Precision editing of the gut microbiota ameliorates cancer immunotherapy.

In this editorial the authors highlight recent findings which could help design a personalized approach for cancer immunotherapy.

Renal function and carotid atherosclerosis in adults with no known kidney disease.

BACKGROUND AND AIMS: A high prevalence of atherosclerotic lesions characterizes patients with chronic kidney disease, though there is little data on the relationship between kidney function and atherosclerotic changes in the healthy population or in people with no known renal impairment. The aim of our study was to analyze, in a comprehensive general population with no known kidney disease, the relationship between renal function and subclinical carotid atherosclerotic damage. METHODS AND RESULTS: A general real-life population of 611 participants (233 males and 378 females; age ≥18 years) with no known kidney failure was selected for the study. The glomerular filtration rate (GFR) was estimated according to the CKD-EPI equation. Carotid intima-media thickness (c-IMT) and plaques were assessed by duplex Doppler ultrasonography of the carotid vessels. The main laboratory and metabolic parameters were evaluated in all participants. When we divided the overall study population into tertiles according to GFR values (I tertile <85; II tertile: 85-99; III tertile >99 ml/min/1.73 m2), the c-IMT mean values and the prevalence of carotid plaques decreased with the increasing tertile of GFR. On univariate analysis, c-IMT was significantly correlated with eGFR (r = -0.33; p < 0.001), serum creatinine (r = 0.17; p < 0.001), and other variables such as age, systolic blood pressure, waist circumference, fasting or random glycemia, and glycated hemoglobin (HbA1c). On multiple regression analysis, serum creatinine was associated with c-IMT (ß = 0.069; p = 0.017), independent of other covariates. CONCLUSION: Our study seems to suggest the importance of early identification of people with near normal or mildly decreased renal function due to its association with carotid atherosclerosis.

Detection of putative stem cell markers, CD44/CD133, in primary and lymph node metastases in head and neck squamous cell carcinomas. A preliminary immunohistochemical and in vitro study.

OBJECTIVES: Investigators hypothesized that cancer stem cells (CSCs) could play a role in determining cancer progression by metastasizing to cervical lymph node (N+) and then influencing prognosis of head and neck squamous cell carcinomas (HNSCCs) patients. DESIGN: To identify CSCs in HNSCCs and their clonogenic capacity. SETTING: In vitro study. PARTICIPANTS: Putative CSCs from 29 primary HNSCCs and 19 corresponding node metastases were analyzed. MAIN OUTCOME MEASURES: Immunohistochemical (IHC) was performed, and CSCs' clonogenic in vitro capacity was tested; ones epithelial nature of cancer cells forming colonies was confirmed by a second IHC, fluorescence-activated cell sorting (FACS) analysis helped in counting CD44/CD133-CSCs markers percentage expression in HNSCC tumour-derived cultures. RESULTS: Immunohistochemical showed CD44 (93.1%) and CD133 (10.34%) expression; FACS-analysis showed the enrichment of CD44/CD133 cancer cells, with the highest clonogenic capacity of CD44+-subpopulation; a higher CD44 rates were documented from N+ subcultures than from original tumours (P < 0.05). CONCLUSIONS: A putative cancer stem-like cell population is detectable in HNSCCs, and our findings show their in vitro clonogenic capacity by demonstrating that CD44+-cultured cells are the main population proliferating obtained by N+ HNSCC metastases, emphasizing their possible role in tumour progression.

Salvage treatment with ganciclovir in a splenectomized, polytransfused patient affected by systemic inflammatory response syndrome.

A 23-year-old man was admitted to hospital with a 12-day history of daily fever. A clinical history revealed that 10 months previously, the patient had been splenectomized and polytransfused for a severe blunt trauma. On admission, laboratory data revealed significant leukocytosis (33,230/ul). The patient's general clinical conditions rapidly worsened into a severe systemic inflammatory response syndrome in four days. After 10 days of broad-spectrum antibiotic treatment, the temperature curve was unmodified and severe leukocytosis persisted (44,300 ul) with absolute lymphocytosis. Laboratory tests ruled out hematological diseases, pneumonia, abscesses and endocarditis. In the light of IgM positivity for CMV (unconfirmed by PCR) and with the support of a PubMed search, we commenced a salvage treatment with intravenous ganciclovir, suspecting a viral infection or reactivation. After two days of therapy, an immediate defervescence was observed with a remarkable clinical improvement. After 10 days, the clinical syndrome had been completely resolved and the patient was discharged in good, general clinical health.

