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Oncolytic viruses have gained attention as a novel form of cancer treatment. Many viral vectors in use today have been rendered safe by deletion of genes encoding viral structural proteins, thus making them unable to spread beyond the first infected cells. Hence, such replication-deficient constructs may lack efficacy. Here, we analyzed the oncolytic potential of the replication-competent vector VA7-EGFP, based on the avirulent Semliki Forest virus (SFV) strain A7(74), to kill cancer cells in culture as well as to target s.c. human melanoma xenografts in severe combined immunodeficient (SCID) mice. VA7-EGFP was able to infect most cancer cell lines studied, leading to complete lysis of the cells within 72 hours after infection. In SCID mice grafted with A2058 human melanoma, marked regression of the xenografts was observed following a single injection of 106 plaque-forming units of virus given either i.p., i.v., or intratumorally. Histologic analysis revealed the presence of virus not only in all treated tumors but also in the brains of the treated mice, causing progressing neuropathology beginning at day 16 after infection. Following initial oncolysis, clusters of viable tumor cells were observed embedded in connective tissue, and at later stages, encapsulated tumor nodules had formed. Infection of melanoma cells from explant cultures of these nodules revealed that a portion of the cells were resistant to virus. To be eligible for use in virotherapy, the ability of avirulent SFV to spread within tumor tissue may have to be improved and the biological safety of the virus may have to be addressed thoroughly in higher animals. (Cancer Res 2006; 66(14): 7185-94)

Supplementary Figures 1-3 from Oncolytic Capacity of Attenuated Replicative Semliki Forest Virus in Human Melanoma Xenografts in Severe Combined Immunodeficient Mice

The paper presents simulated and measurement results of a planar antenna structure at 2 GHz center frequency. The antenna has two ports implemented into the same conductive body. The antenna shows measured -10 dB impedance bandwidth from 1.87 GHz to 2.18 GHz with average 41.3 dB isolation between the antenna ports over the studied frequency bandwidth. Antenna is used to measure transmitted WCDMA FDD signal leakage to the receiver with a presence of blocker signal, which is transmitted over the air. The system measurements show that the RF filtering requirements can be relaxed based on 3GPP standard by using highly isolated antenna structure. Application areas can be found at the both ends of the mobile communications system, mobile devices and small cell base stations.

TDD Ka-band front-end with integrated switch on 22nm FDSOI CMOS technology is implemented for 5G NR at 24–28 GHz bands. Shunt switch technique reduces front-end performance only by 2 dB at 24 GHz compared to stand-alone reference amplifiers. Output power of TX with stacked PA is 13.6 dBm with 15 dB of peak gain, and RX front-end has 5dB noise figure at 24 GHz, both measured at the antenna port. Maximum average channel power at 28 GHz was 4.8 dBm with 100 MHz 64-QAM OFDM signal within 5G ACPR and EVM specifications. The PA and LNA amplifiers dissipate 183 mW and 4.6 mW from 2.8V and 0.8V supplies, respectively, occupying only 0.19mm2.

Digital predistortion (DPD) of a phased array requires that multiple transmit paths must be measured by a feedback (FB) receiver (Rx), This paper proposes a simplified FB architecture to be used for phased array DPD. A single FB line collects the waveform samples from the parallel paths to the FB Rx. The gain and phase of the common FB line is obtained by comparing the FB outputs to over-the-air (OTA) measurements. The overall DPD training is done by collecting the PA outputs with the common FB line, post-equalizing them to model the main lobe waveform and combining them to create the object used for array DPD. The DPD performance was verified by OTA measurements with 5GNR waveform and 28 GHz 8-path phased array transmitter. The DPD trained through the local FB line with the proposed calibration method achieved

Arc fault detection device (AFDD) is the latest protection device for low voltage circuits. It is used to detect arcing faults that cannot be detected by circuit breakers or residual current devices. Arcing faults are one of the main causes for electrical fires. Arc fault detection device is an active electronic device which operation is typically based on measurement of low and high frequency characteristics of the current passing through. Based on measured current characteristics and the knowledge of the arcing unique deviations in current, arc fault detection device detects possible arcing and disconnects the protected circuit. Arc fault detection device as an active electronic device is a potential source and victim of electromagnetic interference. Electromagnetic compatibility requirements are especially very demanding in military applications where low emission levels and high immunity levels are required. This article presents test results from electromagnetic compatibility testing of five different commercial arc fault detection devices against military standard requirements and analyses the suitability of the arc fault detection devices in military electromagnetic environment.

