Quantitative demodulation of distributed low-frequency vibration based on phase-shifted dual-pulse phase-sensitive OTDR with direct detection.

Phase-sensitive optical time-domain reflectometry (Φ-OTDR) has been proposed for distributed vibration sensing purpose over recent years. Emerging applications, including seismic and hydroacoustic wave detection, demand accurate low-frequency vibration reconstruction capability. We propose to use the direct-detection Φ-OTDR configuration to achieve quantitative demodulation of external low-frequency vibrations by phase-shifted dual-pulse probes. Simultaneous pulsing and phase shifting modulation is realized with a single acousto-optic modulator to generate such probes, relaxing the need for an additional optical phase modulator. In the experiments, vibrations with frequency as low as 0.5 Hz are successfully reconstructed with 10 m spatial resolution and 35 dB signal-to-noise ratio. Excellent linearity and repeatability are demonstrated between the optical phase demodulation results and the applied vibration amplitudes. The proposed method is capable of quantitative demodulation of low-frequency vibrations with a cost-effective system configuration and high computation efficiency, showing potential for commercial applications of distributed seismic or hydroacoustic wave acquisition.

Lanosterol reverses protein aggregation in cataracts.

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

In utero Exposure to Anesthetics Alters Neuronal Migration Pattern in Developing Cerebral Cortex and Causes Postnatal Behavioral Deficits in Rats.

During fetal development, cerebral cortical neurons are generated in the proliferative zone along the ventricles and then migrate to their final positions. To examine the impact of in utero exposure to anesthetics on neuronal migration, we injected pregnant rats with bromodeoxyuridine to label fetal neurons generated at embryonic Day (E) 17 and then randomized these rats to 9 different groups receiving 3 different means of anesthesia (oxygen/control, propofol, isoflurane) for 3 exposure durations (20, 50, 120 min). Histological analysis of brains from 54 pups revealed that significant number of neurons in anesthetized animals failed to acquire their correct cortical position and remained dispersed within inappropriate cortical layers and/or adjacent white matter. Behavioral testing of 86 littermates pointed to abnormalities that correspond to the aberrations in the brain areas that are specifically developing during the E17. In the second set of experiments, fetal brains exposed to isoflurane at E16 had diminished expression of the reelin and glutamic acid decarboxylase 67, proteins critical for neuronal migration. Together, these results call for cautious use of anesthetics during the neuronal migration period in pregnancy and more comprehensive investigation of neurodevelopmental consequences for the fetus and possible consequences later in life.

Magneto-optical imaging feature extraction of micro-gap weld joint under nonuniform magnetic field excitation.

To reduce the effect of the nonuniformity of magnetic field excitation on micro-gap weld joint magneto-optical (MO) imaging, a new experimental system based on the Faraday MO effect to detect micro-gap welds (gap width less than 0.1 mm) under nonuniform magnetic field excitation was developed. Horseshoe permanent magnets were used to magnetize the weldment and establish a nonuniform magnetic field at the welding joint. MO images of the micro-gap weld joint were captured using an MO sensor under nonuniform magnetic field excitation. After analyzing the distribution characteristics of the magnetic induction intensity in the weld joint area, a characterization method for the weld zone slope was proposed. The weld zone slope could accurately determine the MO imaging effects under the nonuniform magnetic field. A model based on an error backpropagation (BP) neural network was used to predict the offset of the weld joint center at each moment, and the results performed by BP were utilized to optimize the measured value of the weld joint center. Experimental results show that it can accurately extract the position of micro-gap welds under nonuniform magnetic field excitation.

Modeling for detecting weld defects based on magneto-optical imaging.

A magneto-optical (MO) imaging nondestructive testing (NDT) method for ferromagnetic weldments has been proposed. The mechanism of MO imaging was analyzed by the Faraday MO effect, magnetic domain theory, and magnetic hysteresis loops. Then, the relation between MO images and their corresponding excitation voltages was investigated. To explain the MO imaging system, magnetic domain distribution models of various welding states were established. These models are excited by two kinds of magnetic fields. One is the external magnetic field (Hex), and the other is a weldment remanence field (Mr) after Hex is removed. Relations of magnetic field excitation voltages, thickness of the spacer plate, and the corresponding MO images were also researched, which indicates the proposed NDT method can be used to detect incomplete penetration defect. Then, an experiment that uses MO imaging to detect the defects of high-strength steel (HSS) weldment was performed. Experimental results proved this method can detect crack, sag, and incomplete penetration of weldment effectively. Finally, a series of welded joint MO images of the HSS weldment were captured, which are used as the input data of the defect classification model established by using principal component analysis and an error backpropagation neural network, and the accuracy of this classification model can achieve 92.8%.