Dissection with harmonic scalpel versus cold instruments in parotid surgery.

BACKGROUND: The harmonic scalpel (HS) has been used successfully in several head and neck surgical procedures. Some authors highlighted its advantages in reducing operative time, blood loss, and damages to surrounding tissue. In our study, we compared the results obtained during parotidectomy using the HS with the traditional approach to determine the benefits of the HS. METHODS: 130 patients with benign parotid tumors were enrolled and randomized into two groups for this prospective study. 63 patients underwent HS parotidectomy, and 67 patients received a parotidectomy using cold instruments and bipolar electrocautery hemostatic control (CI). 20 HS and 2 CI patients did not meet the inclusion criteria requirements, and were excluded. RESULTS: The admission time was significantly shorter in the HS group than the CI group (3.9 ± 1.2 days and 4.7 ± 1.4 days, respectively, p < 0.01). In the early post-operative period, 84% of HS patients and 60% of CI cases showed no facial nerve impairment (p = 0.01). Significantly more CI patients than HS patients showed the onset of Frey's syndrome (29% and 9%, respectively, p = 0.01). Multivariate stepwise regression analysis confirmed the reduction in admission length (Odds Ratio (OR): 0.62; p = 0.02) and the lower risk of Frey's syndrome (OR: 0.29; p = 0.04) in HS compared to CI parotidectomies. CONCLUSIONS: In parotid surgery, the HS is useful in preventing Frey's syndrome and reducing early transitory facial nerve dysfunction and admission times, and results in decreased medical costs and increased quality of life.

Early phase insulin secretion is increased in subjects with normal fasting glucose and metabolic syndrome: a premature feature of beta-cell dysfunction.

BACKGROUND AND AIMS: Metabolic syndrome (MS) has been mainly related to insulin resistance, but the role of changes in insulin secretion has not been thoroughly investigated. METHODS AND RESULTS: Using an oral glucose tolerance test (OGTT) we studied beta-cell function and insulin sensitivity in subjects with normal fasting glucose with and without MS, and their relationship to fatty liver which was evaluated by abdominal-ultrasonography. In MS early phase insulin secretion, as measured by insulinogenic index (IG(30)), was increased (p<0.05) independently from insulin sensitivity. Furthermore IG(30) was progressively higher as the number of factors needed for the diagnosis of MS increased (p<0.01). Insulin and C-peptide AUC were also increased (p<0.01 and p<0.05, respectively) but, in contrast to IG(30), these differences disappeared when ISI was used as a covariate. After OGTT, 51% of the subjects with MS had altered post-load glucose tolerance compared to 24.9% without MS (p<0.01). In both groups, the altered glucose tolerance was associated with a similar IG(30) reduction. In normo-tolerant subjects with MS the IG(30) was higher (+54.1%, p<0.01), and this elevation occurred irrespective of ISI; however, the beta-cell compensatory capacity for insulin resistance (disposition index) was impaired (p<0.001). Fatty liver was more frequent (p<0.001) and more severe (p<0.01) in MS, and it was significantly related to total AUC-insulin (p<0.001), independently from ISI. CONCLUSION: These findings indicate that the prevalence of altered tolerance is more frequent in subjects with normal fasting glucose and MS. The hyperinsulinemia might not only be an adaptive response to insulin resistance, but a primary defect of beta-cell function contributing to glucose intolerance.

Long-term anti-tumour necrosis factor therapy reverses the progression of carotid intima-media thickness in female patients with active rheumatoid arthritis.

