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Digital audio sensors have been used in microphone-embedded portable electronics. This paper shows a mixed-signal adaptive readout ASIC for digital audio sensor, which includes a programmable-gain-amplifier, a switched-capacitor sigma-delta modulator, digital signal processing, and power management circuits. The digital part comprises a digital low-pass filter, a digital-gain-compensation and a digital automatic-gain-controller. The clear advantage of this system is to obtain high signal-to-noise ratio (SNR) and wide input range simultaneously. In addition, both a normal operation mode and a sleep mode are realized to address a flexible current budget. The ASIC is fabricated in a 0.18-um CMOS process. Experimental results show the expected adaptive readout function over the input range from 94 to 136 dB SPL. In the normal mode, a system SNR of 68 dB (A-weighted) at 1 kHz 94 dB SPL input is achieved under 600 uA. Further, an impressive acoustic overload point (AOP) of 136 dB SPL is guaranteed. In the standby condition, the sleep mode with current less than 20 uA is obtained, so that the battery life can be extended. Compared to other existing solutions, this adaptive readout ASIC shows the best combination of achievable SNR, AOP and current budget for digital audio sensors. [ABSTRACT FROM AUTHOR]

This paper presents a low power read-out front-end for 3-axis MEMS capacitive accelerometer. The front-end includes the analog preamplifier (to sense the signal coming from the MEMS) and a Successive-Approximation 10b A/D Converter, for digitalization and off-chip digital-signal-processing. Power minimization is achieved by using a continuous-time sensing preamplifier (i.e. constant-charge capacitance-to-voltage conversion) and SAR-ADC with bridge capacitive reduction. Preamplifier programmable in-band gain allows to accommodate different MEMS sensitivities. A very high-impedance MOS transistor is used for MEMS biasing, thus providing very low frequency (<1 Hz) AC coupling. In a 0.13 μm CMOS technology, the full channel consumes 90 μW from a single 1.2 V supply voltage, and achieves an equivalent 67.9 dB@SNR in [1 Hz-4 kHz] bandwidth by exploiting oversampling ratio. [ABSTRACT FROM AUTHOR]

The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3-9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fit the entry criteria of the registry, because they were diagnosed uniformly as CMML or AML by the panel members. The agreement by WHO 2001 classification was strong as well (ICC = 0.83). The concordance of the assessment of dysplastic lineages was substantial for megakaryopoiesis and myelopoiesis and moderate for erythropoiesis. Our data show that in general, the inter-observer agreement was high and a very low percentage of misdiagnosed cases had been entered into the EUMDS registry. Further studies including histomorphology are warranted. [ABSTRACT FROM AUTHOR]

A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS. [ABSTRACT FROM AUTHOR]

The splicing factor SF3B1 is the most commonly mutated gene in the myelodysplastic syndrome (MDS), particularly in patients with refractory anemia with ring sideroblasts (RARS). We investigated the functional effects of SF3B1 disruption in myeloid cell lines: SF3B1 knockdown resulted in growth inhibition, cell cycle arrest and impaired erythroid differentiation and deregulation of many genes and pathways, including cell cycle regulation and RNA processing. MDS is a disorder of the hematopoietic stem cell and we thus studied the transcriptome of CD34+ cells from MDS patients with SF3B1 mutations using RNA sequencing. Genes significantly differentially expressed at the transcript and/or exon level in SF3B1 mutant compared with wild-type cases include genes that are involved in MDS pathogenesis (ASXL1 and CBL), iron homeostasis and mitochondrial metabolism (ALAS2, ABCB7 and SLC25A37) and RNA splicing/processing (PRPF8 and HNRNPD). Many genes regulated by a DNA damage-induced BRCA1-BCLAF1-SF3B1 protein complex showed differential expression/splicing in SF3B1 mutant cases. This is the first study to determine the target genes of SF3B1 mutation in MDS CD34+ cells. Our data indicate that SF3B1 has a critical role in MDS by affecting the expression and splicing of genes involved in specific cellular processes/pathways, many of which are relevant to the known RARS pathophysiology, suggesting a causal link. [ABSTRACT FROM AUTHOR]