This paper presents a triple coil variable transformer that can be used to design RF blocks for millimeterwave 5G transceivers. By employing a third coil with a varying capacitive load in a two coil transformer, simultaneous dual band or a wide-band response can be achieved ranging from 20 GHz to 50 GHz. The idea is validated using simulations and fabricated using 45 nm CMOS SOI technology. In addition, reasons for mismatch between the simulated and measured results are studied. Furthermore, a modified switching configuration is proposed to alleviate the problems with the original design.

This paper presents a broadband linearization technique that can be used for mmWave amplifier circuits. It is based on the well-known principle of derivative superposition, where FETs with different operating points are connected in parallel to generate mutually cancelling third order intermodulation distortion (IM3) products. It is demonstrated by measurements in excess of 10 dB improvement in IM3 obtained from 1 GHz to 30 GHz, practically free by connecting a NMOS with very low gate bias in parallel of an amplifying NMOS. The reasons and limits of the cancellation are discussed. The inherent broadbandness of the technique makes it extremely suitable to be used in CMOS mmWave circuits.

The use of commercial off-the-shelf products in military systems has been a hot topic during recent decades. The fact that commercial off-the-shelf products are typically much cheaper than the military off-the-shelf products has been the main driver to use commercial off-the-shelf products in military systems. And nowadays, unlike in the past, commercial off-the-shelf products typically offer also the latest technology. Commercial off-the-shelf products are obviously designed and tested to be used in much less demanding electromagnetic environment than the military off-the-shelf products. Electromagnetic compatibility requirements are very demanding in military electromagnetic environment where low emission and high immunity levels are required. Different approaches and methodologies to evaluate the commercial off-the-shelf product’s feasibility in military electromagnetic environment have been presented in several articles, reports and standards. This article presents how commercial off-the-shelf products fulfil typical emission requirements for military products, based on statistical analysis of MIL-STD-461 emission test reports. This information can be used to optimize risk mitigation measures related to conducted and radiated emissions of the commercial off-the-shelf products.

Linearization of millimeter-wave (mmW) phased arrays is one of the key enablers for improving the system performance in terms of power, efficiency and linearity. However, phased array transceiver topologies that have multiple parallel nonlinear components with a shared digital input challenge the standard digital predistortion techniques. In addition, different analogue beamforming techniques complicate the linearization even further due to the fact that the signal nonlinearity has to be observed or modelled over-the-air (OTA) together with the impacts of antennas and even the directive mmW radio channel. The best linearization strategy depends on the system level targets of linearity such as error vector magnitude and adjacent channel power ratio which have slightly different nature when observed in the radiated far-field. In this paper, we present our view and the status of the literature on the topic of phased array digital predistortion. We highlight that the nonlinear distortion have a beam shape which may be different from the linear part of the beam. We also review the antenna array figures of merit describing the nonlinearity. Finally, we show an experimental example of OTA linearization of a 28 GHz phased array transmitter.

Objectives: The aim of this retrospective study was to compare subcuticular sutures and Steri-Strip (TM) S in closing median sternotomy incisions in children with regard to wound healing and scar formation. Methods: Fifty-three children and adolescents were enrolled in this study who all underwent a median sternotomy at age 0-18 years and had their presternal cutaneous wounds closed with either a running subcuticular suture (Group 1) or Steri-Strip (TM) S (Group 2). Their scars were assessed using the Patient and Observer Scar Assessment Scale (POSAS). Secondary outcome measures were the scar measurements and the incidence of wound problems post-surgery. Results: A significant difference was found between both groups in median POSAS observer scale scores for the items thickness (p = .027), pliability (p = .045), surface area (p = .045) and the total score (p = .048). All in favor of the subcuticular suture group. There were no significant differences concerning the POSAS patient scale scores. Middle parts of scars of patients in Group 2 were significantly broader (p = .001) than scars of patients in Group 1. No significant differences concerning wound problems were found. Conclusions: There are, according to our results, no significant differences in wound healing of median sternotomy incisions in children closed with either a subcuticular suture or Steri-Strip (TM) S. Significant differences do exist regarding scar formation and final cosmetic results of the scars, in favor of subcuticular closure.

We present a simple, analytic point source model for both static and time-varying point-like heat sources and the resulting temperature profile that solves the heat equation in dimension three. Simple algorithms to detect the location and spectral content of these sources are developed and numerically tested using Finite Element Mesh simulations. The resulting framework for heat source reconstruction problems, which are ill-posed inverse problems, seems promising and warrants for future research. Possible fields of application for our work are material testing, to detect manufacturing defects, and medical imaging to detect abnormal health conditions.

