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Introduction: Prenatal diagnosis of fetal chromosomal aneuploidies has traditionally relied on cytogenetics. In recent times QF-PCR, to detect the common aneuploidies has been reported. In view of the paucity of Indian experience regarding QF-PCR, we present prospective data from our centre. Materials and Methods: 572 AF samples were collected from Indian women with singleton pregnancy between 16-20 weeks gestation after counselling. The samples were collected over one year and followed up till delivery. AF was sent for QF-PCR for chromosomes 13, 18, 21 and 23. Results: There was no procedure related miscarriage, or IUFD. There were seventeen trisomy 21, two 47XXX and one 47XXY. All pregnancies with fetal aneuploidies underwent termination. All 552/572 women with normal report were followed up and none had IUFD or clinical features of trisomy 21 after term or preterm births. Discussion: The current study stresses the clinical importance of shorter TAT advantage and the slight cost advantage of QF-PCR over FISH. The current study shows QF-PCR is a satisfactory method for diagnosing chromosomal aneuploidy from amniotic fluid in screen positive population, has advantages and might be preferred more in near future in place of FISH, especially in the scenario of increasing awareness of biochemical screening for chromosomal aneuploidies in India. However, more such studies with increased numbers and in multiple pregnancies are required. The current study is ongoing and hopefully we will be able to present such data soon. Keywords: QF-PCR, Aneuploidy, Prenatal diagnosis, Segmental duplication.

HOMG1 (hypomagnesemia 1, intestinal) or hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder of magnesium metabolism, characterized by impaired magnesium absorption. This disorder may mimic other conditions presenting with neonatal seizures. Here, we report an infant diagnosed to have hypomagnesemia with secondary hypocalcemia due to novel variants in TRPM6 gene.

Genetic diagnosis depends on having available tissue to test. This can be important for many reasons, such as related to familial diagnosis in the case of another pregnancy. When blood or DNA samples from affected family members are not available, accurate prenatal diagnosis may be much more difficult and hence additional effort may be needed to obtain a genetic diagnosis in such families. We report two families with suspected monogenic disorders where attempts were made to establish the genetic etiology in deceased offspring using dried umbilical cord remnants which had been preserved by the family.

Introduction: Brachytherapy is a preferred choice of radiotherapy in the treatment of sensitive tissues cancer like intestine and gonad. The treatment is expensive because of the frequent replacement of radionuclide sources. A better understanding of cell killing and the cellular responses at different dose rates, might aid in tumor cell killing with fewer doses thereby enhancing a better prognosis.

This paper is a review of the latest advances in ESD protection for analog and digital technologies. The paper will introduce the latest ESD protection devices for FinFET and FDSOI technologies such as Field effect diode, Field effect resistor. We will introduce an example of innovation for analog ESD protection focusing on system level automotive applications namely Mutual ballasting layout technique.

The pulse width dependency of the failure current for NPN structures in a 0.18-μm BiCMOS technology is studied using measurements and TCAD simulation. The desired “Wunsch-Bell” behavior is not observed due to formation of current filaments in this device; however, the failure current for long pulse widths can be increased by layout changes.

The objective of this paper is to develop a Multi Agent System (MAS) for the integrated energy management of a solar micro-grid. We consider a grid connected solar micro-grid which contains two solar Photo Voltaic (PV) systems each contains a local consumer, a solar PV system and a battery. First we calculate the load patterns and solar power generated in the two solar units. Then we use Multi Agent System based distributed energy management of solar micro-grid with smart grid frame work. We develop a simulation model in Java Agent Development Environment (JADE) for dynamic model which considers the intermittent nature of solar power, randomness of load, dynamic pricing of grid and variation of critical loads and choose the best possible action every hour to stabilize and optimize the solar micro-grid. Further more, MAS increases the operational efficiency and thereby maximizes the power production of solar micro-grid and minimizes the operational cost. Thus MAS in micro-grid leads to economic and environmental optimization. Simulated operation of solar generators and loads are studied by performing simulations under different agent objectives. Outcome of the simulation studies demonstrates the effectiveness of proposed MAS in distributed energy management of micro-grid.

