Phase Noise Analysis of Periodically ON/OFF Switched Oscillators

The paper presents a detailed analysis of phase noise in periodically switched oscillators (PSOs) which are emerging as effective multipliers in mmW applications. The analysis shows that the output phase noise of these stages cannot be estimated using the analogy to retimed oscillators. Closed form expressions for the transfer of both the reference and the oscillator noise are derived together with a correction to include the contribution of the oscillator close-in phase noise. The results are validated against Cadence Spectre RF® simulations of a PSO designed in a 28-nm bulk CMOS technology. The excess noise arising from the finite duration of the on-off transients is also discussed

4.5 A 9.25GHz Digital PLL with Fractional-Spur Cancellation Based on a Multi-DTC Topology

The quest of increasingly higher mobile uplink/downlink data-rates has recently driven the communication industry to set extremely challenging requirements on the integrated jitter of local oscillators [1]. In fractional-N PLLs, the adoption of a digital-to-time-converter (DTC) has become ubiquitous to meet performance targets, as it greatly improves integrated jitter by re-aligning the edges of the reference and the divider signals (top-left of Fig. 4.5.1) [2], [2]. Unfortunately, any DTC non-linearity converts the quantization error (QE) , driving the DTC into fractional spurs in the PLL spectrum, thus degrading the integrated jitter. Several digital techniques have been proposed to reduce the DTC non-linearity either at the cost of increasing hardware resources [3] or requiring calibration loops with long convergence times [4]. Other techniques dither the DTC control word [5], [6], spreading the spurious-tones power over a larger bandwidth, but the total jitter improvement is limited. This work introduces a fractional-spur-cancellation technique based on a multi-DTC topology with phase-shifted quantization-error sequences that allows the cancellation of the dominant fractional-spur tones and, at the same time, the reduction of the in-band phase-noise (PN). The concept is demonstrated in a 9.25GHz fractional-N DPLL, which achieves a total rms jitter of 77.1fs (including fractional spurs) for near-integer channels and an in-band fractional spur of −60.3dBc

Intestinal Surgery for Crohn's Disease: Role of Preoperative Therapy in Postoperative Outcome

Purposes: Patients affected by Crohn's disease (CD) require lifelong medical therapy, but they can also often require abdominal surgery. The effect of CD therapy on postoperative course is still unclear. The aim of this study was to evaluate the effect of preoperative medical therapy on the outcome of intestinal surgery in these patients. Methods: Data from a consecutive series of 167 patients with CD operated on at the University of Padova Hospital from 2000 to 2013 were retrieved. Data of preoperative therapy during the 6 months before surgery were available for 146 patients who were enrolled in this retrospective study. Clinical data and surgical details were retrieved and postoperative complications and reoperation were considered outcome measures. Univariate and multivariate analysis were performed. Results: No significant difference was observed between patients without data about their preoperative therapy and those with them. Eight patients underwent reoperation in the first 30 postoperative days: two of them for anastomotic leak, three for bleeding, one for obstruction and two for abdominal wound dehiscence. At multivariate analysis, preoperative adalimumab and budesonide resulted to be an independent predictor of reoperation (OR = 7.67 (95% CI = 1.49-39.20), p = 0.01 and OR = 6.7749 (95% CI = 0.98-46.48), p = 0.05, respectively). At multivariate analysis neither pharmacological nor clinical variables resulted to predict anastomotic leak. Conclusions: In our series, adalimumab seemed to be associated to early reoperation after intestinal surgery. This may be due to a worst disease severity in patients who needed surgery in spite of biological therapy. Preoperative tapering of budesonide dose seems a safe option before elective abdominal surgery for CD

4.3 A 76.7fs-lntegrated-Jitter and −71.9dBc In-Band Fractional-Spur Bang-Bang Digital PLL Based on an Inverse-Constant-Slope DTC and FCW Subtractive Dithering