This paper presents a synthesis flow for building lumped circuit models of arbitrary complexity for mm-wave IC passive components, based on S-parameters obtained by measurements or electromagnetic (EM) field simulations. Lumped circuit models are needed in time-domain simulations, or to speed up the fine-tuning of passive circuit blocks, as iterating is much faster in circuit simulators than in EM simulator. Modeling algorithm is implemented in MATLAB, and the design flow has a few new features. The device model is given by Spice netlist, and its structure or complexity is not limited. Differential and common mode forms of admittance parameters are used to simplify solving the initial model component values that are then refined manually or by numerical optimization. The flow is illustrated by modeling a parallel LC resonator, whose response has been measured from 1 to 40 GHz

This paper discusses the design requirements of class C auxiliary (aux) amplifiers deployed in Doherty power amplifiers (DPA). Taking conduction angle and back-off (BO) level into account a global design chart is presented which can be utilized to properly dimension the aux amplifier. Based on the proposed method a class C power amplifier is designed and exploited in a DPA circuit at 28GHz which is evaluated using simulations based on 45nm CMOS technology. Simulations reveal 27dBm saturated output power, 60% maximum drain efficiency (DE), 45% DE at 6dB BO, and 2 times efficiency enhancement at 6dB BO which is a new record in this trend.

This paper shows how digital predistortion of a phased array can benefit from the parametric variations over parallel power amplifiers (PAs). Different antenna configurations are simulated by varying the PA input drive levels by the Monte-Carlo method. The error vector magnitude (EVM) at the steering angle and total radiated adjacent channel power ratio (TRACPR) are used as performance metrics. The simulation results indicate that array predistortion can benefit from the variations between the PAs to improve the EVM significantly. However, at the same time, the TRACPR performance is reduced. This gives a new trade-off to balance between in-band and out-off-band distortion in the fifth generation beamforming systems.

This paper presents a simultaneous high-Q impedance matching and bandpass filtering technique for low-noise amplifiers (LNA) for radio frequency integrated circuit (RFIC) phased array system at 15 GHz, over the bandwidth of 1 GHz. A non-uniform transmission line (NUTL) segment is used as a major building block, which provides feasible integration for multiple antennas. A feeding network for single element receiver is demonstrated. The simulated and measured results show sufficient impedance matching of input feeds with S11

This paper presents a method to characterize a multi-dimensional polynomial current and charge source models needed for a distortion contribution analysis technique that can identify the dominant nonlinearities and different mixing mechanisms. A separate model characterization step with carefully chosen test signals is used to break the inherent input–output correlation that otherwise complicates the model fitting. The proposed Volterra-on-top-of-harmonic-balance technique and improved polynomial fitting are then verified through the analysis of a 100-W LDMOS RF Doherty amplifier, which showed that, in this circuit, the cubic nonlinearity of the gate capacitance is the main culprit of AM–PM distortion.

This paper presents a fully integrated, four stack power amplifier for 5G wireless systems. The frequency of operation is tunable from 12 GHz to 14 GHz, with a maximum 3 dB bandwidth of 1 GHz and a maximum possible gain of 35 dB. The circuit is designed and fabricated using 45 nm CMOS SOI technology. Maximum RF output power, power-added efficiency (PAE) and output 1 dB compression point under maximum bandwidth configuration are 17.7 dBm, 23.2% and 12.3 dBm, respectively, achieved at 13.7 GHz.

This paper presents an active RF phase shifter with 10 bit control word targeted toward the upcoming 5G wireless systems. The circuit is designed and fabricated using 45 nm CMOS SOI technology. An IQ vector modulator (IQVM) topology is used which provides both amplitude and phase control. The design is programmable with exhaustive digital controls available for parameters like bias voltage, resonance frequency, and gain. The frequency of operation is tunable from 12.5 GHz to 15.7 GHz. The mean angular separation between phase points is 1.5 degree at optimum amplitude levels. The rms phase error over the operating band is as low as 0.8 degree. Active area occupied is 0.18 square millimeter. The total DC power consumed from 1 V supply is 75 mW.

In this paper, we propose a simple polynomial linearisation technique for nonlinear phased arrays including amplitude control. Due to the large number of antennas and thus power amplifiers in the array, it is inefficient to linearise each power amplifier individually. Therefore, it is demonstrated that the array can be linearised over-the-air using single polynomial. The simulations show that the linearisation is achieved by first linearising the higher driven PAs at the precompression region and then cancelling the compression by the heavily expanding lower driven PAs. The proposed approach offers an alternative way of re-thinking the concept of array linearisation over multiple PAs.