The objective of the study is to evaluate the effect of TNF inhibition on carotid thickness over a 2-year period. 144 women with RA diagnosed according to ACR criteria, without clinical evidence of cardiac and/or vascular disease were enrolled and compared with 78 matched controls. All patients received methotrexate (15­20 mg weekly) for 3 months. Responders (n = 79) continued to be treated with methotrexate, non-responders (n = 40) moved to methotrexate plus a TNF alpha antagonist. Echosonographic studies of carotids were obtained before and after 2-year follow-up. A significant decrease of ca-IMT was observed in anti-TNF-treated patients (P < 0.001); on the other hand, no significant variation of ca-IMT was observed after 2 years in MTX-treated patients. Our study indicates that anti-TNF blocking agents, but not methotrexate, are capable of reducing IMT of carotid arteries in female RA patients in a 2-year follow-up.

[Application of an integrated method for risk assessment of related work-stress in health care]. / Applicazione di un metodo integrato per la valutazione dei fattori di rischio stress-correlati nel settore sanitario.

To assess the risk from exposure to occupational stress and burnout in health care workers (HCW), a cross-sectional study was planned to compare objective data that can represent potential job stressors in hospital wards and subjective symptoms reported by the workers. Medical doctors, nurses and ancillary workers of the Internal Medicine Wards of a large public hospital in Northern Italy were enrolled in the study. Three subjective questionnaires were administered: the Job Content Questionnaire, the State-Trait Anxiety Inventory, the Maslach Burnout Inventory. In addition, seven objective parameters were collected as average on the 3 months period prior to the study: a) working understaffed; b) number of patients/HCW on service; c) number of HCW on sick leave/on service; d) number of skipped days off after night shifts; e) number of sick leaves; f) number of deceased patients; g) number of accidents at work. A total group of 230 HCW were examined, employed in six different sub-units of the Medical wards. The female workers were 67.8% and the male workers 32.2%, the mean age was 37.4 years (SD 9.3) in the total group, 35.1 years (SD 7.9) in females and 42.3 years (SD 10.3) in males. The average scores of subjective and objective parameters resulted significantly higher in the same sub-units. The correlation analysis showed that the subjective questionnaires were highly inter-related. The multivariate analysis showed that the number of sick leave days was significantly related to the subjective questionnaires, and the subjective subscales of emotional exhaustion, job demand, decision latitude and STAIt were significantly related to some of the objective parameters. Therefore, the best approach to measure occupational stress is an integrated one, which involves the use of multiple subjective and objective assessment modalities.

[A multidisciplinary preventive intervention in a large Italian hospital]. / Prevenzione dei disturbi del rachide nei lavoratori di un ospedale: intervento multidisciplinare e valutazione di efficacia.

BACKGROUND: A multidisciplinary intervention is necessary to tackle the occupational risk of low back disorders in manual handling ofpatients and to evaluate the effectiveness. METHODS: An intervention was carried out which included risk assessment, testing and purchasing of patient handling devices, training programmes, health surveillance and collection of quantitative and qualitative outcomes to evaluate effectiveness, in a before-after design. RESULTS: The intervention was effective in reducing exposures, increasing knowledge and skills in patient-handling techniques, decreasing low back pain prevalence and injuries related to patient handling; absenteeism seemed to show a decreasing trend. CONCLUSIONS: The multidisciplinary approach was useful in the overall management of low back pain in health care workers performing patient handling.

Methylaminolaevulinate-based photodynamic therapy of Bowen's disease and squamous cell carcinoma.

BACKGROUND: Photodynamic therapy (PDT) with methylaminolaevulinate (MAL) is an approved noninvasive treatment option for actinic keratosis and Bowen's disease (BD), two precursors of invasive squamous cell carcinoma (SCC). OBJECTIVES: To assess efficacy, prognostic features, tolerability and cosmetic outcome of MAL-PDT for the treatment of BD and SCC. METHODS: In total, 112 biopsy-proven lesions of BD and SCC in 55 subjects were treated in an outpatient setting. MAL cream (160 mg g(-1)) was applied for 3 h prior to illumination with a light-emitting diode source (wavelength range 635 +/- 18 nm; light dose 37 J cm(-2)). A second MAL-PDT session was given 7 days later. Complete response rate at 3 months after the last treatment, recurrence rate at the 24-month follow-up, and cosmetic outcome were recorded. RESULTS: The overall complete response rates were 73.2% at 3 months and 53.6% at 2 years. Clinical thickness, atypia and lesion depth were significant predictors of the response at 3 months when using a univariate analysis (P < 0.001). A multivariate logistic regression model, with robust variance estimation, showed that cell atypia was the only statistically significant independent predictor of the treatment outcome at 3 months. CONCLUSIONS: MAL-PDT may represent a valuable, effective and well tolerated treatment option with good cosmetic outcome for superficial, well-differentiated (Broders' scores I and II) BD and microinvasive SCC. In contrast, its use for superficial SCCs with a microinvasive histological pattern and for nodular, invasive lesions, particularly if poorly differentiated keratinocytes are present (Broders' scores III and IV), should be avoided.