Ultra-low-jitter and high-spectral-purity frequency synthesizers are key building blocks for high-performance wireless transceivers and $\text{FMCW}$ radars. A bang-bang $\text{PLL} (\text{BBPLL}$ ) is an attractive solution thanks to its small footprint and low power consumption; however, its operation in the $\text{fractional-N}$ mode is hindered by the large quantization error $(\text{Q-error})$ I caused by the non-integer frequency multiplication saturating the narrow input range of the bang-bang phase detector $(\text{BBPD})$ . A digital-to-time converter $(\text{DTC})$ is typically used to cancel the $\text{Q-error}$ in time domain [1] (Fig. 4.3.1 top-left). Unfortunately, the $\text{DTC}$ non-linearity can generate significant fractional spurs, thus corrupting the $\text{PLL}$ spectral purity and integrated jitter. Solutions to this problem rely on either improving the $\text{DTC}$ linearity or adopting a suitable randomization of the $\text{Q-error}$ sequence to generate lower spurs in the presence of the $\text{DTC}$ non-linearity. The constant slope $\text{DTC} (\text{CS-DTC})$ achieves superior linearity among $\text{DTC}$ architectures [2], even if further improvements are limited by the voltage sensitivity of current generators $(\text{CGs})$ and parasitic capacitances as well as by the non-linearity of the digital-to-analog converter $(\text{DAC})$ adopted in the circuit. On the other hand, those randomization techniques to reduce spurs typically require a larger $\text{Q-error}$ range [3], [4] that increases $\text{PLL jitter}$ for two reasons: the higher quantization-noise power and the larger random jitter induced by the wider range needed for the $\text{DTC}$ . This work introduces a $9.25-\text{to}-10.5\text{GHz} \text{fractional-N BBPLL}$ achieving $-71.9\text{dBc}$ fractional spur and a total rms jitter (including spurs) of $76.7\text{fs}$ at near-integer channels leveraging: $(\mathrm{i})$ a $\text{DTC}$ architecture (denoted as $inverse constant-slope DTC)$ I overcoming the $\text{CS-DTC}$ limitations and $(\text{ii})$ a $\text{Q-error}$ randomization technique (denoted as $FCW$ subtractive dithering), which keeps the $\mathrm{Q}- \text{error}$ range constant thus not degrading $\text{PLL jitter}

Mucosal Immune Environment in Colonic Carcinogenesis: CD80 Expression on Epithelial Cell Peaks in Dysplasia and Its Inhibition Leads to Carcinogenesis Progression

Background A significantly higher expression of the co-stimulatory molecule CD80 in ulcerat- ive colitis (UC) and dysplasia suggesting the presence of an immunosurveillance against cancerogenesis was recently observed. The aims of this study were to verify this hypothesis exploring the interplay between epithelium and CD8 T cell in human colonic carcinogenesis and evaluating the effect of CD80 signalling inhibition. Patients and methods Twenty nine patients diagnosed with UC, UC with colonic dysplasia, colonic adenoma, or colonic cancer were recruited at the moment of colonic resection. Mucosal samples were obtained during the colectomy and included specimens from healthy, dysplastic and neoplastic colon. Single cell suspensions were obtained by enzymatic digestion of mucosal specimens and subjected to Fluorescence-Activated Cell Sorting (FACS) to determine the proportion of epithelial cells (Cytokeratine 20, Cyt-20+) acting as antigen presenting cells (expressing CD80, CD40, HLA I or HLA II) and the proportion of CD8+ T cells activated (positive for CD28, CD38 or CD69). The second part of the study involved a mouse model of inflammation-related colon carcinogenesis with azoxymethane (AOM) and dextran sodium sulfate-induced (DSS). After the injection of AOM mice received 3 or 5 cycles of 3% DSS in their drinking water, each cycle consisted of 5 days of treatment followed by 14 days of rest. Animals were randomized to receive monoclonal anti-CD80 antibodies (10 ug/mouse) or isotype control, and sacrificed after 28 days. Results The proportion of Cyt-20+ CD80+ and Cyt-20+ HLA II+ cells was higher in dysplasia than in non dysplastic colonic tissue (p=0.03 and p=0.07, respectively). The proportion of Cyt-20+ CD80+ and Cyt-20+ CD40+ cells was higher in dysplasia than in invasive adenocarcinoma (p=0.07 and p=0.04, respectively). The proportion of CD8+ T cell expressing CD28 and CD38 was higher in dysplastic mucosa than in the mucosa with no neoplastic changes (p=0.01 and p=0.01, respectively). In mice that received anti-CD80 antibodies after AOM and 3 cycles of DSS inflammation was significantly inhibited (p=0.01) while high grade dysplasia extension was significantly higher than in mice that received a control antibody (p=0.01). The extension of low grade dysplasia was similar in the two groups. Conclusion This study confirmed that the proportion of epithelial cells acting as antigen presenting cells peaks in the dysplastic colonic mucosa and it is associated to activation of mucosal CD8+ T cell. CD80 inhibition increased high grade dysplasia extension without influencing the low grade dysplasia one. All together these data confirm the hypo- thesis that an active immunosurveillance mechanism centred on CD80 signalling is implicated in controlling the colonic carcinogenesis progression at the passage from low to high grade dysplasia

Mucosal Immune Environment in Colonic Carcinogenesis: T-Cell Activation in Ulcerative Colitis and Dysplasia