A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study.

PURPOSE: The aim of this study was to evaluate the tolerability and efficacy of poly(ADP-ribose) polymerase (PARP) inhibition by veliparib during cytotoxic topotecan administration with filgrastim or pegfilgrastim neutrophil support in women with persistent or recurrent uterine cervix cancer. EXPERIMENTAL DESIGN: This phase I-II trial examined twice-daily oral veliparib (10 mg) given during once-daily intravenous topotecan (0.6 mg/m²) on days 1 to 5 of each treatment cycle. Cycles were repeated every 21 days until disease progression or until toxicity prohibited further therapy. Toxicity and objective response rate were primary endpoints. RESULTS: Twenty-seven women were enrolled. Frequently reported grade 3 or higher treatment-related toxicities were anemia (59%), thrombocytopenia (44%), leukopenia (22%), and neutropenia (19%). There were 2 partial responses (7% [90% confidence interval, 1%-22%]). Four patients had a disease progression date more than 6 months after the start of veliparib-topotecan therapy. Patients with low immunohistochemical expression (0-1+) of PARP-1 in their primary uterine cervix cancer were more likely to have a longer progression-free interval (hazard ratio, 0.25; P = 0.02) and survival (hazard ratio, 0.12; P = 0.005) after veliparib-topotecan therapy. CONCLUSIONS: Clinical activity of a veliparib-topotecan combination was minimal in women with persistent or recurrent uterine cervix cancer. Women whose uterine cervix cancers express PARP-1 at low levels may benefit preferentially from PARP inhibitors combined with cytotoxic therapies, suggesting further study of PARP expression as an integral triage biomarker.

Optimized half-wave voltage and insertion loss in a strip-loaded waveguide electro-optic polymer modulator.

A strip-loaded waveguide, electro-optic modulator was designed and analyzed in terms of single mode conditions, optical loss due to the metal electrodes, modulation efficiency, and mode size. Two designs were compared: Design 1 optimized the half-wave voltage (V(π)=1.1 V) with a nearly symmetric waveguide by maximizing modulation efficiency and minimizing the overall thickness of the waveguide; Design 2 optimized the insertion loss by reducing coupling loss by 4.6 dB via a strongly asymmetric waveguide that maximizes the overall mode size to most efficiently overlap with a single mode fiber. Design 2 also has a favorable half-wave voltage (V(π)=1.75 V). Some general guidelines in the selection of cladding layers in a detailed design of a poled-polymer electro-optic modulator incorporating a strip-loaded waveguide structure are suggested.

Human keratinocytes are a source for tumor necrosis factor alpha: evidence for synthesis and release upon stimulation with endotoxin or ultraviolet light.

Tumor necrosis factor alpha (TNF-alpha), in addition to being cytotoxic for certain tumor cells, has turned out as a multifunctional cytokine that is involved in the regulation of immunity and inflammation. Since human keratinocytes have been demonstrated to be a potent source of various cytokines, it was investigated whether epidermal cells synthesize and release TNF-alpha. Supernatants derived from normal human keratinocytes (HNK) and human epidermoid carcinoma cell lines (KB, A431) were tested both in a TNF-alpha-specific ELISA and a bioassay. In supernatants of untreated epidermal cells, no or minimal TNF-alpha activity was found, while after stimulation with lipopolysaccharide (LPS) or ultraviolet (UV) light, significant amounts were detected. Western blot analysis using an antibody directed against human TNF-alpha revealed a molecular mass of 17 kD for keratinocyte-derived TNF-alpha. These biological and biochemical data were also confirmed by Northern blot analysis revealing mRNA specific for TNF-alpha in LPS- or ultraviolet B (UVB)-treated HNK and KB cells. In addition, increased TNF-alpha levels were detected in the serum obtained from human volunteers 12 and 24 h after a single total body UVB exposure, which caused a severe sunburn reaction. These findings indicate that keratinocytes upon stimulation are able to synthesize and release TNF-alpha, which may gain access to the circulation. Thus, TNF-alpha in concert with other epidermal cell-derived cytokines may mediate local and systemic inflammatory reactions during host defense against injurious events caused by microbial agents or UV irradiation.

Differences in the localization and morphology of chromosomes in the human nucleus.