Pilot study on microvascular anastomosis: performance and future educational prospects.

The introduction of microvascular free flaps has revolutionised modern reconstructive surgery. Unfortunately, access to training opportunities at standardised training courses is limited and expensive. We designed a pilot study on microvascular anastomoses with the aim of verifying if a short course, easily reproducible, could transmit microvascular skills to participants; if the chosen pre-test was predictive of final performance; and if age could influence the outcome. A total of 30 participants (10 students, 10 residents and 10 surgeons) without any previous microvascular experience were instructed and tested during a single 3 to 5 hour course. The two microanastomoses evaluated were the first ever performed by each participant. More than the half of the cohort was able to produce both patent microanastomoses in less than 2 hours; two-thirds of the attempted microanastomoses were patent. The pretest predicted decent scores from poor performances with a sensitivity of 61.5%, specificity of 100%, positive predictive value of 100% and negative predictive value of 40%. Students and residents obtained significantly higher scores than surgeons. Since our course model is short, cost-effective and highly reproducible, it could be introduced and implemented anywhere as an educational prospect for preselecting young residents showing talent and natural predisposition and having ambitions towards microvascular reconstructive surgery.

The supraclavicular artery island flap (SCAIF) in head and neck reconstruction: an Italian multi-institutional experience.

The supraclavicular artery island flap (SCAIF) is a thin and pliable pedicled flap that is easy and quick to harvest. Thanks to its particular features and high reliability, it is best indicated for the elderly or most fragile patients. SCAIF is very versatile, as it can be used for reconstruction of oral cavity, oropharynx, hypopharynx, facial and cervical skin and tracheostomal defects. We began using this flap in four Italian tertiary referral centres, with several indications, both as first treatment and as salvage surgery. The aim of the study was to demonstrate the easy reproducibility of the flap among four different centres. A series of 28 patients underwent head and neck reconstructions with SCAIF with no recorded complications during flap harvesting. After the very first cases, harvesting time was approximately 45 minutes; 24 patients had successful flap integration at the recipient site, while the remaining 4 suffered from partial flap necrosis, two of whom needed revision surgery. Other minor complications were reported at the recipient site, always at the most distal and most delicate portion of the flap. Donor site was always closed primarily, with only three cases of partial suture dehiscence. We only selected the most fragile patients for SCAIF reconstruction, such as the elderly or those with one or more comorbidities; for this reason, we reported some serious systemic complications and one intraoperative death. SCAIF is an easy reproducible flap, with multiple possible indications. Its use as an alternative to free flaps in the head and neck region is nowadays under discussion. Its use should be encouraged among head and neck surgeons thanks to its various advantages.

Effect of dual blockade of renin-angiotensin system on TGFbeta1 and left ventricular structure and function in hypertensive patients.

The effects of 24 weeks losartan and ramipril treatment, both alone and in combination, on left ventricular mass (LVM), circulating transforming growth factor beta1 (TGFbeta1), procollagen type I (PIP) and III (PIIIP), have been evaluated in hypertensive (HT) patients. A total of 57 HT with stage 1 and 2 essential hypertension were included. After 4 weeks run in, a randomized double-blind, three arms, double dummy, independent trial was used. All HT patients were randomly allocated to three treatment arms consisting of losartan (50 mg/daily), ramipril (5 mg/ daily) and combined (losartan 50 mg/daily + ramipril 5 mg/daily) for 24 weeks. TGFbeta1, PIP and PIIIP, LVM, LVM/h(2.7) and other echocardiographic measurements, blood urea nitrogen, creatinine and clearance and potassium were determined after run in and after 24 weeks. All groups were comparable for gender, age, body mass index, blood pressure and LVM. The prevalence of baseline left ventricular hypertrophy (LVH) was not significantly different among three groups. At the end of treatment, a significant (P<0.05) reduction in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), TGFbeta1, PIP, PIIIP, LVM and LVM/h(2.7) was observed in all groups. The absolute and percent reduction in TGFbeta1 and LVM/h(2.7) were significantly higher in combined than losartan or ramipril groups and also in HT patients with LVH. No significant change in absolute and percent reduction of SBP, DBP and MBP were found. Our data indicate an additional cardioprotective effect of dual blockade of renin-angiotensin in HT patients.

