings and patient characteristics (sex, age, and tumor-node-metastasis). On univariate analysis, hENT1 and Ki-67 expression were associated with overall survival (OS). Specifically, those patients with overexpression of hENT1 showed a shorter OS (P = 0.022) and those with high Ki-67 staining showed a shorter survival (P = 0.05). CONCLUSIONS: hENT1 expression is a molecular prognostic marker for patients with resected ampullary cancer and holds promise as a predictive factor to assist in chemotherapy decisions.

Cost-effectiveness of capsule endoscopy in screening for colorectal cancer.

BACKGROUND AND STUDY AIMS: Capsule endoscopy (Pillcam Colon) has recently shown acceptable accuracy in detecting colonic lesions when compared with colonoscopy. The aim of this analysis is to provide a model to assess the cost and effectiveness of population-based screening for colorectal cancer (CRC) using capsule endoscopy and to compare the cost-effectiveness with that of a colonoscopy screening program. METHODS: The cost-effectiveness of two screening strategies using colonoscopy or capsule endoscopy were compared by a computer model based on a Markov process. In this model, a hypothetical population of 100,000 individuals aged 50 years and over, undergoes a 10 yearly screening procedure. Different thresholds for postcapsule polypectomy referral were simulated. RESULTS: At baseline, the incremental cost-effectiveness (compared with no screening) of colonoscopy and capsule endoscopy was $ 16,165 and $ 29,244 per life-year saved, respectively. When equal compliance was simulated, the colonoscopy program was more effective and less costly than a strategy based on capsule endoscopy. When simulating an initial compliance to capsule endoscopy 30% better than colonoscopy, capsule endoscopy became the more effective and more cost-effective option. A 20% better compliance was sufficient when a higher accuracy of capsule endoscopy for polyps was assumed. A 6 mm threshold for polypectomy referral was associated with a substantial cost reduction in the capsule endoscopy program with only a small loss of efficacy. CONCLUSIONS: The cost-effectiveness of capsule endoscopy depends mainly on its ability to improve compliance to CRC screening.

Q&A on diagnosis, screening and follow-up of colorectal neoplasia.

The impressive and brisk evolution of medical science prevents many physicians from a thorough update on all the research fields. Colorectal cancer diagnosis, screening and follow-up is well known to require a multi-disciplinary approach, as it is faced by several specialties such as primary care physicians, gastroenterologists, non-gastroenterologist internists, radiologists and surgeons. To address this issue in a mutual perspective, we focused on the main points of the epidemiology, diagnosis, screening and follow-up of colorectal neoplasia by using a simple "Question & Answers" structure.

Triple therapies plus different probiotics for Helicobacter pylori eradication.

The Helicobacter pylori (H. pylori) cure rate following standard triple therapies is decreasing worldwide. Therefore, further approaches aimed to improve standard triple therapy efficacy should be attempted. This prospective, pilot study aimed to evaluate the therapeutic role of either Lactobacillus reuteri (L. reuteri) or a high concentration of probiotics in addition to standard triple therapies for H. pylori eradication. The study enrolled 65 consecutive dyspeptic patients with H. pylori infection. All patients underwent upper endoscopy with gastric biopsies. Patients were assigned to receive one of the following therapies: (a) standard 7-day triple; (b) the same 7-day triple therapy plus L. reuteri supplementation; (c) the same 7-day triple therapy plus a probiotic mixture; and d) a 14-day standard triple therapy plus a probiotic mixture. H. pylori eradication was checked by using a 13C-urea breath test performed 4-6 weeks after treatment. No therapy regimen achieved > 80% eradication rate at both intention-to-treat (ITT) and per protocol (PP) analyses. Although the 14-day therapy plus a probiotic mixture tended to achieve higher eradication rate (71%), no statistically significant difference emerged among the different therapy regimens tested (range: 53-71%). The lowest incidence of side-effects was observed following the 7-day therapy plus L. reuteri (6%) and highest with the 14-day triple therapy plus probiotic mixture (33%), although the difference failed to reach the statistically significance. In conclusion, our data found that 7-14 days triple therapy with or without probiotic supplementation failed to achieved acceptable H. pylori eradication rates.