Biallelic mutations in the gene encoding HCLS-associated protein X-1 (HAX1) cause autosomal recessive severe congenital neutropenia (SCN). Some of these patients have neurological abnormalities including developmental delay, cognitive impairment, and/or epilepsy. Recent genotype-phenotype studies have shown that mutations in HAX1 affecting transcripts A (NM_006118.3) and B (NM_001018837.1) cause the phenotype of SCN with neurological impairment, while mutations affecting isoform A but not B lead to SCN without neurological aberrations. In this study, we identified a consanguineous family with two patients suffering from SCN and neurological disease caused by a novel, homozygous genomic deletion including exons 4-7 of the HAX1 gene. Quantitative MRI analyses showed generalized alterations in cerebral proton density in both of the patients, as well as in an additional unrelated patient with another HAX1 mutation (Arg86X) known to be associated with neurological manifestations. This study provides first in vivo evidence of aberrant neuroimaging findings associated with HAX1 deficiency in SCN patients.

We investigate, for the first time, the potential for SEE mitigation of a newly-developed device architecture in a 3rd generation high-speed SiGe platform. This new device architecture is termed the ?inverse-mode cascode SiGe HBT? and is comprised of two standard devices sharing a buried subcollector and operated in a cascode configuration. Verification of the TID immunity is demonstrated using 10 keV X-rays, while an investigation of the SEE susceptibility is performed using a 36 MeV 16O ion. IBICC results show strong sensitivities to device bias with only marginal improvement when compared to a standard device; however, by providing a conductive path from the buried subcollector (C-Tap) to a voltage potential, almost all collected charge is induced on the C-Tap terminal instead of the collector terminal. These results are confirmed using full 3-D TCAD simulations which also provides insight into the physics of this new RHBD device architecture. The implications of biasing the C-Tap terminal in a circuit context are also addressed.

We investigate a novel implementation of junction isolation to harden a 200 GHz SiGe:C HBT technology without deep trench isolation against single event effects. The inclusion of isolation is shown to have no effect on the dc or ac performance of the nominal device, and likewise does not reduce the HBTs inherent tolerance to TID radiation exposure on the order of a Mrad. A 69% reduction in total integrated charge collection across a slice through the center of the device was achieved. In addition, a 26% reduction in collected charge is reported for strikes to the center of the emitter. 3-D NanoTCAD simulations are performed on RHBD and control device models yielding a good match to measured results for strikes from the emitter center to 8 ?m away. This result represents one of the most effective transistor layout-level RHBD approaches demonstrated to date in SiGe.

Background The main features of severe congenital neutropenia are the onset of severe bacterial infections early in life, a paucity of mature neutrophils, and an increased risk of leukemia. In many patients, the genetic causes of severe congenital neutropenia are unknown. Methods We performed genomewide genotyping and linkage analysis on two consanguineous pedigrees with a total of five children affected with severe congenital neutropenia. Candidate genes from the linkage interval were sequenced. Functional assays and reconstitution experiments were carried out. Results All index patients were susceptible to bacterial infections and had very few mature neutrophils in the bone marrow; structural heart defects, urogenital abnormalities, and venous angiectasia on the trunk and extremities were additional features. Linkage analysis of the two index families yielded a combined multipoint lod score of 5.74 on a linkage interval on chromosome 17q21. Sequencing of G6PC3, the candidate gene encoding glucose-6-phos...

The radiation tolerance of strained Si/SiGe n-MODFETs is investigated, using 10 keV X-rays, 63 MeV high energy protons, and 4 MeV low energy protons. The effects of radiation exposure on two major device design parameters (LSD and LG) in T-gate Si/SiGe n-MODFETs devices are examined. A strong dependence on source-drain spacing is observed for both the DC and RF characteristics. A drift-diffusion TCAD framework is used for 2-D device simulations. We believe that the low energy protons damage the SiGe/strained-Si/SiGe lattice, leading to partial strain relaxation. The conduction band-offset (CBO) of the strained SiGe/Si heterojunction is lowered leading to higher gate current leakage. The presence of radiation-induced bulk traps in the unrelaxed SiGe layers on the device behavior is also investigated.

The impact of 63.3 MeV proton and 10 keV X-ray irradiation on the DC and AC performance of complementary SiGe HBTs on thick-film SOI is investigated. Proton and X-ray induced changes in the forward and inverse Gummel characteristics, the output characteristics, and avalanche multiplication are reported for both npn and pnp SiGe HBTs, at both room temperature (300 K) and at cryogenic temperatures (down to 30 K). Comparison of room temperature and cryogenic data suggests interface trap formation at two distinct physical locations in the transistors. Experimental data and calibrated TCAD simulations are used to compare the radiation response of both thick-film SOI devices and thin-film SOI SiGe HBTs.

