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Long-term safety evaluations of biologics are needed to inform patient management decisions.

Receptor tyrosine kinases (RTKs) are cell surface receptors that initiate signal cascades in response to ligand stimulation. Abnormal expression and dysregulated intracellular trafficking of RTKs have been shown to be involved in tumorigenesis. Recent evidence shows that these cell surface receptors translocate from cell surface to different cellular compartments, including the Golgi, mitochondria, endoplasmic reticulum (ER) and the nucleus, to regulate physiological and pathological functions. Although some trafficking mechanisms have been resolved, the mechanism of intracellular trafficking from cell surface to the Golgi is not yet completely understood. Here we report a mechanism of Golgi translocation of epidermal growth factor receptor (EGFR) in which EGF-induced EGFR travels to the Golgi via microtubule-dependent movement by interacting with dynein and fuses with the Golgi through syntaxin 6-mediated membrane fusion. We also demonstrate that the microtubule- and syntaxin 6-mediated Golgi translocation of EGFR is necessary for its consequent nuclear translocation and nuclear functions. Thus, together with previous studies, the microtubule- and syntaxin 6-mediated trafficking pathway from cell surface to the Golgi, ER and the nucleus defines a comprehensive trafficking route for EGFR to travel from cell surface to the Golgi and the nucleus.

Backbround The relationship between Helicobacter pylori (Hp) infection and oesophageal squamous-cell carcinoma (ESCC) risk is still inconclusive. Our previous study found an inverse association between the two, but its mechanism is still unknown. Thus, we conducted in vitro studies to clarify the issue. Materials and methods One ESCC (CE 81T/VGH) cell line was co-cultured with Hp, using one gastric adenocarcinoma (AGS) cell line as the control. Hp–induced cell apoptosis was determined by flow cytometry, terminal transferase-mediated dUTP nick end labelling (TUNEL) assay and staining; caspase-3 protein expressions in cell lysates were detected by Western immunoblot. Results Increased apoptosis was found in CE 81T/VGH, but not in AGS cells, by flow cytometry and TUNEL assay after being co-cultured with Hp at the multiplicity of infection of 1/100 (but not at 1/400) for 36 h. The amount of activated caspase-3 (17/19 kDa) also increased in CE 81T/VGH, but not in AGS cells, after co-culturing with Hp at MOI of 1/100 for 36 h. The results were confirmed by triplicate experiments in which the different apoptotic assays remained consistent. Conclusions Our study provides indirect evidence of the inverse association between Hp infection and ESCC risk, which is possibly due to Hp-induced apoptosis in ESCC cells. A further in vivo study is necessary to confirm our findings.

Loofah (Luffa cylindrical) is a common vegetable crop in Taiwan and other Asian countries. Reported here is a novel rapid approach for detecting loofah witches’ broom (LfWB) phytoplasma in single leafhoppers. Field samples of suspected diseased plants and potential vectors from southern Taiwan were processed to test for the presence of the LfWB phytoplasmas using both strain-specific DNA hybridization (DH) and polymerase chain reaction (PCR) assays. The commonest pathogen causing loofah disease in southern Taiwan is LfWB phytoplasma. Leafhoopers collected at nine locations near LfWB-infected plants were found to be positive for LfWB by PCR / DH at an incidence of 28.5–40.0%. Of the different leafhopper species tested, only Hishimonus concavus was positive for LfWB, suggesting that H. concavus is a natural vector of LfWB in Taiwan. Using our proposed primers in this PCR assay, a single LfWB-infected leafhopper can be detected rapidly and directly.

An infrared photodetector that contains a superlattice structure and a blocking barrier was investigated. The photodetector shows advantages including a low operating voltage (