Circulating substance P levels and shoulder joint contracture after arthroscopic repair of the rotator cuff.

OBJECTIVE: To determine the plasma levels of substance P (SP) in patients with postoperative stiffness after arthroscopic rotator cuff repair. DESIGN: Plasma samples were obtained at 15 months from surgery from two groups of patients who underwent arthroscopic repair of a rotator cuff tear. In group 1, 30 subjects (14 men, 16 women; mean age 64.6 years, range 47 to 78) with shoulder stiffness 15 months after arthroscopic rotator cuff repair were recruited. In group 2, 30 patients (11 men, 19 women; mean age 57.8 years, range 45 to 77) were evaluated 15 months after successful arthroscopic rotator cuff repair. Immunoassays were performed with commercially available assay kits to measure the plasma levels of SP. RESULTS: Plasma levels of SP in patients with postoperative stiffness were significantly greater than those in the control group (mean 81.06 (SD 27.76) versus 23.49 (5.64), p<0.05). CONCLUSIONS: The plasma concentrations of substance P in patients with shoulder stiffness after arthroscopic rotator cuff repair are higher compared with plasma levels of SP in patients with a good postoperative outcome. The neuronal upregulation of SP shown in the plasma of patients with postoperative shoulder stiffness may underlie not only the symptoms but also its development of adhesive capsulitis.

Functional anatomy of trunk flexion-extension in isokinetic exercise: muscle activity in standing and seated positions.

AIM: This study examined the functional differences existing in the trunk flexion-extension movement in standing and seated positions during isokinetic exercises, as well as the influence of position on overload of the lumbar column. METHODS: Nine females underwent an isokinetic test at 60 and 180 degrees /s in standing and seated positions. Muscle electrical activity was assessed by means of surface electromyography (EMG). Motion angles related to the different body segments were extrapolated from video images. RESULTS: The range of motion for hip movements was statistically significantly higher in the standing position, whereas it was similar for all the other segments studied in both positions. During the first phases of the movement, the lumbar tract showed a more marked lordosis in standing position. Peak torque values were significantly higher for flexion in standing position. Surface EMG showed significant differences in both positions only for the gluteal and biceps femoris muscles. CONCLUSION: The seated position allowed made it possible to limit the involvement of the hip muscles, particularly the iliopsoas during flexion, whereas there was little contribution to the trunk extension from hip extensor muscles. In addition, trunk extensors/flexors ratio showed values variable with velocity in standing position. Therefore, if the participation of accessory muscles is avoided, the seated position allows us to more accurately assess these two groups of antagonist muscles, whose balanced ratio is essential in the prevention of spine pathologies. The seated position has also been found to be more suitable in order to limit functional overload of the lumbar column.

Primary antibiotic resistance in Helicobacter pylori strains isolated in northern and central Italy.

BACKGROUND: Helicobacter pylori resistance to antibiotics is increasing worldwide, and it reduces the efficacy of therapy. AIM: To assess current primary antibiotic resistance in H. pylori strains isolated in Italy. METHODS: Between June 2004 and June 2006, H. pylori strains were isolated consecutively in the two participating centres (Bologna, northern Italy; Rome, central Italy) from patients never previously treated for the infection. Isolated strains were tested for primary clarithromycin, metronidazole and levofloxacin resistance using as break point the minimal inhibitory concentration >/=1, >/=8 and >/=1 mg/L for the three antibiotics, respectively. RESULTS: Overall, 255 H. pylori strains were evaluated. The resistance rate was 16.9% for clarithromycin, 29.4% for metronidazole and 19.1% for levofloxacin. Clarithromycin resistance was significantly higher in non-ulcer dyspepsia than in peptic ulcer patients (19.1% vs. 0%, P = 0.02), metronidazole resistance was higher in foreign than Italian patients (50% vs. 22.9%, P = 0.0004) and levofloxacin resistance was higher in old than younger patients (28.4% vs. 14.4%, P = 0.048). Levofloxacin resistance was also more frequent in those strains with either clarithromycin or metronidazole resistance. CONCLUSION: A very high rate of primary resistance towards the tested antibiotics was detected in our study.