Using fluorescence in situ hybridization we show striking differences in nuclear position, chromosome morphology, and interactions with nuclear substructure for human chromosomes 18 and 19. Human chromosome 19 is shown to adopt a more internal position in the nucleus than chromosome 18 and to be more extensively associated with the nuclear matrix. The more peripheral localization of chromosome 18 is established early in the cell cycle and is maintained thereafter. We show that the preferential localization of chromosomes 18 and 19 in the nucleus is reflected in the orientation of translocation chromosomes in the nucleus. Lastly, we show that the inhibition of transcription can have gross, but reversible, effects on chromosome architecture. Our data demonstrate that the distribution of genomic sequences between chromosomes has implications for nuclear structure and we discuss our findings in relation to a model of the human nucleus that is functionally compartmentalized.

Extended intracranial applications for ethylene vinyl alcohol copolymer (Onyx): mycotic and dissecting aneurysms. Technical note.

The authors describe the off-label use of Onyx for embolization of fusiform mycotic and dissecting intracranial aneurysms based on their experience with 3 patients treated at the University of Utah Hospital from 2006 through 2007. Technical success in occluding the parent artery/aneurysm was achieved in all patients. There were no complications. The authors conclude that Onyx can be used to achieve occlusion of fusiform mycotic and dissecting intracranial aneurysms in conjunction with parent artery occlusion.

Deprivation influences the functional outcome from total hip arthroplasty.

UNLABELLED: Socioeconomic inequality through deprivation and access to healthcare is an aetiological factor in many disease processes. It is associated with the development of osteoarthritis, the need for joint arthroplasty and poorer access to secondary healthcare. Few studies have investigated the influence of deprivation on the function of patients undergoing total hip arthroplasty. The aim of this study was to investigate the association between deprivation and function in these patients before their operation and at 18 months. The secondary aim was to investigate if deprivation was associated with comorbidity or adverse outcomes. A prospectively database of functional scores of 1865 patients undergoing total hip arthroplasty over seven years was used. Deprivation was categorized using the Scottish Index of Multiple Deprivation (SIMD) government rating. The most deprived quintiles had lower absolute functional scores at time of operation. At 18 months the least deprived quintile had a greater SF36 physical function score and relative improvement. Deprivation was not linked with length of stay or BMI. There was a higher proportion of ASA (American Society of Anesthesiologists) category 1 patients in the least deprived group signifying less comorbidity. Smoking was more prevalent in patients from areas of greater deprivation. There was no observed difference in mortality, infection, dislocation or thromboembolism. This study demonstrates a socioeconomic gradient in the function of patients undergoing total hip arthroplasty. Further investigation is required to elucidate the biological and social mechanisms driving these outcomes, and to determine whether these gradients persist at longer term follow-up. LEVEL OF EVIDENCE: II (Prognostic Studies--Investigating the effect of a patient characteristic on the outcome of disease).

Intraprocedural predictors of post-stent retriever thrombectomy subarachnoid hemorrhage in middle cerebral artery stroke.

BACKGROUND: Stent retriever thrombectomy (SRT) in acute thromboembolic stroke can result in post-thrombectomy subarachnoid hemorrhage (PTSAH). Intraprocedural findings associated with PTSAH are not well defined. OBJECTIVE: To identify angiographic findings and procedural factors during SRT that are associated with PTSAH. MATERIALS AND METHODS: This was a retrospective, observational cohort study of consecutive patients with middle cerebral artery (MCA) acute ischemic stroke treated with SRT. Inclusion criteria were: (1) age ≥18 years; (2) thromboembolic occlusion of the MCA; (3) at least one stent retriever pass beginning in an M2 branch; (4) postprocedural CT or MRI scan within 24 hours; (5) non-enhanced CT Alberta Stroke Program Early CT Score >5. Exclusion criteria included multi-territory stroke before SRT. RESULTS: Eighty-five patients were enrolled; eight patients had PTSAH (group 1) and 77 did not (group 2). Baseline demographic and clinical characteristics were comparable between the two groups. In group 1, a significantly greater proportion of patients had more than two stent retriever passes (62.5% vs 18.2%, P=0.01), a stent retriever positioned ≥2 cm along an M2 branch (100% vs 30.2%, P=0.002), and the presence of severe iatrogenic vasospasm before SRT pass (37.5% vs 5.2%, P=0.02). One patient with PTSAH and associated mass effect deteriorated clinically. CONCLUSIONS: An increased number of stent retriever passes, distal device positioning, and presence of severe vasospasm were associated with PTSAH. Neurological deterioration with PTSAH can occur.