This paper proposes a time domain measurement technique for characterizing the thickness of dielectric material based on pulse-domain microwave photonics and pulsed time-of-flight configuration. Short laser pulses from a semiconductor laser diode are converted to electrical pulses using a wideband photodetector. These pulses are fed to an antenna, providing a simple and accurate non-destructive measurement technique for material characterization. The thickness of the sample is calculated based on the propagation delay of a radio wave by measuring the transit time of a short electromagnetic pulse. The propagation delay is determined from the front edge of the energy envelope. Results show that the measured propagation delay is linearly dependent on the sample thickness. The technique achieves a measurement precision in the sub-mm range with a measurement time of 40ms.

Purpose – The purpose of this paper is to propose a method to reduce the non-linear distortion of a transistor to its input and output ports to aid distortion contribution analysis (DCA). This is especially needed when the internal structure of a device model is complex. Design/methodology/approach – The non-linear distortion generated by all non-linear sources inside a device model are reduced to transistor i/o ports by LMSE fitting techniques. Simulations of an LDMOS power transistor are used to compare the reduced distortion results with the actual non-linear sources. Findings – It is shown, that device models where the current sources are split by intermediate nodes cause superficial results, when distortion contributions are calculated as a superposition of contributions from individual non-linear sources. The proposed iterative fitting technique works. Research limitations/implications – Some non-quasistatic effects and the transfer functions from external terminals to internal controlling nodes are not covered. Practical implications – The analysis is a step toward a generic non-linear distortion contribution simulation tool that would aid the designers to develop more linear analog circuits. Originality/value – The concept of DCA itself is fairly new. This paper makes a step to represent the distortion sources in a canonical way.

Purpose – The purpose of this paper is to propose methods to improve the least square error polynomial fitting of multi-input nonlinear sources that suffer from strong correlating inputs. Design/methodology/approach – The polynomial fitting is improved by amplitude normalization, reducing the order of the model, utilizing Chebychev polynomials and finally perturbing the correlating controlling voltage spectra. The fitting process is estimated by the reliability figure and the condition number. Findings – It is shown in the paper that perturbing one of the controlling voltages reduces the correlation to a large extend especially in the cross-terms of the multi-input polynomials. Chebychev polynomials reduce the correlation between the higher-order spectra derived from the same input signal, but cannot break the correlation between correlating input and output voltages. Research limitations/implications – Optimal perturbations are sought in a separate optimization loop, which slows down the fitting process. This is due to the fact that each nonlinear source that suffers from the correlation needs a different perturbation. Originality/value – The perturbation, harmonic balance run and refitting of an individual nonlinear source inside a device model is new and original way to characterize and fit polynomial models.

This paper uses hand analysis and a new fully numerical distortion contribution analysis technique to explain and optimize the nonlinear performance of analog circuits. Several example circuits are studied, where mixing of nonlinear distortion from one harmonic band to another is important. In some circuits the band-to-band mixing can be employed to reduce the overall distortion.

Purpose To study retinal blood flow and vessel diameter after intra-ocular pressure (IOP) reduction in high- and low-pressure glaucomas, that is, exfoliation glaucoma (ExG) and normal-tension glaucoma (NTG). Methods The study included 17 eyes with ExG and 20 with NTG. A minimum of 25% IOP reduction was achieved by deep sclerectomy. Blood flow in the temporal peripapillary retina was measured with scanning laser Doppler flowmetry (Heidelberg Retina Flowmeter, HRF), and retinal vessel diameters were evaluated with the retinal vessel analyser (RVA). Examinations were carried out before and 3 months after the operation. Results Pre-operative IOP was significantly higher in ExG than in NTG (median 26 mmHg, range 20–33 mmHg versus 15 mmHg, 12–20; p

Volterra analysis can be used to perform distortion contribution analysis. It is shown here that an ordinary time-invariant (TI) Volterra analysis with fitted polynomial models can be used in such a non-linear application as mixers and switching power amplifiers, where time-varying (TV) Volterra analysis has often been used. TI and TV Volterra analyses are compared behaviorally, and the use of TI Volterra with fitted polynomial coefficients is illustrated by analyzing two highly non-linear example circuits using a recently developed Volterra-on-Harmonic-Balance (VoHB) analysis tool.