Using mixed-mode annealing to help evaluate the responses of modern bipolar transistors, we compare the damage processes associated with X-ray irradiation-induced and hot carrier-induced damage in SiGe HBTs. Stress and radiation measurements indicate that the by-products of both X-ray irradiation-induced and hot carrier-induced trap reactions are identical. We use calculations to better understand the operative damage mechanisms, and find that a hydrogen reaction-diffusion model can predict the observed characteristics of our measurements. Calculations indicate that the transport of hydrogen molecules inside the emitter-base oxides determines the trap generation and recovery processes.

We present a new ldquocurrent-sweeprdquo stress methodology for quantitatively assessing the mixed-mode reliability (simultaneous application of high current and high voltage) of advanced silicon-germanium (SiGe) HBTs. This electrical-stress methodology allows one to quickly obtain the complete ldquodamage spectrumrdquo of a given device from a particular technology platform, enabling better understanding of the complex voltage, current, and temperature interdependence associated with electrical stress and burn-in of advanced transistors. We consistently observe three distinct regions of mixed-mode damage in SiGe HBTs and find that hot-carrier-induced damage can be introduced into SiGe HBTs under surprisingly modest mixed-mode-stress conditions. For more aggressively scaled technology generations, a larger percentage of hot carriers generated in the collector-base junction are able to travel to and hence damage the emitter-base (EB) spacer, leading to enhanced forward-mode base-current leakage under stress. A new self-heating-induced mixed-mode-annealing effect is observed for the first time under specific high-voltage- and high-current-stress conditions, and a new damage mechanism is observed under very high-voltage and high-current conditions. Finally, as an example of the utility of our stress methodology, we quantify the composite mixed-mode damage spectrum of a commercial third-generation (200 GHz) SiGe HBT. We find that if devices are stressed with either voltage or current alone during burn-in, they can easily withstand extreme overstress conditions. Unfortunately, devices can easily be damaged when stressed with a combination of stress voltage and current, and this has significant implications for the lifetime prediction under realistic mixed-signal-circuit operating conditions.

The inverse-mode operational regime of silicon germanium (SiGe) heterojunction bipolar transistors (HBTs) has to date been largely ignored and is typically dismissed as a viable possibility for circuit applications due to the general perception of its limited dc and ac performance capabilities. In this paper, the inverse-mode performance of four distinct generations of SiGe HBTs is investigated and is found to improve impressively with generational scaling. The physics behind these scaling-induced improvements is examined in detail using a combination of measurements and calibrated simulations. A novel lateral dependence of the inverse-mode base current is identified and is shown to potentially present new opportunities for even larger improvements in inverse-mode performance in SiGe HBTs. A record peak fT in inverse mode of 25 GHz is reported for a prototype fourth-generation device

The off-state drain current leakage characteristics of 130 nm CMOS technology are investigated using x-ray irradiation and operating temperature as variables. Radiation-induced interface traps in the gate oxide to gate-drain overlap region strongly enhance the off-state leakage as a function of gate bias. Due to the thin gate oxide in these 130 nm devices, we find that drain-edge direct tunneling is more plausible than conventional gate-induced-drain-leakage in explaining the observed increase in drain leakage. Radiation-induced traps in the shallow trench isolation oxide create parasitic channels in the p-well and produce another source of off-state drain leakage with increasing total dose. The drain current increase from both the gate overlap region and the shallow trench edge are enhanced with increasing total dose and suppressed by cooling

To identify the relative incidence and profile of adverse drug reaction (ADR) to various topical ocular hypotensives in a hospital setting.All the patients presenting in outpatients clinic and accident and emergency with an ADR to topical hypotensive agent from August 2000 to January 2001 were included in the study. Details regarding the type date of commencing the treatment, the date of developing ADR, time to resolution of the ADR were noted.Over the period of 6 months, 66 patients presented with 73 ADRs. Brimonidine was the most frequent offending agent. In total, 23 (34.8%) presented with ADR after being commenced on treatment for more than 12 months. In all, 16 (24%) patients had IOP21 on presentation, eight (12%) patients underwent filtration surgery following the development of ADR.Adverse drug reaction to ocular hypotensive agents is not uncommon and can have a major impact on glaucoma management. Delayed presentation and association with raised intraocular pressure presentation emphasise the need for effective patient education to encourage prompt reporting of ADR.