Diclofenac (DIC), a nonsteroidal anti-inflammatory drug, is known to exert anti-nociceptive and anti-convulsant actions; however, its effects on ion currents, in neurons remain debatable. We aimed to investigate (1) potential effects of diclofenac on membrane potential and potassium currents in differentiated NSC-34 neuronal cells and dorsal root ganglion (DRG) neurons with whole-cell patch-clamp technology, and (2) firing of action potentials (APs), using a simulation model from hippocampal CA1 pyramidal neurons based on diclofenac's effects on potassium currents. In the NSC-34 cells, diclofenac exerted an inhibitory effect on delayed-rectifier K⁺ current (I(KDR)) with an IC₅₀ value of 73 μM. Diclofenac not merely inhibited the I(KDR) amplitude in response to membrane depolarization, but also accelerated the process of current inactivation. The inhibition by diclofenac of IK(DR) was not reversed by subsequent application of either naloxone. Importantly, diclofenac (300 μM) increased the amplitude of M-type K⁺ current (I)(KM)), while flupirtine (10 μM) or meclofenamic acid (10 μM) enhanced it effectively. Consistently, diclofenac (100 μM) increased the amplitude of I(KM) and diminished the I(KDR) amplitude, with a shortening of inactivation time constant in DRG neurons. Furthermore, by using the simulation modeling, we demonstrated the potential electrophysiological mechanisms underlying changes in AP firing caused by diclofenac. During the exposure to diclofenac, the actions on both I(KM) and I(KDR) could be potential mechanism through which it influences the excitability of fast-spiking neurons. Caution needs to be made in attributing the effects of diclofenac primarily to those produced by the activation of I(KM).

Long-term safety evaluations of biologics are needed to inform patient management decisions.To evaluate the safety of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years.Safety data were pooled from four studies of ustekinumab for psoriasis. Rates of adverse events (AEs), serious AEs (SAEs) and AEs of interest [infections, nonmelanoma skin cancers (NMSCs), other malignancies and major adverse cardiovascular events (MACE)] per 100 patient-years (PY) of follow-up were analysed by ustekinumab dose (45 or 90 mg) and by year of follow-up (years 1-5) to evaluate the dose response and impact of cumulative exposure. Observed rates of overall mortality and other malignancies were compared with those expected in the general U.S. population.Analyses included 3117 patients (8998 PY) who received one or more doses of ustekinumab, with 1482 patients treated for ≥4 years (including 838 patients ≥5 years). At year 5, event rates (45 mg, 90 mg, respectively) for overall AEs (242·6, 225·3), SAEs (7·0, 7·2), serious infections (0·98, 1·19), NMSCs (0·64, 0·44), other malignancies (0·59, 0·61) and MACE (0·56, 0·36) were comparable between dose groups. Year-to-year variability was observed, but no increasing trend was evident. Rates of overall mortality and other malignancies were comparable with those expected in the general U.S. population.No dose-related or cumulative toxicity was observed with increasing duration of ustekinumab exposure for up to 5 years. Rates of AEs reported in ustekinumab psoriasis trials are generally comparable with those reported for other biologics approved for the treatment of moderate-to-severe psoriasis.

There is a controversial problem concerning the wetting properties in the three-liquid-phase region of the system water +n-hexadecane+C 6 E 2 , where C i E j denotes the nonionic surfactant poly(oxyethylene) alcohol C i H 2i+1 (OCH 2 CH 2 ) j OH. In this study, both interfacial tension measurements and direct contact angle measurements are used to further reconfirm that the middle phase of this system does exhibit a wetting at the interface separating the upper and the lower phase as temperature is increased towards the upper critical consolute temperature. The effect of chain length of oil on the wetting transition is also discussed in the ternary system water+n-alkane+C 6 E 2 by using three different oils: n-tetradecane, n-hexadecane, and n-octadecane

Children born with single ventricle heart defects typically undergo a staged surgical procedure culminating in a total cavopulmonary connection (TCPC) or Fontan surgery. The goal of this work was to perform physiologic, patient-specific hemodynamic simulations of two post-operative TCPC patients by using fluid-structure interaction (FSI) simulations. Data from two patients are presented, and post-op anatomy is reconstructed from MRI data. Respiration rate, heart rate, and venous pressures are obtained from catheterization data, and inflow rates are obtained from phase contrast MRI data and are used together with a respiratory model. Lumped parameter (Windkessel) boundary conditions are used at the outlets. We perform FSI simulations by using an arbitrary Lagrangian-Eulerian finite element framework to account for motion of the blood vessel walls in the TCPC. This study is the first to introduce variable elastic properties for the different areas of the TCPC, including a Gore-Tex conduit. Quantities such as wall shear stresses and pressures at critical locations are extracted from the simulation and are compared with pressure tracings from clinical data as well as with rigid wall simulations. Hepatic flow distribution and energy efficiency are also calculated and compared for all cases. There is little effect of FSI on pressure tracings, hepatic flow distribution, and time-averaged energy efficiency. However, the effect of FSI on wall shear stress, instantaneous energy efficiency, and wall motion is significant and should be considered in future work, particularly for accurate prediction of thrombus formation.