Objective: Follow-up studies of patients surviving emergency resternotomy, open cardiac massage, and additional emergency cardiac surgery following coronary artery bypass grafting (CABG) remain sparse and studies focusing on health-related quality of life are lacking. Our aim was to elucidate the long-term course of patients experiencing this hazardous complication. Methods: Between 1988 and 1999, 76 patients suffered sudden hemodynamic collapse following isolated CABG. All patients underwent emergency resternotomy and open cardiac massage. An emergency cardiac reoperation was performed in the 62 (82%) primary survivors. Additional 76 patients were pair-matched to the study patients on the basis of their preoperative characteristics and served as controls. Of the study patients, 41 (54%), and of the controls, 76, (100%) weredischarged.In December 2009,allpatientsweretracedwithrespecttomortalitydataandthehealth-relatedqualityoflifeoflivingpatients was studied using the RAND-36 Item Health Survey questionnaire. Results: Altogether 19 (73%) of the 26 study patients, and 38 (84%) of the 45 controls were available. After exclusion of the early deaths, the life expectancy was similar between the groups: neither overall (p = 0.60) nor cardiac (p = 0.64) survival differed significantly after a mean follow-up time of 15.1 3.5 years. In addition, cardiac re-interventions were equally frequently required in both the groups. The RAND-36 scores were congruent (p = ns) between the groups and the age- and sex-matched national reference population in the health-related quality-of-life dimensions describing physical, mental, and social domains. Conclusions: Patients who have survived severe hemodynamic collapse, open cardiac massage, and emergency cardiac reoperation following CABG achieve similar long-term prognosis in terms of survival and cardiac interventions as the pair-matched control patients. In addition, 15 years postoperatively, they have a good health-related quality of life, similar to that of an age- and sex-matched national reference population. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

The extracellular tumor microenvironment is acidified, whereas the intracellular pH of tumor and stromal cells is neutral. cis-Urocanic acid (cis-UCA), an endogenous compound of the skin, can acidify the cytosol by transporting protons into the cells. This phenomenon, termed the protodynamic concept, was studied here in human cancer cells. cis-UCA dose-dependently reduced the number of viable human melanoma, cervical carcinoma, and fibrosarcoma cells at weakly acidic extracellular pH. The intracellular pH decreased by up to 0.5 pH units in a concentration-dependent manner with 0.3-30 m cis-UCA at extracellular pH 6.5 but not at pH 7.4. Under the same conditions, 30 mM cis-UCA induced annexin-V binding and activation of caspase-3 in A2058 melanoma cells as signs of apoptotic cell death. Finally, growth of human melanoma xenografts in SCID mice was suppressed by 60% following intratumoral injection of cis-UCA. Accordingly, the percentage of tumor necrosis and active caspase-3-immunopositive cells increased, whereas proliferation activity decreased. These results identify cis-UCA as an anticancer agent inhibiting melanoma growth by immediate intracellular acidification followed by apoptotic cell death in vivo.

In this paper, a Volterra analysis built on top of a normal harmonic balance simulation is used for a comprehensive analysis of the causes of AM-PM distortion in a LDMOS RF power amplifier (PA). The analysis shows that any nonlinear capacitors cause AM-PM. In addition, varying terminal impedances may pull the matching impedances and cause phase shift. The AM-PM is also affected by the distortion that is mixed down from the second harmonic. As a sample circuit, an internally matched 30-W LDMOS RF PA is used and the results are compared to measured AM-AM, AM-PM and large-signal S11.

Oncolytic viruses have gained attention as a novel form of cancer treatment. Many viral vectors in use today have been rendered safe by deletion of genes encoding viral structural proteins, thus making them unable to spread beyond the first infected cells. Hence, such replication-deficient constructs may lack efficacy. Here, we analyzed the oncolytic potential of the replication-competent vector VA7-EGFP, based on the avirulent Semliki Forest virus (SFV) strain A7(74), to kill cancer cells in culture as well as to target s.c. human melanoma xenografts in severe combined immunodeficient (SCID) mice. VA7-EGFP was able to infect most cancer cell lines studied, leading to complete lysis of the cells within 72 hours after infection. In SCID mice grafted with A2058 human melanoma, marked regression of the xenografts was observed following a single injection of 106 plaque-forming units of virus given either i.p., i.v., or intratumorally. Histologic analysis revealed the presence of virus not only in all treated tumors but also in the brains of the treated mice, causing progressing neuropathology beginning at day 16 after infection. Following initial oncolysis, clusters of viable tumor cells were observed embedded in connective tissue, and at later stages, encapsulated tumor nodules had formed. Infection of melanoma cells from explant cultures of these nodules revealed that a portion of the cells were resistant to virus. To be eligible for use in virotherapy, the ability of avirulent SFV to spread within tumor tissue may have to be improved and the biological safety of the virus may have to be addressed thoroughly in higher animals. (Cancer Res 2006; 66(14): 7185-94)