DEMOS devices have poor ESD robustness due to kirk effect induced snapback. Isolated DEMOS devices, in addition to the kirk effect induced second snapback, are also vulnerable to failures induced by the parasitic NPN to isolation. In addition, we demonstrate here, that some DEMOS devices show intrinsically non-scalable breakdown current (IT1) behavior due to insufficient body resistance. We then demonstrate techniques to restore IT1 scalability in these devices. We finally demonstrate the effectiveness of using selectively SBLKed drain fingers to enable self protection in small DEMOS devices.

Object. Anorectal malformations are known to be associated with neurological deficits, which may contribute to the disability suffered by patients with these malformations. This study was undertaken to determine the incidence and pattern of sacral abnormalities in children with anorectal malformations, the incidence and nature of the neurological deficits, and the incidence and nature of operable intraspinal abnormalities in patients with this condition.Methods. Neurological evaluation was performed in 81 children with anorectal malformations. Plain x-ray films were obtained to identify the presence of sacral abnormalities. The patients with neurological deficits were evaluated for the presence of operable intraspinal anomalies, and when such anomalies were identified, correction of the same was undertaken. In 21% of these children radiographic evidence of sacral abnormalities was shown. Fifteen percent of patients harbored neurological deficits, and 10% harbored operable intraspinal anomalies. In addition, one patient had split notochord syndrome. Patients with operable intraspinal anomalies underwent surgical correction, with resultant neurological improvement.Conclusions. Bone abnormalities of the sacrum, neurological deficits, and operable intraspinal lesions are not uncommon in children with anorectal malformations. Because the neurological deficits can contribute to the disability suffered by these individuals, we recommend routine screening of patients with anorectal malformations and neurological deficits and/or sacral abnormalities for the early identification and treatment of potentially correctable intraspinal lesions.

Inverse-mode (collector-up) operation is proposed as a solution to the single-event-upset susceptibility observed in commercially available bulk silicon-germanium heterojunction bipolar transistors. Inverse-mode performance optimization techniques, which require no process changes or added lithographic masks, are demonstrated, yielding inverse-mode transistor performance capable of supporting gigabit-per-second digital logic needed in space-based communication systems.

A 37-year-old man presented to the emergency department with a visor impacted in the left orbit after a motorbike accident. His initial injury appeared to be limited to the orbit. Because the bleeding appeared disproportionate to the orbital injury, an intracranial injury was suspected. Subsequently, on hemicraniotomy, the tip of the visor was found at the bifurcation of the internal carotid artery. The avulsed upper eyelid was found under the frontal lobe. The patient underwent the clipping of internal carotid artery and middle and anterior cerebral artery with replantation of the upper eyelid. Neurologic damage was limited to loss of vision, right foot drop, and bowel and bladder incontinence. This case of penetrating orbital trauma demonstrates that the absence of focal neurologic deficit and radiologic signs suggestive of intracranial injury may not rule out life-threatening intracranial injury.

We report a new challenge to IEC protection of high-speed devices caused by current filamentation due to voltage-overshoot effects in forward-biased diodes. While well understood in reverse-biased junctions, filamentation has never been reported in forward-biased junctions, which are often used in high-speed designs such as USB3 and HDMI. An analytical model is presented to estimate the voltage overshoot as a function of rise-time and bias conditions to predict the trade-offs inherent in low-capacitance ESD diodes.

The aims were to compare a novel conjunctival mould used to assist the delivery of intravitreal drugs to a conventional technique with respect to patient, surgeon and cost benefit.A prospective review of 200 intravitreal injections was undertaken, 100 using a 'conventional' freehand technique (group 1) and 100 using a novel conjunctival mould (group 2). Intraoperative visual analogue scale (VAS) pain scores, patient preference, surgeon perception of the ease of insertion of the conjunctival mould were recorded as well as a cost comparison.VAS pain score in the conventional group was 2.58 compared to 1.38 in the conjunctival mould group (p0.01). The surgeon reported the insertion of the conjunctival mould as easy in 89 cases, moderate in 10 cases, and difficult in one case. The cost saving with a conjunctival mould pack compared to a conventional pack was £7.70; an annual saving of £19,250 for the trust.The reduction in the VAS pain score with the conjunctival mould was statistically significant (p0.01). The surgeons found that the device, which was easy to insert, offered excellent globe stability and a safe, reproducible entry site and angle of needle insertion.