The crisis level in the worldwide suicide rate has revealed a severe suicide problem in Taiwan that is now well above the world average of 16 per 100,000 individuals. Many countries have relied on suicide care volunteers training programmes to conduct suicide prevention programmes. However, there is a dearth of research evaluating the effect of volunteers on psychological distress and the impact of volunteer experience level. An evaluation of the impact of experienced and novice volunteers in alleviating psychological distress of suicide survivors was conducted. A supervised programme trained 15 volunteers at Years 1 and 2. Year 1 volunteers completed 400 h of service with continuing education. Programme evaluation occurred after Year 2 volunteers had completed training. Eighty-two suicide survivors were recruited. With 60 suicide survivors completing 3 month of volunteer care, a significant group difference with time interaction in suicide survivors who exhibited moderate to severe distress between the veteran care and novice care groups was found. Compared with novice volunteers, veteran volunteers with at least 1 year of experience are more effective with suicide survivors reporting higher psychological distress.

Electronics Products that achieve high levels of integrated communications, computing and entertainment, multimedia features in small, stylish and robust new form factors are winning in the market place. Due to the high costs that an industry may undergo and how a high yield is directly proportional to high profits, IC (Integrated Circuit) manufacturers struggle to maximize yield, but today-s customers demand miniaturization, low costs, high performance and excellent reliability making the yield maximization a never ending research of an enhanced assembly process. With factors such as minimum tolerances, tighter parameter variations a systematic approach is needed in order to predict the assembly process. In order to evaluate the quality of upcoming circuits, yield models are used which not only predict manufacturing costs but also provide vital information in order to ease the process of correction when the yields fall below expectations. For an IC manufacturer to obtain higher assembly yields all factors such as boards, placement, components, the material from which the components are made of and processes must be taken into consideration. Effective placement yield depends heavily on machine accuracy and the vision of the system which needs the ability to recognize the features on the board and component to place the device accurately on the pads and bumps of the PCB. There are currently two methods for accurate positioning, using the edge of the package and using solder ball locations also called footprints. The only assumption that a yield model makes is that all boards and devices are completely functional. This paper will focus on the Monte Carlo method which consists in a class of computational algorithms (information processed algorithms) which depends on repeated random samplings in order to compute the results. This method utilized in order to recreate the simulation of placement and assembly processes within a production line., {"references":["C. Y. Huang, \"Reducing Solder Paste Inspection in Surface Mount\nAssembly through Mahalanobis-Taguchi Analysis,\" IEEE Transactions\non Electronics Packaging Manufacturing, Vol. 33, No. 4, pp. 265-274,\n2010.","S. H. Mannan, N. N. Ekere, \"Predicting Scooping and Skipping in Solder\nPaste Printing for Reflow Soldering of SMT Devices,\" Soldering and\nSurface Mount Technology Journal, Vol. 15, pp. 14-17, 1993.","C. Y. Huang, M. S. Li, J. L. Ku, H. C. Hsieh, \"Chemical Characterization\nof Failures And Process Materials for Microelectronics Assembly,\"\nMicroelectronics International, Vol. 26, No. 3, pp. 41-48, August 2009.","S. Chada, A. Herrmann, W. Laub, R. Fournelle, D. Shangguan, and A.\nAchari, \"Microstructural Investigation of Sn-Ag and Sn-Ag Solder\nJoints,\" Soldering and Surface Mount Tech. Vol. 9, Iss. 2, pp. 9, 1997.","A. Fazzi, L. Magagni, M. De Dominicis, P. Zoffoli, R. Canegallo1, P.L.\nRolandi1, A. Sangiovanni-Vincentelli2 and R. Guerrieri, \"Yield\nPrediction for 3D Capacitive Interconnections,\" Conference on\nComputer-Aided Design, 2006. ICCAD '06. IEEE/ACM Internationa,\npp.809 - 814."]}