This paper presents an analysis technique implemented on top of normal harmonic-balance simulation, where the simulated nonlinear voltage and current spectra is used for fitting a polynomial device model around the large-signal bias point. Further, using the fitted model and spectra of the controlling voltages, the detailed structure of the third-order intermodulation distortion is calculated using a simplified form of Volterra analysis. This detailed information can be used to find the dominant causes of distortion and possible cancellation mechanisms, to study the bandwidth-dependent memory effects caused by up- or down-converted mixing results, or to find harmonic matching impedances that minimize the overall distortion.

Purpose: To describe a new treatment protocol to deliver panretinal photocoagulation that may avoid further deterioration of vision in patients with type 1 diabetes mellitus with proliferative retinopathy with high risk characteristics for severe visual loss and cystoid macular oedema. Methods: Fundus photography, measurement of foveal thickness with optical coherence tomography and best corrected visual acuity (BCVA) determined by Snellen and ETDRS charts were measured before and after treatment in a 28-year-old man. Results: Over 9 weeks, BCVA improved from 0.05 to 0.25 and the number of letters read at 2 metres from four to 39 after panretinal photocoagulation and adjuvant intravitreal triamcinolone injection under intraconal anaesthesia. Foveal thickness decreased from 691 µm to 239 µm and cysts disappeared by 15 weeks. By 22 weeks, foveal thickness had increased to 282 µm and small cysts had reappeared, but BCVA remained at 0.2 and the number of letters read at 30. Conclusion: Proliferative retinopathy regressed, cystoid macular oedema disappeared and vision improved after panretinal photocoagulation and adjuvant intravitreal triamcinolone acetonide injection under intraconal anaesthesia. This represents a feasible option in cases where pain during laser treatment and impairment of vision afterwards due to cystoid macular oedema result in poor compliance with standard laser treatment under topical anaesthesia.

The TGF beta family member growth differentiation factor-9 (GDF-9) is an oocyte-derived factor that is essential for mammalian ovarian folliculogenesis. GDF-9 mRNAs have been shown to be expressed in the human ovarian follicle from the primary follicle stage onward, and recombinant GDF-9 has been shown to promote human ovarian follicle growth in vitro. In this study with primary cultures of human granulosa-luteal (hGL) cells, we investigated whether recombinant GDF-9 activates components of the Smad signaling pathways known to be differentially activated by TGF beta and the bone morphogenetic proteins (BMPs). As with TGF beta, GDF-9 treatment caused the phosphorylation of endogenous 53-kDa proteins detected in Western blots with antiphospho-Smad2 antibodies (alpha PS2). However, unlike BMP-2, GDF-9 did not activate the phosphorylation of antiphospho-Smad1 antibody (alphaPS1)-immunoreactive proteins in hGL cells. Infection of hGL cells with an adenovirus expressing Smad2 (Ad-Smad2) confirmed that GDF-9 activates specifically phosphorylation of the Smad2 protein. Infection of hGL cells with Ad-Smad7, which expresses the inhibitory Smad7 protein, suppressed the levels of both GDF-9-induced endogenous and adenoviral alpha PS2-reactive proteins. Furthermore, GDF-9 increased the steady state levels of inhibin beta(B)-subunit mRNAs in hGL cells and strongly stimulated the secretion of dimeric inhibin B. Again, Ad-Smad7 blocked GDF-9-stimulated inhibin B production in a concentration-dependent manner. We identify here for the first time distinct molecular components of the GDF-9 signaling pathway in the human ovary. Our data suggest that GDF-9 mediates its effect through the pathway commonly activated by TGF beta and activin, but not that activated by many BMPs. The results are also consistent with the suggestion that in addition to endocrine control of inhibin production by gonadotropins, a local paracrine control of inhibin production is likely to occur via oocyte-derived factors in the human ovary.