Background In patients with ulcerative colitis (UC) the cumulative rate of dysplasia is at least 25% but the cumulative risk of colon cancer is approximately 8% twenty years after the diagnosis. The inconsistency between dysplasia rate and incidence of cancer suggests the presence of immunosurveillance mechanisms that can activate T lymphocytes against dysplastic antigens. We recently demonstrated a CD80 up-regulation in UC and dysplasia. The aim of our study was to analyse the activation of T lymphocyte CD8+ (CTL) in the colonic mucosa at the different stages of UC-related and non inflammatory carcinogenesis. Patients and methods Five groups of patients affected by UC (10 pts), UC with colonic dysplasia (7 pts), colonic adenoma (7 pts), UC and cancer (5 pts), sporadic colonic cancer (10 pts) and a group of healthy control (10 pts) were enrolled in our study. Mucosal CD8beta and CD69 (markers of CTL activation) as well as CD80 and CD86 (co-stimulatory molecules) mRNA levels were quantified with Real Time PCR. Mucosal expression of CD80, CD86, CD3, CD20, CD68 and p53 was analysed by immunohistochemistry. Mucosal levels of IL- 1\u3b2, IL-2 and IFN-gamma were measured with immunometric assays. Non-parametric Krus- kal-Wallis ANOVA, Mann-Whitney U test and Kendall's tau correlation test were used. Results In the different steps of UC-related carcinogenesis CD8beta expression resulted similar while in non inflammatory carcinogenesis it resulted lower at the invasive cancer stage (p=0.01). CD8beta expression correlated with CD80 and CD86 mRNA expression (tau=0.47, p<0.01, tau=0.38, p<0.01, respectively). CD69 mRNA expression was higher in patients with UC and dysplasia than in patients with UC and in those with UC and cancer (p=0.05 and p=0.04, respectively). This difference was not evident in the non inflammatory carcinogenesis (p=0.47). In these patients, at each step of the carcinogenesis, the expression of CD69 was lower in patients with UC, UC and dysplasia and UC and cancer (p=0.01, p<0.01 and p=0.02, respectively). CD69 expression directly correlated with CD80 mRNA and protein expression (tau=0.53, p<0.01, tau=0.30, p<0.01, respectively). Conclusion Our study showed that, in UC, mucosa infiltrating T-cell CD8beta+ are equally distributed along the carcinogenesis pathway but their activation state is significantly enhanced in the dysplastic colonic tissue. Moreover, this activation was strictly correlated with CD80 expression sug- gesting the effectiveness of this immunosurveillance mechanism in UC. On the contrary, in non inflammatory carcinogenesis CTL seemed reduced in invasive cancer. Furthermore, neither CD80 up-regulation nor consequent CTL activation were observed suggesting that the lack of CD80 expression may be the cause of the progression of dysplastic adenoma once occurred

Mucosal immune environment in colonic carcinogenesis: CD80 expression is associated to oxidative DNA damage and TLR4-NF\u3baB signalling.

BACKGROUND: CD80 has been thought to play an active role in immunosurveillance as it has been found to be up-regulated in ulcerative colitis (UC) patients with dysplasia. The aim of the present study was to analyse early events in UC-related and non-inflammatory carcinogenesis with reference to CD80 expression to clarify what stimuli are involved in its up-regulation in these patients. PATIENTS AND METHODS: Sixty-two patients affected with UC, UC with dysplasia, UC and cancer, colonic adenoma, or colonic cancer and 11 healthy subjects were enroled in our study. Tissue samples were taken from surgical specimens during colonic resection or during colonoscopy. Mucosal mRNA expression of Toll-like receptor-4 (TLR4) and nuclear factor-kappaB (NF-\u3baB) was quantified with Real Time RT-PCR. TLR4, \u3b2-catenin and p53 expressions were analysed by immunohistochemistry. Mucosal levels of activated NF-\u3baB were measured with immunometric assays while 8-Hydroxydeoxyguanosine (8-OHdG) levels were quantified by high-performance liquid chromatography with electrochemical detection (HPLC-ED). Non-parametric tests were used for statistical analysis. RESULTS: 8-OHdG mucosal levels were higher in the patients with UC + dysplasia with respect to those in the patients with UC only (p=0.03). CD80 mRNA mucosal levels were directly correlated with 8-OHdG mucosal levels (\u3c4=0.26, p=0.04), TLR4 protein expression (\u3c4=0.45, p<0.01) and NF-\u3baB mRNA expression and activity (\u3c4=0.24, p=0.02; \u3c4=0.34, p=0.02, respectively). CD80 protein expression, instead, was directly correlated with 8-OHdG mucosal levels (\u3c4=0.19, p=0.05) and inversely correlated with TLR4 mRNA expression (\u3c4=-0.25, p=0.03). CONCLUSION: Oxidative DNA damage peaked in UC-related dysplasia and was found to be directly correlated to CD80 expression. The direct correlation between TLR4 protein expression and CD80 mRNA and the indirect correlation between CD80 protein and TLR4 mRNA expressions give substance to the hypothesis that they play a role in immunosurveillance. No significant correlations between CD80 expression and p53 and \u3b2-catenin accumulation during oncogenesis were, instead, observed