[A survey on musculoskeletal disorders in physiotherapists]. / Fisioterapisti e disturbi muscoloscheletrici: analisi di una casistica.

Only few studies focused on musculoskeletal disorders (MSD) among physiotherapists (PT). The study population consisted of 50 PT and 50 clerical workers belonging to the same three rehabilitation hospitals in Northern Italy. The participants filled in a specifically designed questionnaire focused on risk factors, symptoms and diseases related to MSD. Data were self reported. Preliminary data show a significantly higher prevalence of low back symptoms (70%) and upper limb symptoms (36%) in PT than controls (16% and 4% respectively). PT had a higher prevalence of lumbar disk degeneration (20%), shoulder disorders (14%), wrist and hand tendinopathy (10%) than clerical workers (4% and 2% respectively). Both PT and clerical workers attributed their cervical symptoms to work (85% and 95% respectively). Only PT believed that low back and upper limb symptoms were work related (83% and 94% respectively). Our survey supported the findings that PT have e high prevalence of MSD. Specific preventive intervention should be applied to reduce risk of work related MSD.

[LBP and disability in nursing personnel performing manual handing of patients in a large Italian hospital]. / Disabilità e lombalgia in addetti alla movimentazione manuale pazienti in una grande Azienda Ospedaliera.

Low back pain (LBP) has been recognized as a major cause of sickness and disability among health care workers (HCW) who perform handling of patients. A survey was carrying out to investigate risk factors for LBP and related absenteeism and disability in a group of HCW. 333 HCW were examined in 2003 and 2005 and data were collected on personal, occupational and clinical history and on risk factors for LBP and related absenteeism. Psychosocial factors and LBP related disability were evaluated by means of Karasek's Job Content questionnaire and Oswestry Low Back disability Index. Most of our study population were female (80%) and the prevalence of acute and chronic LBP was 37%. Subjects with chronic LBP referred a significantly higher level of disability as compared to acute LBP subjects. Moreover, a significantly relationship was found (p = 0.04) between high level of disability (group III e IV of ODI index) and high perceived job demand. The introduction of questionnaires to collect disability and psychosocial factors is highly recommended in periodic health surveillance program of HCW performing manual handling of patients.

[Susceptibility to varicella-zoster, measles, rosacea and mumps among health care workers in a Northern Italy hospital]. / Suscettibilità per varicella, morbillo, rosolia e parotite negli operatori sanitari di un ospedale del Nord Italia.

BACKGROUND: Nosocomial transmission of varicella (V), rubella (R), mumps (Mu) and measles (Me) may be a significant cause of morbidity in health care workers (HCW). Susceptible HCW might be a relevant part of the workforce. METHODS: A seroprevalence study was performed in a public hospital. Antibodies (Ab) against V, R, Mu and Me were determined by ELISA. Sociodemographic, clinical, occupational data and sera were obtained during health surveillance. RESULTS: 2934 tests on 1106 HCW were performed. Seropositivity was 91% for V, 89% for R, 80% for Mu, 92% for Me. No significant differencies were found for the variables tested, except for age (< 36 years) and certain job tasks (e.g. residents). 22% of HCW tested were seronegative for at least 1 virus. More seronegatives were detected as compared with the majority of literature data. DISCUSSION: This study showed a relevant number of susceptible to V, R, Mu and Me. Seroprevalence data are useful for risk assessment, HCW health surveillance, to evaluate fitness for work and to promote vaccination programmes, according to scientific guidelines. OP should include serological screening for Me, Mu, V and R to protect HCW and third parties.