The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity. [ABSTRACT FROM AUTHOR]

This paper presents a design methodology for high-order class-D amplifiers, based on their similarity with sigma-delta ( $$\Upsigma\Updelta$$ ) modulators, for which established theory and toolboxes are available. The proposed methodology, which covers the entire design flow, from specifications to component sizing, is validated with three design examples, namely a second-order, a third-order, and a fourth-order class-D amplifier. Moreover, the third-order class-D amplifier has been integrated on silicon and characterized, further confirming the validity of the whole design flow. The achieved results demonstrate that high-order class-D amplifiers can achieve total-harmonic-distortion (THD) performance compatible with the specifications of high-end audio applications (THD ≈ 90 dB), which would be unfeasible with conventional first-order class-D amplifiers. [ABSTRACT FROM AUTHOR]

Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as 'normal', 'suggestive of', or 'diagnostic of' MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced. The working group is dedicated to initiate further studies to establish robust diagnostic and prognostic FC panels in MDS. An ultimate goal is to refine and improve diagnosis and prognostic scoring systems. Finally, the working group stresses that FC should be part of an integrated diagnosis rather than a separate technique. [ABSTRACT FROM AUTHOR]

A MASH bandpass $$\Upsigma\Updelta$$ modulator for wide-band code division multiple access (WCDMA) applications is presented. The signal bandwidth of the proposed modulator is 10 MHz centered around an intermediate frequency (IF) of 70.5 MHz. Two two-path second-order bandpass $$\Upsigma\Updelta$$ modulators make the MASH architecture, which realizes a noise transfer function with four couples of complex conjugate zeros. The proposed circuit, fabricated with a 0.18 μm CMOS technology, uses a sampling frequency of 180 MHz to obtain a resolution of about 12 bits in the 10 MHz bandwidth around the IF. The measured modulator power consumption is 95 mW with a supply voltage of 1.8 V. The achieved figure-of-merit ( FoM) is 0.37 pJ/conversion-level. [ABSTRACT FROM AUTHOR]

This paper presents a single-inductor 4-outputs DC-DC buck converter. In order to independently regulate the four output voltages, a multiple control loop operates on linear combinations of the output voltage errors. An original self-boosted snubber circuit enables load power switches control signals boosting without area and power efficiency penalties. The circuit, fabricated using a 0.5-μm CMOS process, provides four output voltages that can be independently regulated from 0 V to the used supply voltage −500 mV. The supply voltage can range from 2.3 up to 5 V. The overall minimum and maximum output currents are 0.15 and 1.8 A, respectively. The measured maximum cross regulation is 40 mV/V with a peak of power efficiency equal to 85%. [ABSTRACT FROM AUTHOR]

In this paper an integrated interface circuit for condenser MEMS microphones is presented. It consists of an input buffer followed by a multi-bit (12-levels), analog, second-order ΣΔ modulator and a fully-digital, single-bit, fourth-order ΣΔ modulator, thus providing a single-bit output signal with fourth order noise shaping, compatible with standard audio chipsets. The circuit, supplied with 3.3 V, exhibits a current consumption of 215 μA for the analog part and 95 μA for the digital part. The measured signal-to-noise and distortion ratio ( SNDR) is 71 dB, with an input signal amplitude as large as −1.8 dB with respect to full-scale, obtained thanks to the use of a feed-forward architecture in the analog ΣΔ modulator, which relaxes the voltage swing requirements of the operational amplifiers. The test chip, fabricated in a 0.35-μm CMOS process, occupies an area of 3 mm, including pads. [ABSTRACT FROM AUTHOR]