Patients with psoriasis are believed to be at an increased risk of cardiovascular (CV) morbidity, and the effect of biological agents on CV safety is not fully understood.To evaluate the effect of ustekinumab on CV events using detailed analyses of pooled data from the phase II/III clinical studies of its use in moderate to severe psoriasis.The incidence of major adverse CV events [MACE: myocardial infarction (MI), stroke or CV death] is reported. Meta-analyses using risk difference and odds ratio estimates are presented based on data collected during the placebo-controlled period of ustekinumab trials. The cumulative numbers of events and rates of MIs and strokes over time were compared with those expected in the psoriasis and/or general populations.During the placebo-controlled period (12/20 weeks), five MACE were reported in 1582 ustekinumab-treated patients [0·3%; 95% confidence interval (CI) 0·1-0·7%] compared with no events in 732 placebo-treated patients (0·0%; 95% CI 0·0-0·5%). MACE rates were stable over time during both the controlled and uncontrolled study periods, with 19 of 3117 ustekinumab-treated patients (0·6%) experiencing 21 events for a combined event rate per 100 patient-years of follow-up of 0·44 (95% CI 0·27-0·67) through up to 3 years. Standardized incidence ratios for comparison of ustekinumab clinical data with external data sources ranged from 0·34 to 0·52, suggesting no increased risk of MI or stroke in ustekinumab-treated patients compared with the general U.S. and psoriasis populations.The totality of available clinical data suggests neither a detrimental nor a beneficial effect of ustekinumab on serious CV events. Additional data are needed to define the net effect of ustekinumab on CV events.

A vertical channel SONOS memory, which is compatible with current CMOS process and has four physical storage nodes per unit area, is fabricated and electrically evaluated. Comparing with a planar device, the array cell tuning is much easier since the channel length is no longer limited by array area. After reviewing key performances including program/erase (P/E) speeds, second bit effect, program disturbance, endurance, and retention on a NOR-type array, it is found that four physical bits/cell is hard to achieve due to a serious program disturb. Unavoidable high energy 2nd hot electron between neighbor cells is identified as the root cause. In this paper, operation procedures and array layouts, which are suitable for three physical bits per cell (3bits/cell), is then proposed.

We study the phase behavior and observe wetting and nonwetting behaviors, as well as the wetting transition which occurs in the four‐component surfactant system water+n‐octadecane+diethylene glycol monohexyl ether+NaCl. All experiments are performed at constant weight ratio of water:n‐octadecane (1:1) and constant temperature 35.0±0.05 °C, with varying NaCl concentration. It is found that the system water+n‐octadecane+C6E2 exhibits a wetting transition lying at 17.1 wt. % of NaCl in water. This observation is further confirmed by interfacial tension measurements. In addition to that of lyotropic salt (NaCl), the effect of hydrotropic salt on the interfacial wetting transition is also discussed.

In a system with three coexisting phases (α, β and γ) at equilibrium and having densities in the order ρ α < ρ β < ρ γ, the interfacial tensions (σ αβ, σ βγ and σ αγ) either obey Antonow’s rule, which gives wetting behavior, or conform to Neumann’s inequality, which gives non-wetting behavior. The validity of these implications has been experimentally investigated and the influence of salt concentration and salt type determined.

The high prevalence of C. trachomatis worldwide has underscored the importance of identifying specific immunogenic antigens in facilitating diagnosis as well as vaccine development. The aim of this study is to evaluate IncA antibody and antigen production in natural human infections. Our temporal expression study showed that IncA transcription and protein expression could be detected as early as 4 hours after the start of infection. Antibody responses could be detected in urine and genital swab samples from C. trachomatis-positive patients. It is especially interesting to note that the IncA antigen could be detected in urine. In conclusion, we have identified IncA as an important antigen in human. The potential applicability of the IncA antibody or antigen in the diagnosis as well as to vaccine development for C. trachomatis is also discussed.