While the matching properties of MOSFETs have been extensively studied, the impact of temperature on matching remains poorly understood. Recent efforts at understanding the effects of temperature on matching [1, 2] report improved matching at higher temperatures. Here, we examine the impact of cryogenic temperatures on the matching performance of a 90 nm bulk CMOS technology. Cryogenic operation improves many of the MOSFET performance metrics and cryogenic MOSFETs have been shown to achieve lower broadband noise at cryogenic temperatures [3], opening up the possibility of their application in radio astronomy that require very low noise. As suggested in [1], however, device matching could potentially degrade with cooling. In addition to the enhancement of columbic scattering and the associated variations due to dopant fluctuations [2], cryogenic temperatures impose additional variability due to incomplete ionization and enhanced quantum effects.

We present a novel device structure using an inverse-mode, cascoded (IMC) SiGe HBT for improved tolerance of heavy ion irradiation. The cascoded SiGe device consists of a forward-mode, common-emitter SiGe HBT cascoded with a common-base inverse-mode SiGe HBT, with the subcollector region of the two devices shared. The device was fabricated in both first and third-generation, commercially-available SiGe HBT technologies. The third-generation IMC device was measured to have over 20 dB of current gain and over 30 dB of power gain at 10 GHz. In addition, the measured total dose radiation response and simulated current transients are presented. These results demonstrate the potential use of these devices in high-speed circuits intended for operation in space or other extreme environments.

An investigation of the high-voltage/high-current mixed-mode (M-M) stress-induced damage mechanisms of pnp silicon-germanium (SiGe) heterojunction bipolar transistors (HBTs) is presented. Different accelerated stress methods, including mixed-mode stress, reverse emitter-base (EB) stress, and forward collector plus reverse EB stress, were applied to pnp SiGe HBTs from a state-of-the-art complementary-SiGe BiCMOS process technology platform. The operative damage mechanism from the M-M stress method is identified. Experimental evidence of collector current change due to the M-M stress, and the experimental proof of the type of hot carriers (electrons vs. holes) responsible for the observed M-M stress damage are presented.

We investigate, for the first time, the impact of deep trench isolation on the total ionizing dose (TID) and single event upset (SEU) tolerance of advanced SiGe HBTs. We employ a combination of 63MeV protons, 10keV X-rays, and 36MeV oxygen ion microbeam irradiation and compare a 3rd generation, high-performance (HP), deep-trench isolated, SiGe BiCMOS platform with its cost-performance (CP) variant without deeptrenches. Although the CP SiGe HBTs are shown to be more susceptible to TID damage, the elevated damage is not attributed to variations in deep trench isolation (DTI), but to spacer oxide differences. CP SiGe HBTs are surprisingly found to offer a potential built-in self-mitigation mechanism for SEU, which is a direct result of the influence of the deep trench isolation on the charge collection dynamics associated with ion strikes. Calibrated, full 3D ion strike TCAD simulations are employed to explain the results, revealing substantial enhancement of radial charge diffusion for structures implemented with little to no deep trench. Mitigation of charge collection events are found to occur for emitter-center strikes for devices with limited/eliminated DTI with the caveat of larger collection for outside-DTI ion strikes.

The degradation of SiGe HBTs due to mixed-mode DC and RF stress (simultaneous application of high current and voltage) has been modeled for the first time. State-of-the-art 200 GHz SiGe HBTs were first characterized, and then DC and RF stressed. Using TCAD simulations and calculations based upon a reaction-diffusion model, the excess base current due to stress was modeled as a function of the stress current and voltage. This physics-based stress model was then designed as a sub-circuit in Cadence, and incorporated into a cascode SiGe PA design to predict the DC and RF stress-induced excess base current. Predicted degradation is in agreement with RF stress results.

A new method for analyzing breakdown phenomena and differentiating between damage created by hot electrons and hot holes under impact ionization induced stress within SiGe HBTs is presented. Measurements demonstrate that electrons are more effective than holes for creating impact ionization induced damage under mixed-mode stress. Lucky electrons and lucky holes can be directly observed using this approach, and the induced hot carrier current yields important insight into understanding reliability of SiGe HBTs under aggressive stress.