Levofloxacin-based triple therapy for Helicobacter pylori re-treatment: role of bacterial resistance.

BACKGROUND: First-line Helicobacter pylori therapy fails in more than 20% of patients. Quadruple therapy is the suggested second-line therapy, but bismuth salts are not anymore available worldwide. This study aimed to assess the efficacy of a levofloxacin-amoxycillin triple therapy as a second-line treatment, and the role of primary levofloxacin resistance. METHODS: Forty patients, in whom first treatment with either standard 10-day triple or sequential therapy had failed, received 10-day triple therapy with rabeprazole (20mg b.d.), levofloxacin (250mg b.d.), and amoxycillin (1g b.d.). Cure rates were evaluated by the (13)C-urea breath test. Primary levofloxacin resistance was detected by culture. RESULTS: Bacterial culture was available in 33 (82.5%) out 40 patients, and primary levofloxacin resistance was detected in 10 (30.3%) patients. Overall, 33 of 40 patients accepted to participate in this study, and all returned for follow-up after therapy. Compliance to the therapy was safe except 1 patient only who stopped earlier the treatment due to side effects (oral candidiasis). H. pylori infection was eradicated in 24 patients, accounting for a 72.7% (95% CI: 57-88) eradication rate at both intention-to-treat and per protocol analyses. The eradication rate was higher in patients harbouring levofloxacin-susceptible than resistant strains (75% versus 33.3%; P=0.074). CONCLUSIONS: The eradication rate achieved by a levofloxacin-based re-treatment seems to be decreasing, and its efficacy is reduced in presence of levofloxacin resistance.

Tumour necrosis factor alpha down-regulation parallels inflammatory regression in ulcerative colitis patients treated with infliximab.

BACKGROUND: Treatment with the anti-tumour necrosis factor alpha monoclonal antibody infliximab has been shown to be effective in moderate-to-severe ulcerative colitis. However, its effect on the mucosal histopathological abnormalities of this disease is largely unknown. This study aimed to assess the immunohistological effect of infliximab in ulcerative colitis. METHODS: Nine patients with moderate-to-severe ulcerative colitis received infliximab (5mg/kg) at weeks 0, 2 and 6, respectively. Colonic biopsies were collected before therapy and at week 10, when the Mayo score (including the endoscopic subscore) was also assessed. Severity of inflammation was evaluated by histologic score and histomorphometry. Immunohistochemical staining with antibody against tumour necrosis factor alpha was performed on all biopsies and expressed as percentage of positive stromal cells/1000 counted (tumour necrosis factor alpha score). RESULTS: A profound down-regulation of mucosal tumour necrosis factor alpha occurred in all the six patients who achieved a clinical response, but not in the three who did not respond. Median tumour necrosis factor alpha score dropped from 44.8 (range 35-58.3) to 12.8 (range 5.3-15.3) in the responders (p=0.03), whilst it remained unchanged in the non-responders. Such effect was related with a dramatic regression of the median histologic score, which dropped from 2.7 (range 2-3) to 0.5 (range 0.0-1.5) in responder patients (p=0.002). This was related to a virtual disappearance of neutrophils in responders (r=0.72; p=0.002; Spearman's test), but not in those who did not improve. Tumour necrosis factor alpha score appeared to be correlated with the histologic, endoscopic and clinical activity. CONCLUSIONS: A profound tumour necrosis factor alpha down-regulation appears to be strictly associated with a dramatic regression of the inflammation in patients with moderate-to-severe ulcerative colitis treated with infliximab. Such immunohistochemical effect seems to be critical for a clinical and endoscopic response to therapy.

The colorectal malignant polyp: scoping a dilemma.