In this paper, the simulating dynamic behavior of a grid-linked wind farm power system in Taiwan is investigated. Some models including wind model, aerodynamic model, machine model, electromechanical model are employed to cater for the dynamic behavior of the system. Simulation results show that the system operates satisfactorily under normal and abnormal conditions.

According to the literature, half of the schwannoma cases occur in the head and neck areas and only less than 4% occur in the sinonasal tract. In this case, a 39-year-old male patient, with a-year-long progressive left side nasal obstruction and purulent rhinorrhea, is presented. The CT reveals a mass filling the left nasal cavity and nasopharyngeal space, with bony erosion of the inferior turbinate and medial maxillary bone. During surgical intervention, the mass is found to originate from the medial side of the left middle turbinate with maxillary sinusitis and inferior turbinate atrophy. The pathological examination reveals a noncapsulated tumor with palisading cellular arrangement and high cellular density. The pathological findings and nervous origin of the tumor are discussed after an extensive review of the literature.

In order to determine the prevalence of childhood allergic diseases, infectious diseases, and the relationship between them, 8723 children from three junior high schools in Tou-Cheng City, Taipei County, were studied using questionnaires developed according to the International Study of Asthma and Allergies in Childhood (ISAAC) criteria combined with supplementary questions about infectious diseases. Students and their parents completed the questionnaires at home. The age of the children ranged from 10 to 18 years old (14.12 +/- 0.89 years), the majority (96.03%) was aged from 13 to 15 years old. The 12-month prevalences of self-reported allergic disease symptoms were: asthma symptom 8.2%, allergic rhinitis symptom 39.6%, and atopic dermatitis symptom 5.9%. The prevalences of diagnosis of the allergic diseases were: asthma 8.7%, allergic rhinitis 24.1%, and atopic dermatitis 3.9%. The 12-month prevalences of diagnosis of infectious diseases were: pneumonia 0.6%, bronchitis 7.2%, sinusitis 7.2%, purulent conjunctivitis 2.5%, otitis media 4.3%, encephalitis or meningitis 0.4%, gastroenteritis 14.5%, acne 23.9%, purulent dermatitis 1.3%, and other infectious diseases 1.2%. Lifetime admission rates of children due to infectious diseases were: pneumonia 1%, bronchitis 1.8%, sinusitis 0.3%, purulent conjunctivitis 0.2%, otitis media 0.3%, encephalitis or meningitis 0.3%, gastroenteritis 2.1%, and other infectious diseases 0.6%. The prevalence of infectious diseases was significantly higher in children with allergic disease symptoms (defined as asthma, allergic rhinitis, or atopic dermatitis). These results demonstrated the presence of a link between allergic diseases and infectious diseases, which may have some important clinical implications.

The purpose of this study was to investigate the role of insulin-degrading enzyme (IDE, EC 3.4.22.11) in insulin degradation in alveolar epithelium. The primary culture of isolated rat type-II pneumocytes was used for the in-vitro characterization of IDE. Insulin was then administered intratracheally with various inhibitors to assess the improvement in its pulmonary bioavailability. In cultured type-II pneumocytes, the cytosolic insulin-degrading activity contributed 81% of total insulin degradation, reached a maximum at pH 7.5 and had an apparent Michaelis-Menten constant (Km) of 135 nM. N-Ethylmaleimide, p-chloromercuribenzoic acid and 1,10-phenanthroline inhibited insulin-degrading activity almost completely in both crude homogenate and cytosol. An immunoprecipitation study showed that IDE contributed 74% of cytosolic insulin-degrading activity. Western blot analysis showing a single band of 110 kDa on reduced SDS (sodium dodecylsulphate) gels confirmed the presence of IDE in cultured type-II cells. When given intratracheally with insulin, inhibitors including N-ethylmaleimide, p-chloromercuribenzoic acid, and 1,10-phenanthroline significantly enhanced the absolute bioavailability of insulin and the compound's hypoglycaemic effects. These results suggest that IDE is present in alveolar epithelium and might be involved in limiting insulin absorption in the lung.