We report, for the first time, the low frequency noise characteristics of both fully- and partially-depleted SiGe HBTs-on- SOI, both in forward and inverse modes of operation. These SiGe HBTs on thin-film SOI are then compared with bulk SiGe HBTs in order to evaluate how the fundamentally different device structure affects 1/f noise performance. In addition, the impact of substrate voltage, collector doping, and temperature on low-frequency noise is investigated.

The inverse mode operation of SiGe HBTs down to cryogenic temperatures is examined for the first time. A novel base current "flattening" is observed at low temperatures, and the physics behind this unusual current-gain enhancing behavior is examined in detail using a combination of measurement and TCAD simulations.

The effects of 63 MeV proton irradiation on 90 nm strained silicon CMOS on insulator is examined for the first time. The devices show no observable degradation in DC performance up to an equivalent total dose of 600 krad(Si). The performance of the strained pFETs is identical to unstrained pFETs and demonstrates the immunity of strain to displacement damage. There is no significant enhancement observed in back channel leakage for the maximum dose. Passive exposure to 2 Mrad(Si) using 4 MeV protons doesn't induce any significant performance degradation.

To evaluate whether the measurement of retinal nerve fiber layer (RNFL) thickness using optical coherence tomography (OCT) changes after cataract surgery.This prospective, randomized, observational, cross-sectional clinical study included 24 eyes of 24 patients who underwent phacoemusification with implant. All patients had no preexisting retinal or optic nerve pathology or other media opacities that might influence the RNFL thickness. The classification and the grading of cataract were based on the Lens Opacities Classification System III (LOCS III). All eyes were scanned immediately before cataract surgery with OCT using Fast RNFL program. All eyes had circular scans around the optic disk with a diameter of 3.4 mm. The OCT was repeated 4 weeks after surgery when the patients returned for postoperative check using the same programme.The mean preoperative RNFL thickness was 84.9 +/- 16.5. The postoperative mean RNFL thickness was 93.0 +/- 17.6. The pre-and postoperative values of the mean RNFL and signal/noise ratio (SNR) are statistically significant (P0.05).Lens opacities may affect the image quality of OCT scans used to measure RNFL thickness as indicated by preoperative low SNR. Cataract extraction results in an apparent increase of the RNFL thickness.

The analysis of the HBTs operating in the reverse active mode ("reverse mode" for short), with emitter and collector terminals swapped, has largely been ignored until recently (Khater et al., 2004). However, it is important to understand the device behavior in the reverse mode because these high-performance HBTs can operate inadvertently in the reverse mode under certain circuit-relevant conditions. Moreover, in historically important merged-transistor logic (MTL) or integrated injection logic (I2L), the npn bipolar transistors are intentionally operated in the reverse mode to achieve high gate density (Berger et al., 1972). The reverse mode operation of 0.12 times 1.0 mum2 SiGe HBTs in a 200 GHz technology (Jagannathan et al., 2002) is investigated in this work, including, for the first time, the reverse mode ac characteristics. The schematic cross-section of the 200 GHz SiGe HBTs featuring raised extrinsic base is shown

A new negative differential resistance (NDR) effect is reported for the first time in cryogenically-operated SiGe HBTs. A physical explanation based on heterojunction barrier effect (HBE) is presented, and confirmed using calibrated 2-D TCAD simulations. The ac consequences of this NDR effect and the impact of technology scaling on the phenomenon are also addressed.

The hydrodynainic pressures due to random waves around a pipeline near a rigid bed of slope 1:10 have been measured. The tests were performed for pipelines normal and parallel to the wave direction. These tests were carried out for three gap ratios of the pipeline from the sloping bed. The pressures were resolved in the horizontal and vertical directions and integrated for the force time history in the respective directions. The effects of relative clearance of pipe from the bed and wave steepness on the probability distribution of the forces on the pipeline are reported. The average statistical force ratios as a function of scattering parameter and the variation of the force coefficients as a function of Keulegan-Carpenter number are also presented. The details of the model setup, experimental procedure, analysis of results and discussion are reported in this paper.