Colorectal adenomas containing invasive carcinoma represent the majority of early colorectal cancers. The malignant polyp carries a significant risk of lympho-haematic metastasis and mortality due to the penetration of cancerous cells into the submucosal layer. The therapeutic dilemma is whether to perform endoscopic or surgical resection. A thorough assessment of the endoscopic, histological and clinical variables is needed to unravel the best treatment for each patient. In particular, a unique staging of such lesions, based on certain histopathological features, has been deeply implicated in the therapeutic choice. Aim of this article is to review the main endoscopic, histological and clinical features of the malignant polyp in order to propose a systematic management of this lesion.

Helicobacter pylori eradication with either quadruple regimen with lactoferrin or levofloxacin-based triple therapy: a multicentre study.

BACKGROUND: Helicobacter pylori eradication rate following standard triple therapy is decreasing worldwide. A quadruple therapy with lactoferrin and a levofloxacin-based triple therapy has been found to achieve a very high (>90%) cure rate. This study aimed to confirm these encouraging results. METHODS: This was a prospective, open-label, randomised, multicentre, Italian study enrolling consecutive H. pylori infected patients. The infection at entry was assessed by endoscopy and biopsies (histology plus rapid urease test) in all patients, whilst bacterial eradication was assessed by 13C-urea breath test 4-6 weeks after therapy ended. Patients were randomised to receive either a 7-day, triple therapy with rabeprazole 20mg o.d., levofloxacin 500 mg o.d., and amoxycillin 1g b.i.d. (4 tablets/day) or a 7-day quadruple therapy comprising of rabeprazole 20mg, clarithromycin 500 mg, tinidazole 500 mg plus bovine lactoferrin 200mg, all given twice daily (10 tablets/day). RESULTS: Overall, 144 consecutive patients were enrolled in the study. Following the triple therapy, H. pylori infection was cured in 49 out of 72 (68.1%; 95% CI=57-79) patients and in 49 out of 71 (69.1%; 95% CI=58-80) at intention-to-treat and per protocol analyses, respectively. Following the quadruple regimen, the infection was cured in 52 out of 72 (72.2%; 95% CI=62-83) and in 52 out of 68 (76.5; 95% CI=66-87) patients at intention-to-treat and per protocol analyses, respectively. No statistically significant difference emerged between the two therapy regimens. CONCLUSIONS: H. pylori eradication rate following both quadruple therapy with lactoferrin and a low-dose PPI, triple therapy with levofloxacin is disappointingly low.

Colon cancer prevention in Italy: cost-effectiveness analysis with CT colonography and endoscopy.

BACKGROUND: Colorectal cancer (CRC) is a major cause of mortality in Italy. Although prevention of CRC is possible, its cost-effectiveness when applied to the Italian population is unknown. Recently, computerized tomographic colonography (CTC) has been proposed for CRC screening. AIM: To compare the efficacy and cost-effectiveness of CTC screening in a simulated Italian population with those of colonoscopy and flexible sigmoidoscopy (FS). METHODS: The cost-effectiveness of different screening strategies was compared using a Markov process computer model, in which in a hypothetical population of 100,000 50 year-olds were investigated by CTC, colonoscopy or FS every decade. Outcomes were projected to the Italian national level. RESULTS: CRC incidence reduction was calculated at 40.9%, 38.2%, and 31.8% with colonoscopy, CTC and FS, respectively. As compared to no screening, all screening programs were shown to be cost-saving, allowing a saving of 11 Euro, 17 Euro, and 48 Euro per person with colonoscopy, FS and CTC, respectively. FS appeared to be less cost-effective than CTC, whilst colonoscopy appeared to be an expensive option as compared to CTC. Undiscounted national expenditure was calculated to be 1,042,489,512 Euro, 1,093,268,285 Euro, and 1,198,783,428 Euro for FS, CTC and colonoscopy, respectively, as compared to 695,818,078 Euro without screening. CONCLUSION: CRC screening is cost-saving in Italy, irrespective of the technique applied. CTC appeared to be more cost-effective than FS, and it may also become a valid alternative to colonoscopy.