This paper presents a novel SU-8 micromachining process for MEMS series switch fabrication. The switch is designed with a clamped–clamped SU-8 (5 µm)/Cu (2 µm)/SU-8 (3 µm) beam structure driven by electrostatic force, which is fabricated on a silicon substrate with a resistivity of ~5 Ω cm. Experimental results show that the switch can exhibit better than −4.48 dB insertion loss and −28.2 dB isolation up to 12 GHz. Such a large insertion loss is mainly caused by substrate loss which can be further reduced down to −0.75 dB as long as the substrate resistivity is increased up to 100 Ω cm.

Subdermal Norplant-2 implantation, developed for contraception based on sustained release of levonorgestrel, has already been conducted in many countries around the world. From October 1986 to November 1988, a total of 267 female volunteers were enrolled in Norplant studies at the National Taiwan University Hospital. After a follow-up of 36 months, only one of the 231 evaluable cases (0.4%) became pregnant. The continuation rate was 84.5%, 61.3%, and 52.0% at the end of 12, 24 and 36 months after insertion, respectively. Menstrual problems were the most common adverse effects and were also the main reason for discontinuation. In the 23 patients who wished to become pregnant, fertility occurred soon after removal of the Norplant implant. After insertion, serum total cholesterol and triglyceride levels significantly decreased and the hemoglobin concentrations were increased. No liver or renal toxicities were detected. The data suggest that Norplant-2 is a highly effective, safe and long-acting method of reversible contraception. It would be worthwhile to introduce this contraceptive system into Taiwan's family planning program.Between October 1986 and November 1988, physicians enrolled 267 20-41 year old women in a clinical trial of Norplant-2 (2 Silastic rods with 70 mg levonorgestrel each) at the National Taiwan University Hospital to evaluate the advantages and side effects of Norplant-2. 36 women were lost to follow up. 63% suffered from menstrual problems during the first 3 months. 73.6% of these women still had menstrual problems at 6 months. 6 women then chose to discontinue using Norplant-2. 51.8% of the remaining women had persistent menstrual problems at 1 year. 62% of women who discontinued Norplant-2 before the end of 3 years discontinued it due to menstrual problems. The continuation rate was 84.5% at 1 year, 61.3% at 2 years, and 52% at 3 years. 78.6% of women who discontinued Norplant-2 to become pregnant conceived within 1 year after its removal. Just 1 woman (.04%) became pregnant while using Norplant-2. She was thin and smoked heavily. Her aborted fetus had an abnormal fetus had an abnormal karyotype (47,XY,+22). The mean serum total cholesterol and triglyceride levels dropped considerably after Norplant-2 implantation from 164 to 147 mg/dl and from 81 to 63 mg/dl at 12 months, respectively; p .05). Mean hemoglobin levels increased from 12.6 g/dl to 13 g/dl at 12 months (p .05). Levonorgestrel did not affect liver or renal functions. Mean body weight and blood pressure remained the same. Observed psychophysiologic symptoms included depression, acne, headaches, nervousness, and insomnia. These findings indicated Norplant-2 to be safe, reversible, long-acting, and very effective, therefore the family planning program in Taiwan should add it to its contraceptive menu.

IUDs are rigid and heavy thus irritating the endometrium. Their design accounts for many side effects and encourages pelvic infections. IUDs may even facilitate transmission of HIV. Since some health professionals and patients consider some IUDs to be harmful or unacceptable, researchers have worked on developing a newly designed IUD which meets the criteria for and ideal IUD. Some criteria include soft and flexible in nature and inside the uterus, safe, no migration, and light in weight. Taiwanese researchers have developed such an IUD. The silicone skeleton of the Wang SS (soft and safe) Copper 380 and 300 IUDs is bow-shaped with each arm of the bow tapering off from the middle and ending with a small rounded knob. Copper wire (0.31 mm x 380 sq mm or 0.31 mm x 300 sq mm) coils around the holeless vertical stem (3 cm). The monofilament nylon string is fixed in the middle of the stem by an enlarged top. Researchers designed the Wang SS Cu 300 for nulliparous women and the Wang SS Cu 380 for multiparous women. If physicians use a Wang IUD from a sterilized package, they can insert it without wearing sterile gloves. They need to clean the cervix. They must use a single tooth tenaculum to stabilize the uterus and to straighten the uterine axis. After placing the Wang IUD in the inserter, adjusting the flange, and putting the plunger on the inserter, they need to safely introduce the inserter into the uterine cavity to the point where the inserter touches the fundus or the flange touches the cervix. They then must push the plunger to insert the IUD. Insertion should be done immediately after menstruation. Clinicians need to conduct clinical trials to test the safety and effectiveness of the Wang Ss Cu IUDs.