This paper presents an ultra-low power successive approximation analog-to-digital converter. An improved implementation of the binary weighted capacitors array and a novel comparator that operates in the time instead of the voltage domain are effective and power efficient. The circuit, fabricated in a conventional 0.18-μm CMOS technology, achieves a sampling rate of 100 kS/s and an effective number of bit of 9.4. Using a 1-V supply voltage, the achieved power consumption is 3.8 μW, leading to a Figure of Merit as low as 56 fJ/conversion-level. [ABSTRACT FROM AUTHOR]

In this paper a dual operating mode 8-bit, 1.1-V pipeline ADC for Gigabit Ethernet applications is presented. In the two operating modes, the ADC features different sampling frequency (125 and 250 MHz) and power consumption (9.4 and 22.8 mW). Considering a signal bandwidth of 60 MHz in both operating modes, as required by the Gigabit Ethernet standard, the ADC achieves a SNDR always larger than 39.4 dB at 125 MHz and 38.7 dB at 250 MHz (6.25-bit and 6.13-bit ENOB, respectively), with a FoM of 0.84 pJ/conv at 125 MHz and 2.2 pJ/conv at 250 MHz. The ENOB achieved is mainly limited by clock jitter. The ADC is fabricated with a 90-nm CMOS technology, with an active area of 1.25 × 0.65 mm2. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to the mutation of the gene AsXL1 in myelodysplastic and myelodysplastic syndromes.

To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or −7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with −7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Abstract  This paper presents a novel technique for on-line calibration and digital correction of the mismatches among the elements of the digital-to-analog converter (DAC) used in the feedback loop of multi-bit sigma–delta (ΣΔ) modulators. The proposed method, with an extremely limited amount of additional circuitry, allows the mismatches among the elements of the DAC to be accurately measured and corrected in the digital domain, thus improving the linearity performance of the modulator. A switched capacitor (SC) 4-bit second-order ΣΔ modulator has been implemented to validate the proposed solution. The experimental results confirm that the proposed technique allows us to achieve an improvement in the spurious-free dynamic range of the ΣΔ modulator as large as 26 dB. [ABSTRACT FROM AUTHOR]

Abstract  A single-inductor dual-output (SIDO) DC–DC buck converter is presented. The circuit uses only one (external) inductor to provide two independent output voltages ranging from 1.2 V to the power supply (2.6–5 V) with a maximum total output current of 200 mA. The proposed converter has been fabricated in a 0.35-μm p-substrate CMOS technology. Measurement results demonstrate that a peak power efficiency as high as 93.3% can be achieved. An automatic substrate bias switch technique, that cancels the body effect of the p-channel output power transistors, improves the converter power efficiency performance. [ABSTRACT FROM AUTHOR]

Abstract  In this paper, we propose a transmitter baseband architecture for the present and up-coming WLAN applications (IEEE 802.11a/g, 802.11n, 802.16), based on a 600-MS/s current-steering DAC with a passive output load, to perform the baseband signal processing, avoiding the use of any active analog reconstruction filter. The DAC, fabricated in a 0.13-μm CMOS technology, consumes 2.4 mW from a 1.2-V single supply voltage. The DAC exhibits 68 dB of SFDR at full-scale for a 12-MHz input signal frequency and 9.7 bits of full-scale dynamic range in the bandwith from dc to 10 MHz. [ABSTRACT FROM AUTHOR]

Circulating endothelial cells (CECs) are associated with neoangiogenesis in various malignant disorders. Using flow cytometry, we studied CECs in 128 patients with myelodysplastic syndrome (MDS). MDS patients had higher CEC levels than controls (P<0.001), and an inverse relationship was found between CECs and international prognostic scoring system risk (r=−0.55, P<0.001). There was a positive correlation between marrow microvessel density and CECs, low-risk patients showing the strongest association (r=0.62, P<0.001). We calculated a progenitor-to-mature CEC ratio, which was higher in MDS patients than in healthy subjects (P<0.001), the highest values were found at diagnosis. CECs assessed by flow cytometry positively correlated with the ability to produce endothelial colony-forming cells in vitro (ECFCs; r=0.57, P=0.021), which was significantly higher in MDS patients than in controls (P=0.011). Fluorescence in situ hybridization analysis showed that a variable proportion of CECs (from 40 to 84%) carried the same chromosomal aberration as the neoplastic clone, while endothelial cells isolated from in vitro assays were negative. This study suggests that CECs reflect the abnormal angiogenesis found in MDS, especially in the early stages of the disease. The increased number of functional endothelial progenitor cells in MDS strengthens the rationale for therapeutic interventions aimed at restoring a normal interaction between hematopoietic progenitors and marrow microenvironment.Leukemia (2008) 22, 530–537; doi:10.1038/sj.leu.2405069; published online 20 December 2007 [ABSTRACT FROM AUTHOR]