Abstract 2170 Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency causes congenital neutropenia in conjunction with various cardiac or urogenital developmental aberrations. We here describe a consanguineous pedigree of maroccan descent. Four patients presented with early-onset inflammatory bowel diseases associated with severe congenital neutropenia. Two children died in early childhood, two patients (19-years old female, 17-years old male) are alive with signs of recurrent infections (mouth ulcera, otitis, upper and lower respiratory tract infections) and refractory Crohn's like enterocolitis. Mutations in the Glucose-6-phosphate translocase (SLC37A4) gene were excluded. In an attempt to discover the underlying molecular pathophysiology, we performed SNP-based homozygosity mapping followed by in depth next-generation exome sequencing. We identified two genes with potentially deleterious homozygous sequence variations: P2RY11 (exon 13; c.C2160G, p.Y720X), encoding a protein with antiapoptotic function, and G6PC3 (exon 2; c.C323T, p.P108L). The G6PC3 mutation segregates with the disease phenotype, whereas the P2RY11 variant was also found in a healthy sibling. Functional experiments in patient's neutrophil granulocytes showed an accelerated oxidative burst capacity (OxyBurst Assay, Phagoburst Assay). Furthermore, G6PC3-deficient individuals showed a rapid dissipation of the mitochondrial membrane potential upon treatment with valinomycin, whereas the inner mitochondrial membrane potential in neutrophils from healthy individuals was maintained. We observed increased apoptosis in G6PC3-deficient neutrophils upon exposure to staurosporine. Interestingly, increased apoptosis was also seen in granulocytes from the healthy sibling with the P2RY11 sequence variant, suggesting that P2RY11 deficiency may aggravate the phenotype of G6PC3 deficiency. In summary, our study indicates that the clinical spectrum of G6PC3 deficiency may be more diverse than previously appreciated and that P2RY11 may have a modifying effect on G6PC3-deficient neutrophil granulocytes. J.D. and D. K. contributed equally to this work and should be considered aequo loco. Disclosures: Schäffer: National Institues of Health: Employment; Intramural Research Program of the National Institues of Health, NLM: Research Funding.

We here describe a previously unrecognized nosological entity in 12 patients from 8 unrelated pedigrees. All patients presented with severe congenital neutropenia and severe invasive bacterial infections. In addition, patients had a variety of additional syndromic features such as congenital heart disease (8/12), urogenital malformations (5/12), inner ear hearing loss (2/12), and myopathy (1/12). Furthermore, most patients (10/12) showed increased visibility/angiectasia of subcutaneous veins. The bone marrow smear was characterized by a typical “maturation arrest” due to premature apoptosis of mature neutrophils. Similar to Kostmann’s disease secondary to mutations in HAX1, myeloid cells from patients with this novel syndrome showed increased susceptibility to apoptosis. Myeloid progenitor cells revealed an abnormally enlarged rough endoplasmic reticulum and increased endoplasmic reticulum stress evidenced by increased expression of BiP. A genome-wide linkage study, performed in two consanguineous pedigrees, gave statistical evidene of a linkage interval on chromosome 17q21 (LOD score 5.74). We identified homozygous missense mutations in G6PC3, a ubiquitously expressed paralog of glucose-6-phosphatase. Biochemical studies confirmed deficient enzymatic activity. Using retroviral G6PC3-gene transfer into primary hematopoietic stem cells and in vitro differentiation into myeloid cells, the phenotype of increased susceptibility to apoptosis could be reverted. Eight distinct biallelic mutations were found, including missense and nonsense mutations. G6PC3-deficient myeloid cells showed a predominance of the unphosphorylated form of GSK3beta, a key molecule controlling cellular differentiation and apoptosis. As a consequence of increased GSK3beta activity, increased phosphorylation of the antiapoptotic molecule Mcl1 was detected, explaining increased susceptibility to apoptosis in neutrophils. In summary, our study describes a novel disease, determines its molecular etiology, and sheds light on the role of glucose-dependent pathways in controlling the homeostasis of the endoplasmic reticulum and control of apoptosis.

Barbiturates inhibit thelh surge and release of gonadotrophins (lh and fsh) and prolactin from the pituitary in rats and hamsters. In the present study administration of phenobarbital (7-5mg) or barbital sodium (20 mg) twice a day from day 8–11 interrupts the pregnancy in rats with little or no foetal survival. The ovaries and the uterus of these rats resemble those of non-pregnant rats when autopsied on day 20 of pregnancy. These results suggest that the failure of maintenance of pregnancy by barbiturate treatment may be due to the inhibition of luteotrophic hormones from the pituitary during the crucial period of pregnancy, resulting in the insufficient secretion and release of ovarian progesterone and also estrogen.