Neurological and neuropsychological features in Parkinsonian patients exposed to neurotoxic metals.

BACKGROUND: Environmental exposure to heavy metals and especially manganese (Mn) took place in Valcamonica, Italy, where a high prevalence of Parkinsonism was observed (age and sex standardized 407/100,000; 95% CI: 393.87-420.12), and the Standardized Morbidity Ratios was associated with environmental Mn levels. METHODS: A cross sectional study compared Parkinsonian patients residents in Valcamonica with patients from Brescia, Italy. Age- and sex-matched healthy individuals were recruited as controls. The protocol included information on clinical, occupational, residential history and life habits, neuro-psychological testing, and assessment of genetic polymorphism. RESULTS: The target group included 65 patients and 52 controls from Valcamonica, 28 patients and 14 controls from Brescia. Age at onset of the disease was lower in women from both areas. After adjusting for age and age at onset, patients from Valcamonica showed more severe motor impairment at the UPDRS scale, higher damage of cognitive and motor functions at MMSE, Token and Trial Making tests. Genetic variables showed a different allelic distribution of DRD4 gene between cases and controls, outside Valcamonica, where a less frequent familiarity for parkinsonism was reported. CONCLUSIONS: Parkinsonian patients with previous exposure to metals showed a more severe neuropsychological phenotype, without detectable contribution from genetic factors.

Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children.

CONTEXT: GH acts through the GH receptor (GHR), whose polymorphisms might affect the growth response to recombinant human GH (rhGH). OBJECTIVE: The objective of this study was to investigate possible influences of GHR polymorphisms on the growth response to rhGH in GH-deficient (GHD) children. DESIGN: This was a 2-yr study (first year, spontaneous growth; second year, growth during rhGH treatment). SETTING: This study was performed at a referral center. PATIENTS: Fifty-four prepubertal GHD children (11 females; mean age, 7.8 yr; sd, 3.96) were studied. INTERVENTION: Patients were treated with rhGH (0.2 mg/kg.wk) for at least 1 yr after diagnosis. Growth velocity (GV) was measured 1 yr before treatment and during the first treatment year. GHR exons were amplified by PCR using pairs of intronic primers. The presence of single or multiple mismatches in the PCR products was revealed by denaturing high-pressure liquid chromatography. For exons in which mismatches were found by denaturing high-pressure liquid chromatography, direct sequencing was performed by automatic sequencer. MAIN OUTCOME MEASURES: Before the start of treatment, the mean height (Ht) sd score was -1.93 (sd, 0.70), and the mean GV sd score was -1.49 (sd, 1.26). RESULTS: The posttreatment (first 12 months) mean GV sd score was 3.55 (sd, 3.27). Molecular analysis revealed a high frequency of GHR polymorphisms; in particular: exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 in 44 (82%), and polymorphism 1576 A>C at codon 526 of exon 10 in 35 (65%). In most patients, these different polymorphisms recurred in association. We found no significant differences in GV between the groups of subjects defined by the polymorphic genotypes. CONCLUSION: The most common GHR polymorphisms, alone or in association, do not appear to affect the growth response to rhGH in GHD children.

Obesity: a main factor of metabolic syndrome?

The metabolic syndrome (MS) is a common metabolic disorder that has been recently related to the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology has been largely attributed, in the past years, to insulin-resistance, even if several epidemiological and pathophysiological data are attractive to indicate visceral obesity as a main factor in the occurrence of the MS, promoting new definitions and re-evaluation of the pathogenesis of this syndrome. In this review, we have analyzed the role of visceral obesity in the new definition of the MS such as the pathophysiological role of the abnormal fat distribution in the occurrence of this syndrome. In view of this, relationships between visceral obesity, free fatty acids, dyslipidaemia and insulin-resistance have been reported. In addition, the effects of some adipocytokines and other proinflammatory factors produced by fat accumulation on the appearance of the MS have been also emphasized. Finally, according to recommendations of several international societies, the role of the life-style change and of the weight loss in the prevention and treatment both of obesity and of other associated risk factors has been analyzed.