Yoga induces long-term changes in respiratory function and control. We tested whether it represents a successful strategy for high-altitude adaptation. We compared ventilatory, cardiovascular and hematological parameters in: 12 Caucasian yoga trainees and 12 control sea-level residents, at baseline and after 2-week exposure to high altitude (Pyramid Laboratory, Nepal, 5,050 m), 38 active lifestyle high-altitude natives (Sherpas) and 13 contemplative lifestyle high-altitude natives with practice of yoga-like respiratory exercises (Buddhist monks) studied at 5,050 m. At baseline, hypoxic ventilatory response (HVR), red blood cell count and hematocrit were lower in Caucasian yoga trainees than in controls. After 14 days at altitude, yoga trainees showed similar oxygen saturation, blood pressure, RR interval compared to controls, but lower HVR (−0.44 ± 0.08 vs. −0.98 ± 0.21 l/min/m/%SaO2, P < 0.05), minute ventilation (8.3 ± 0.9 vs. 10.8 ± 1.6 l/min, P < 0.05), breathing rate (indicating higher ventilatory efficiency), and lower red blood cell count, hemoglobin, hematocrit, albumin, erythropoietin and soluble transferrin receptors. Hypoxic ventilatory response in monks was lower than in Sherpas (−0.23 ± 0.05 vs. −0.63 ± 0.09 l/min/m/%SaO2, P < 0.05); values were similar to baseline data of yoga trainees and Caucasian controls, respectively. Red blood cell count and hematocrit were lower in monks as compared to Sherpas. In conclusion, Caucasian subjects practicing yoga maintain a satisfactory oxygen transport at high altitude, with minimal increase in ventilation and with reduced hematological changes, resembling Himalayan natives. Respiratory adaptations induced by the practice of yoga may represent an efficient strategy to cope with altitude-induced hypoxia. [ABSTRACT FROM AUTHOR]