Midterm outcomes of paclitaxel-eluting stents for the treatment of intracranial posterior circulation stenoses.

OBJECT: Symptomatic intracranial vertebral and basilar artery atherosclerotic stenoses carry a high risk of stroke and permanent disability if refractory to maximal medical therapy. The authors conducted a study to determine the technical feasibility and midterm clinical and angiographic outcomes in patients in whom paclitaxel-eluting stents were placed for the treatment of symptomatic intracranial posterior circulation stenoses. METHODS: A retrospective review of medical records and imaging studies was performed for 13 consecutive patients in whom paclitaxel-coated stents were used to treat symptomatic posterior circulation intracranial stenoses between 2002 and 2005. Clinical follow-up data were supplemented by telephone interviews. The technical success rate for stent placement was 100%. One patient (8%) suffered a periprocedural stroke. Twelve patients (92%) underwent clinical follow up for a minimum of 3 months postsurgery, and 11 (92%) of these patients remained asymptomatic after a mean period of 10.9 months. Nine patients (69%) underwent catheter angiographic follow up, and no patient had significant in-stent recurrence of stenosis after a mean period of 5.4 months. CONCLUSIONS: Treatment of intracranial posterior circulation stenoses with drug-eluting stents is technically feasible, and the rate of clinically significant periprocedural complications is low. Rates of stenosis recurrence are reduced compared with those of bare-metal stents in the midterm. Midterm clinical outcome is excellent; no symptom recurrence was observed in this patient cohort.

An 11-year retrospective review of venlafaxine ingestion in children from the California Poison Control System.

Venlafaxine is commonly used in the United States for approved and non-Food and Drug Administration-approved indications in adults. It is used off-label to treat children for psychiatric diagnoses. The aim of the study was to describe venlafaxine toxicities in children and to identify the venlafaxine dose per weight that correlates with toxicities. An 11-year retrospective study of venlafaxine ingestion in children was performed using the California Poison Control System (CPCS) database. Data was extracted from phone calls received by CPCS clinicians and follow-up phone calls made to assess the patient's progress in a health-care setting. Inclusion criteria were venlafaxine ingestion cases reported to CPCS between January 2001 and December 2011, children aged 20 years and under, venlafaxine as the only ingested substance, managed in a health-care facility, and followed to a known outcome. Two hundred sixty-two cases met the study criteria. Common presentations included gastrointestinal (14.9%), altered mental status (13.7%), and tachycardia (13.4%). The majority of the cases resulted in no effect (51.5%) or minor effect (19.9%). The average estimated dose per weight was 18.3 mg/kg in all patients and 64.5 mg/kg in those experiencing moderate-to-severe adverse effects. Seizures occurred in only 4 of the 262 cases at doses ranging from 1500 to 7500 mg. Although the estimated dose per weight exceeded 10 mg/kg for the majority of the cases, only 12 cases resulted in moderate or severe outcomes. The majority of venlafaxine ingestion cases in children resulted in either no clinical effects or minor clinical effects.

High affinity uptake by isolated rat hepatocytes of a linear pseudo-hexapeptide, ditekiren.

The hepatic elimination of many oligopeptides is both rapid and extensive, and often limits their potential as therapeutic agents. The linear, hydrophobic pseudo-hexapeptide ditekiren, a renin inhibitor, is one such example. The mechanism(s) involved in its hepatic clearance are largely unknown; accordingly, the characteristics of ditekiren's transport into isolated rat hepatocytes was investigated. In addition to a concentration-independent, linear process, uptake also involved a carrier-mediated component (Km = 0.2 +/- 0.05 microM; Vmax = 11.6 +/- 0.6 pmol (mg protein)[-1] min[-1]). Phenobarbital pretreatment in vivo resulted in marked induction of such transport. Negative results from cis-inhibition studies with substrates and/or inhibitors of well-established hepatic transport systems, e.g., sodium-dependent bile acid, sodium-independent multispecific bile acid and cation carriers, ruled out their involvement in ditekiren's uptake. By contrast, a number of cyclic and linear oligopeptides inhibited the uptake process to varying extents and in the case of EMD-59121, the most inhibitory compound, the interaction was competitive in nature. Collectively, these data suggest the presence of a novel high affinity, low capacity transporter in rat hepatocytes with specific affinity for ditekiren and possibly other oligopeptides.

Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes.