In the mammalian ovary cell growth and differentiation is regulated by several members of the transforming growth factor beta (TGF beta) superfamily including activins, inhibins, growth differentiation factors and bone morphogenetic proteins (BMPs). The effects of TGF beta family members are mediated to the target cells via heteromeric complexes of type I and II serine/threonine kinase receptors which activate Smad signaling protein pathways in various cell types. We have previously shown that inhibin B, a hormonally important product from human granulosa cells, is up regulated by activin and BMPs. Here, we report the use of adenoviral gene transfer methodology to manipulate the TGF beta growth factor signaling system in primary cultures of human granulosa cells. These cells are exceedingly difficult to transfect by conventional transfection methods, but were virtually 100% infected with recombinant adenoviruses expressing green fluorescent protein (GFP). Adenoviruses expressing constitutively active forms of the seven known mammalian type I activin receptor-like kinase receptors (Ad-caALK1 through Ad-caALK7) cause activation of endogenous and adenovirally transferred Smad signaling proteins so that Ad-caALK1/2/3/6 and Ad-caALK4/5/7 induced phosphorylation of the Smad1 and Smad2 pathways, respectively. Activin A and BMP-2 activated the Smad1 and Smad2 pathways as well as inhibin B production as did all the Ad-caALKs. Furthermore, overexpression of adenoviral Smad1 and Smad2 proteins without exogenously added ligands induced inhibin B production. The inhibitory Smad7 protein suppressed BMP-2 and activin induced inhibin B production. Collectively, the present data demonstrate that adenoviral gene transfer provides an effective approach for dissecting the TGF beta signaling pathways in primary ovarian cells in vitro and more specifically indicate that the Smad1 and Smad2 pathways are involved in the regulation of inhibin B production by TGF beta family ligands in the ovary.

OBJECTIVE To determine if the cumulative incidence of severe retinopathy in patients with type 1 diabetes has changed. RESEARCH DESIGN AND METHODS The study looked at 3,781 patients diagnosed with type 1 diabetes (1939–2005), median age at onset 13 (interquartile range [IQR] 9–21) years, and duration of diabetes 19 (IQR 13–27) years. The severe retinopathy was based on a history of laser treatment. Patients were divided into RESULTS The cumulative incidence of severe retinopathy has declined (P < 0.0001). After 20 years of duration, the cumulative incidence was 23% (95% CI 21–25) and 33 (30–35) in the earliest cohorts, 18 (15–21) in the next cohort, and 6 (4–9) in the recent cohort. After 30 years, the cumulative incidence was 52 and 48% in the earliest cohorts, while it was 62% after 40 years in the earliest cohort. CONCLUSIONS The cumulative incidence of severe retinopathy has declined in patients with type 1 diabetes.

Behavioral modelling often aims in a simple black-box input-output response with minimal rms error with the used excitation. However, this may grossly overestimate the sensitivities to certain changes in the inputs, causing the model to be prone of big errors with a different excitation. This also makes it difficult to separate different nonlinear effects. In this paper we compare the effect of different model fitting strategies to the shape of the modeled I-V response and distortion contribution analysis, that very much relies on the fact, that besides accurate I-V match also the shape of the model and its higher derivatives are physically meaningful and correct.

Electronic design relies heavily on simulation, and nowadays most of the designs start by behavioral simulations. Previously modeling has been done by people who have good understanding on heavy numerical computing, but now most designers need to write some behavioral models. In this paper we discuss how well electrical engineering students are prepared to that and what can to be done to give them sufficient skills for behavioral modeling.

Polynomial models for transistor I-V curves are needed for example for Volterra analysis. The polynomial models can be fitted with least-square error techniques from DC data, measured time-series, or measured spectra. This paper shows that with sufficiently broadband spectrum measurement the time-domain and frequency-domain fitting techniques result in the same model. It is also demonstrated that redundancy can be found in the spectrum, meaning that a significant part of the spectral content can be discarded during the fitting, and one still achieves the same fit.

Objectives The aim of this study was to investigate the associations between lipid profiles and retinopathy in the large nationwide FinnDiane Study and to examine interactions and correlations between retinopathy, nephropathy and lipid variables. Design and subjects A total of 1465 patients with type 1 diabetes, available lipid profiles, ophthalmic records and fundus photographs were included in the study. The Early Treatment of Diabetic Retinopathy Study scale was used to assess the severity of retinopathy. In an independent cohort of 1100 patients, laser treatment was used to define severe diabetic retinopathy. Results HDL cholesterol was associated with proliferative retinopathy (PDR), and triglycerides were associated with mild nonproliferative retinopathy (NPDR) independently of nephropathy and other conventional risk factors (P

Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5–6 short periods of hypoxia each day over 1–3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease. We tested whether IH over 1 day could initiate a long-lasting response potentially leading to better adaptation to hypoxia. In 15 patients with type 1 diabetes, we measured hypoxic and hypercapnic ventilatory responses (HCVRs), ventilatory recruitment threshold (VRT-CO2), baroreflex sensitivity (BRS), blood pressure, and blood lactate before and after 0, 3, and 6 h of a 1-h single bout of IH. All measurements were repeated on a placebo day (single-blind protocol, randomized sequence). After IH (immediately and after 3 h), hypoxic and HCVR increased, whereas the VRT-CO2 dropped. No such changes were observed on the placebo day. Systolic and diastolic blood pressure increased, whereas blood lactate decreased after IH. Despite exposure to hypoxia, BRS remained unchanged. Repeated exposures to hypoxia over 1 day induced an initial adaptation to hypoxia, with improvement in respiratory reflexes. Prolonging the exposure to IH (>2 weeks) in type 1 diabetic patients will be a matter for further studies.

Research indicates occupational injuries and diseases are not evenly distributed among workers. We investigated the distribution and characteristics of compensated occupational injuries and diseases requiring medical care in the Finnish farming population.The study population consisted of 93,564 Finnish farmers, spouses, and salaried family members who were covered by the mandatory workers' compensation insurance in 2002. This population had a total of 133,207 occupational injuries and 9,148 occupational diseases over a 26-year period (1982-2008).Clustering of claims was observed. Nearly half (47.1%) of the population had no compensated claims while 52.9% had at least one; 50.9% of farmers had one or more injuries and 8.1% had one or more diseases. Ten percent of the population had half of injury cases, and 3% of the population had half of occupational disease cases. Claims frequently involved work tasks related to animal husbandry and repair and maintenance of farm machinery. Injury and disease characteristics (work activity, cause, ICD-10 code) differed between individuals with high and low personal claim rate. Injuries and diseases of the musculoskeletal system had a tendency to reoccur among those with high claim rate. These outcomes were often related to strenuous working motions and postures in labor-intensive animal husbandry.Analyses of longitudinal insurance data contributes to better understanding of the long-term risk of occupational injury and disease among farmers. We suggest focusing on recurrent health outcomes and their causes among high risk populations could help design more effective interventions in agriculture and other industries.

This paper presents a distortion contribution analysis of a 100 watt LDMOS RF Doherty power amplifier. The analysis is performed using recently developed distortion contribution analysis technique called as Volterra-on-top-of-harmonic-balance that is able to show the originating cause of nonlinearity and mixing mechanisms between harmonic bands. The analysis shows that the nonlinear output capacitance of the carrier amplifier is the main cause of distortion at peak power levels.

This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment. The effect of HbA1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n = 1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n = 1,346). The ratio of intrapersonal SD and mean of serially measured HbA1c was considered an estimate of HbA1c variability. A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2 ± 2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA1c variability and 10% (95% CI 7, 12) in the lowest quartile (p

Retinal vascular changes other than diabetic retinopathy (DRP) namely microaneurysms, intraretinal microvascular abnormalities so called IRMA, microinfarctions, hemorrhages, lipid exudates and edema, as well as venous beading and new vessels (NV) on the disk and/or on the retina and their sequalae pre-retinal and vitreous hemorrhages and fibrovascular proliferations and vitreoretinal tractions are common in diabetic patients. These changes are general or focal arteriolar narrowing or arteriolar or venous dilatation, arteriolar sinusoidal elongation or straightening, venous tortuosity, increased arteriolar wall reflex and arterio-venous crossing signs. They reflect cumulative response to aging, cardiovascular risk factors such as hyperglycemia, hypertension and dyslipidemia, as well as inflammation and endothelial dysfunction. Retinal vascular changes are under the influence of both systemic and environmental as well as genetic factors and serve as cardiovascular risk stratification indicator. Furthermore, these changes may cause as such ocular morbidity and threaten vision and influence the occurrence and progression of DRP. Many of these changes were recognized soon after the invention of ophthalmoscope by von Helmholz in 1851 and have since been described in literature. Many of these changes can be accurately measured today.

The conversion gain in mixers is traditionally calculated using a time-varying (TV) gain model and small signal excitation. In this paper we compare this approach with a brute force expansion of a polynomial model with multitone input. It is seen that the polynomial expansion preserves more information, and shows some distortion products that the time-varying model ignores. The polynomial expansion is used in Volterra-on-Harmonic Balance distortion contribution analysis to analyse both mixing and amplifying circuits.