Erythroid dysplasia is the pathologic hallmark of myelodysplastic syndromes (MDS). To develop a quantitative flow-cytometry approach to its evaluation, we analyzed the expression of CD71, CD105, cytosolic H-ferritin (HF), cytosolic L-ferritin (LF) and mitochondrial ferritin (MtF) in erythroblasts from 104 MDS patients, 69 pathologic control patients and 19 healthy subjects. Six-parameter, 4-color flow cytometry was employed, and data were expressed as mean fluorescence intensity. Compared with pathologic and healthy controls, MDS patients had higher expression of HF (P<0.001) and CD105 (P<0.001), and lower expression of CD71 (P<0.001). MtF was specifically detected in MDS with ringed sideroblasts, and there was a close relationship between its expression and Prussian blue staining (r=0.89, P<0.001). In vitro cultures of myelodysplastic hematopoietic progenitors showed that both HF and MtF were expressed at a very early stage of erythroid differentiation, and that MtF expression is specifically related to mitochondrial iron loading. A classification function based on expression levels of HF, CD71 and CD105 allowed us to correctly classify >95% of MDS patients. This flow-cytometry approach provides an accurate quantitative evaluation of erythroid dysplasia and allows a reliable diagnosis of sideroblastic anemia, and may therefore be a useful tool in the work-up of patients with MDS.Leukemia (2006) 20, 549–555. doi:10.1038/sj.leu.2404142; published online 23 February 2006 [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a flow cytometric approach to the evaluation of marrow dysplasia in myelodysplastic syndromes (MDS). We first studied a cohort of 103 MDS patients as well as 46 pathological and healthy controls. Flow cytometry data were expressed as percentage of positive cells. Analysis of erythroid cells showed higher proportions of immature cells (P<0.001) and decreased levels of CD71 expression on nucleated red cells (P=0.02) in MDS. Analysis of myeloid cells showed lower proportions of CD10+and higher proportions of CD56+granulocytes (P<0.001), and increased ratios of immature to mature cells (P=0.007). Since no single immunophenotype could accurately differentiate MDS from other conditions, we used discriminant analysis for generating erythroid and myeloid classification functions using combinations of immunophenotypic parameters. These functions were prospectively validated in a testing cohort of 69 MDS patients and 46 pathological controls. A diagnosis of MDS was obtained in 60/69 cases (87%). No false-positive results were noticed among controls. Significant correlations between values of these functions and both degree of morphological dysplasia and the International Prognostic Scoring System were found. These findings indicate that flow cytometry evaluation of marrow dysplasia is feasible and may be useful in the work-up of individual MDS patients.Leukemia (2005) 19, 776-783. doi:10.1038/sj.leu.2403680 Published online 24 March 2005 [ABSTRACT FROM AUTHOR]

Summary:The aim of this study was to investigate thiotepa (TT) and fludarabine (Fluda) as a preparative regimen for allogeneic peripheral stem cell transplant in patients not eligible for a standard myeloablative regimen due to comorbidities and/or poor performance status. TT was given at a dose of 10?mg/kg over 2 days and Fluda at 125?mg/m2 over 5 days. In all, 21 patients (14 male, seven female; 10 acute leukaemia, eight myelodysplastic syndrome, two non-Hodgkin's lymphoma, one Hodgkin's disease) were treated. The median age was 51 years (range 30-55 years). All patients achieved full donor-type chimaerism. Adverse events included mild nausea and vomiting in two patients and a slight increase of serum amylase in three. A total of 13 patients received RBC transfusions (median 6?U, range 1-23), and all received platelets (median 4?U, range 1-27). Four patients died of nonrelapse causes and five of relapse. The 1-year probabilities of transplant-related mortality and relapse were 19 and 29%, respectively. In total, 12 patients remain in complete remission (median follow-up: 786 days). The 3-year overall survival probability was 58%. We conclude that this regimen is feasible and well tolerated.Bone Marrow Transplantation (2004) 34, 1039-1045. doi:10.1038/sj.bmt.1704717 Published online 1 November 2004 [ABSTRACT FROM AUTHOR]

Among rare inherited deficiencies of coagulation factors, congenital afibrinogenaemia is characterised by the lack of fibrinogen in plasma. In the last few years, several genetic defects underlying afibrinogenaemia (mostly point mutations) have been described in the fibrinogen gene cluster. In this study, the molecular basis responsible for afibrinogenaemia in a Thai proband was defined. Point mutation screening was accomplished by directly sequencing the three fibrinogen genes. The impossibility to amplify fibrinogen Aa-chain gene (FGA) exons 5 and 6 suggested the presence of a homozygous deletion. A specific long-range PCR assay enabled the identification of a novel 15-kb deletion, representing the largest afibrinogenaemia-causing deletion described so far. Direct sequencing of the deletion junction allowed mapping of the breakpoints in FGA intron 4 and in the intergenic region between Aa- and Bß-chain genes. Since the mutation was inherited only from the mother and nonpaternity was ruled out, a maternal uniparental disomy (UPD) was hypothesised. UPD test, carried out with markers covering the whole chromosome 4, revealed that maternal isodisomy was responsible for homozygosity of the 15-kb deletion in the proband. The apparently normal phenotype of the proband, except for afibrinogenaemia, suggests that UPD for chromosome 4 is clinically silent. This represents the first case of a documented complete isodisomy of chromosome 4 causing the phenotypic expression of a recessive disorder. In silico analyses of the regions surrounding the breakpoints suggested that the 15-kb deletion might have originated from an inappropriate repair of a double-strand break by the nonhomologous end joining mechanism.European Journal of Human Genetics (2004) 12, 891-898. doi:10.1038/sj.ejhg.5201207 Published online 22 September 2004 [ABSTRACT FROM AUTHOR]

Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family (CHRNA4 and CHRNB2, coding for the α4 and β2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, ADNFLE is genetically heterogeneous and mutations in CHRNA4 and CHRNB2 account for only a minority of ADNFLE cases. Additional nAChR subunits expressed in the brain are candidates for this epilepsy. The involvement of all genes coding for brain-expressed nAChR subunits, with known chromosome localization (CHRNB2, 1q21; CHRNA2, 8p21; CHRNA6, CHRNB3, 8p11.2; CHRNA7, 15q14; CHRNA5/A3/B4, 15q24 and CHRNA4, 20q13.2) was investigated in four unrelated ADNFLE Italian families for at least three generations. Families were selected on the basis of anamnestic and videopolysomnographic analyses. Individuals were typed for polymorphic markers located in the above mentioned chromosome regions. Linkage and mutation analyses were performed. In none of the families was linkage between ADNFLE and the analysed chromosome regions detected. These findings support the hypothesis that genes different from those coding for α2-7 and β2-4 neuronal nAChR subunits could be responsible for ADNFLE. [ABSTRACT FROM AUTHOR]

Genes coding for the α5, α3, and β4 subunits (CHRNA5, CHRNA3, and CHRNB4) of the neuronal nicotinic acetylcholine receptors (nAChRs) are clustered on chromosome 15q24. Linkage of this chromosomal region to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), an idiopathic partial epilepsy, was reported in one family. Moreover, mutations in other neuronal nAChR subunit genes coding for the α4 (CHRNA4) and the β2 (CHRNB2) subunits were associated with ADNFLE. Apart from the exon-intron structure of CHRNA3, the geno-mic organization of this gene cluster was unknown, making comprehensive mutational analyses impossible. The genomic structure of CHRNA5 and CHRNB4 is here reported. Moreover, two hitherto unknown introns were identified within the 3′ untranslated region of CHRNA3, causing a partial tail-to-tail overlap with CHRNA5. Four novel intragenic polymorphisms were identified and characterized in the cluster. [ABSTRACT FROM AUTHOR]

Standard conditioning for allogeneic bone marrow transplantation induces high transplant-related mortality (TRM) in patients with a poor performance status. Less intensive regimens have been tested to reduce the TRM; our purpose was to evaluate the feasibility and tolerability of a new combination: thiotepa and fludarabine (TT-FLUDA). Six patients received 5 mg thiotepa/kg daily from day -8 to -7 and 25 mg fludarabine/m2 daily from day -6 to -2 followed by an allogeneic peripheral blood progenitor cell infusion; three of these patients with signs of overt leukemia received 18 mg idarubicin/m2 i.v. at day -12. Graft-versus-host-disease (GVHD) prophylaxis was performed i.v. with 1 mg cyclosporine A/kg per day from day -5 to the day of marrow engraftment, then 6 mg/kg per day orally up to day +100, and 10 mg methotrexate/m2 at day +1, and 8 mg/m2 at days +3, +6, and +11. Chimerism was studied with fluorescent in situ hybridization for sex chromosomes (XY-FISH) and minisatellite polymerase chain reaction (PCR) at days +30, +100, +180, and +360. Engraftment was achieved in all cases with complete donor chimerism in all but one patient who had refractory acute leukemia. No major toxicity was noticed; only one patient died at day +51 of acute GVHD because of early cyclosporine A discontinuation. One patient with refractory non-Hodgkin's lymphoma (NHL) had a testicular relapse at day +180. Three patients (one with mantle cell lymphoma, two with acute myeloid leukemia) are still in continuous complete remission (CR) with complete donor chimerism at days +180, +210, and +450, respectively. TT-FLUDA seems to be well tolerated, allowing engraftment and stable donor chimerism in patients who are poor candidates for conventional conditioning regimens. [ABSTRACT FROM AUTHOR]