Peptidic glucagon antagonists have been shown to lower blood glucose levels in diabetic models (1-3), but attempts to identify small molecular weight glucagon receptor-binding antagonists have met with little success. Skyrin, a fungal bisanthroquinone, exhibits functional glucagon antagonism by uncoupling the glucagon receptor from adenylate cyclase activation in rat liver membranes (1). We have examined the effects of skyrin on cells transfected with the human glucagon receptor and on isolated rat and human hepatocytes. The skyrin used was isolated from Talaromyces wortmanni American Type Culture Collection 10517. In rat hepatocytes, skyrin (30 micromol/l) inhibited glucagon-stimulated cAMP production (53%) and glucose output (IC50 56 micromol/l). There was no detectable effect on epinephrine or glucagon-like peptide 1 (GLP-1) stimulation of these parameters, which demonstrates skyrin's selective activity. Skyrin was also evaluated in primary cultures of human hepatocytes. Unlike cell lines, which are largely unresponsive to glucagon, primary human hepatocytes exhibited glucagon-dependent cAMP production for 14 days in culture (EC50 10 nmol/l). Skyrin (10 micromol/l) markedly reduced glucagon-stimulated cAMP production (55%) and glycogenolysis (27%) in human hepatocytes. The inhibition of glucagon stimulation was a specific property displayed by skyrin and oxyskyrin but not shared by other bisanthroquinones. Skyrin is the first small molecular weight nonpeptidic agent demonstrated to interfere with the coupling of glucagon to adenylate cyclase independent of binding to the glucagon receptor. The data presented in this study indicate that functional uncoupling of the human glucagon receptor from cAMP production results in metabolic effects that could reduce hepatocyte glucose production and hence alleviate diabetic hyperglycemia.

Water intoxication, psychosis, and inappropriate secretion of antidiuretic hormone.

A review of the literature and the three presented cases indicate that multiple factors are often involved in the development of water intoxication in the psychotic. Although the syndrome of inappropriate secretion of antidiuretic hormones (SIADH) is one of these factors, it is usually associated with other causes of the SIADH. Evidence is lacking that the SIADH is an essential feature of a psychotic illness.

Side effects of corticosteroid therapy. Psychiatric aspects.

We reviewed the literature to determine the characteristics of corticosteroid-induced mental disturbances. We conclude that (1) while dosage may be correlated to the risk of developing mental disturbances, neither dosage nor duration of treatment seems to affect the time of onset, duration, severity, or type of mental disturbances; (2) euphoria, depression, and psychotic reactions are the common manifestations of corticosteroid-induced mental disturbances; (3) females seem to be more prone to these disturbances than males; (4) patients with past mental illness are not necessarily predisposed to such disturbances; and (5) corticosteroid-induced mental disturbances are usually reversible on dose reduction or discontinuation of the drug. At present there are no simple models to explain the psychotic reactions, anxiety, or agitation seen in corticosteroid-induced mental disturbances.

Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach.

BACKGROUND: Numerous case reports have linked clozapine to the development of diabetes mellitus and hyperlipidemia in patients with schizophrenia. However, investigators have been unable to clearly demonstrate this association when compared with a control group receiving conventional antipsychotics. METHODS: Medical and pharmacy claims from the Iowa Medicaid program were used to compare incidence rates for diabetes, hyperlipidemia, and hypertension in 552 patients receiving clozapine and 2461 patients receiving conventional antipsychotics (eg, haloperidol, chlorpromazine hydrochloride), with the use of a retrospective cohort design. Logistic regression was used to compare incidence rates adjusting for age, sex, and duration of available follow-up. RESULTS: No significant differences in overall incidence rates for diabetes, hyperlipidemia, or hypertension were observed in patients receiving clozapine vs conventional antipsychotics. However, among younger patients (aged 20-34 years), clozapine administration was associated with a significantly increased relative risk of diabetes (2.5 [95% confidence interval, 1.2-5.4]) and hyperlipidemia (2.4 [95% confidence interval, 1.1-5.2]), but not hypertension (0.9 [95% confidence interval, 0.4-2.0]). CONCLUSIONS: These data suggest that clozapine may not be an independent cause of diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible populations by increasing weight or affecting insulin secretion and resistance. This finding requires confirmation in other settings and patient populations and with the other atypical antipsychotics (risperidone, olanzapine, and quetiapine fumarate). The potential long-term medical and economic implications of the early induction of diabetes and hyperlipidemia in patients with schizophrenia warrant further study.