A second order switched capacitor sigma-delta modulator operating at a supplyvoltage of 1 V is presented. This low supply voltage restricts the gate overdrivevoltage available for switching transistors. The design relies on the elimination ofcritical switches by using a modified switched op amp for the integrator and novelswitched half-supply and reference voltage generators. The design has been carried outin a fully differential configuration in order to minimize errors arising from chargeinjection and clock-feedthrough effects. The converter has been implemented using aconventional 0.8 μm double-poly double-metal CMOS process, having a nominalthreshold voltage of 0.75 V. Test results, showing more than 9 bits of resolutionwith an oversampling ratio of 64, are also presented. [ABSTRACT FROM AUTHOR]

This study was performed to investigate the influence of breathing control on the autonomic cardiac regulation at high altitude in adapted and non-adapted awake subjects. We recorded electrocardiogram and pulse oximetry in 14 short-term acclimatized lowlanders and 14 Himalayan Sherpas during resting conditions at an altitude of 5,050 m. Spectrum analysis was performed on synchronized 15 min periods of R-R intervals and the oxygen saturation of arterial blood (SaO2). Despite mean SaO2 being similar in lowlanders and Himalayan Sherpas [78.5 (SD 7.0)% compared to 79.4 (SD5.8)%, respectively], fluctuations in SaO2 were significantly increased in lowlanders compared to Sherpas, thus indicating an unstable regulation of respiration control in lowlanders. Regression analysis demonstrated a significant relationship between spectrum power of SaO2 and the relative power of R-R intervals in the frequency band between 0.01 and 0.08 Hz in lowlanders, but not in Sherpas. Our results demonstrate differences in respiratory and autonomic cardiac control between non-adapted lowlanders and Himalayan high-altitude residents and indicate that unstable breathing control during chronic hypobaric hypoxia is significantly correlated with the autonomic cardiocirculatory regulation. [ABSTRACT FROM AUTHOR]

Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin’s disease, 22 non-Hodgkin’s lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52–289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P < 0.001) and BCV regimen (P < 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309–313. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P < 0.001). bradyarrhythmia was noticed in two of 75 pbpc patients and in 14 of 51 bm patients (P < 0.001). in the former group one patient had heart block; he died of renal failure 10 days later. bradycardia and hemoglobinuria were more common in patients receiving bm where a higher concentration of red cells was present (P < 0.001). since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed bm. the strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content. [ABSTRACT FROM AUTHOR]

Ten patients with acute leukemia (AL) in early relapse after allo-BMT were treated with a modified MEC (mitoxantrone, etoposide and Ara-C) regimen followed by donor PBPC collected after mobilization with G-CSF. Seven patients achieved CR or had normal hemopoietic reconstitution: two had an early relapse at days +53 and +48, two patients died from acute GVHD at days +31 and +96, one died of interstitial pneumonia at day +55, and two patients experienced long-term survival. One patient with refractory disease and nodal involvement who did not respond to the first BMT had overt expansion of the leukemia at day +36; one patient with Ph+ ALL and one with ANLL evolving from MDS, both with skin involvement, had blast cells in peripheral blood at day +27 and +26, respectively. Transient cytopenia occurred in all patients; a normal granulocyte and platelet count was achieved within 3 weeks in all patients but one; acute GVHD occurred in six patients, and four had chronic GVHD. This approach is feasible in patients in early relapse after allo-BMT. It assists prompt re-establishment of normal donor hematopoiesis avoiding the prolonged cytopenia observed after donor lymphocyte infusion in AL patients relapsed after allo-BMT. [ABSTRACT FROM AUTHOR]