Cystic fibrosis (CF) is a common recessive lethal genetic disorder, affecting 1 in 1,600 Caucasians. The disease causes defective regulation of chloride-ion transport in exocrine cells. Although in all CF families the disease is linked to a locus on chromosome 7q31, there is clinical heterogeneity in the severity of the disease and the age at which it is diagnosed. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. A three-nucleotide deletion (delta F508) causing the loss of a phenylalanine residue in the tenth exon of the CFTR gene has been found on 70% of CF chromosomes. We have now characterized a CF family in which neither parent of the affected individual carries the common mutation, and identified a two-nucleotide insertion in the CF allele of the mother. The mutation introduces a termination codon in exon 13 of the CFTR gene at residue 821, and is predicted to result in the production of a severely truncated nonfunctional protein.

A library of the 8000 tripeptides derivable from coded amino acids was prepared in 20 sets of 400 using solid phase synthesis on a benzhydrylamine resin. The peptide mixtures, as C-terminal amides, were screened for inhibition of secreted alkaline phosphatase expression in a cellular (COS) system wherein a transfected SeAP gene construct was under control of the HIV-1 LTR promoter, activated by the product of a cotransfected HIV Tat gene construct. Thus, YPG-NH2 was discovered as an inhibitor of HIV-1 Tat function and then shown to block HIV replication in a CD4+ T-cell line (CEM) with IC50 = 35μM.

This study presents ultrastructural confirmation of the embolic method of producing an ischemic lesion. The embolic method was shown to produce more advanced parenchymal changes than those reported for the same postocclusion period following vascular clipping. With this method there was less alteration in the morphological intergrity of occluded extraparenchymatous areas of the arterial bed, especially in the associated nerve bundles.

Cerebral blood flow (CBF) and metabolism were measured before and after withdrawal of 5 to 6 ml of cerebrospinal fluid (CSF) in 17 baboons. The measurements were made before and after infusion of tyrosine, the precursor amino acid of the putative neurotransmitters, dopamine and norepinephrine, in the brain. The same observations were made in another experimental group, i.e., before and after acute cerebral multiembolization induced by microfil emboli. In the steady state CBF was unaltered following reduction of intracranial pressure by removal of CSF. After infusion of tyrosine, CBF was decreased, and cerebrovascular resistance increased significantly on removal of CSF. Cerebral embolization did not influence changes in CBF at reduced intracranial pressure. It appears that the cerebral resistance vessels constrict following reduction of intracranial pressure by removal of CSF and that cerebrospinal fluid pressure-CBF autoregulatory mechanisms are resistant to cerebral ischemia induced by middle cerebral artery embolization.

A new modeling technique is introduced for on-line sensor time constant identification, both for the resistance temperature detector (RTD) and for the pressure sensor using power plant operational data. The sensor's time constant is estimated from a real characteristic root of the fitted autoregressive moving average model. The RTD's time constant values were identified to be 8.4 s, with a standard deviation of 1.2 s. The pressure sensor time constant was identified to be 28.6 ms, with a standard deviation of 3.5 ms.

A clinical method for noninvasive measurement of regional cerebral blood flow (rCBF) and blood volume (rCBV) is described, based on Obrist's 10 minute, desaturation method after 1 minute inhalation of 133Xe. Sixteen collimated probes are placed over both hemispheres and brain stem-cerebellar regions. End-tidal 133Xe curves are used for correction of recirculation. KEV discriminators are set to record gamma and x-ray activity separately. Values are printed out automatically by a computer on a brain map. Extracerebral contamination is reduced by 1) computing curves from gamma activity, 2) applying pressure on the scalp beneath the probes, 3) 1 minute inhalation of 133Xe and recording desaturation curves for 10 minutes, thereby minimizing slow clearance from extracranial tissues. Normal values for both fast and slow compartments are reproducible and are in good agreement with the carotid injection method. The speech dominant hemishpere has higher flow than the right under conditions described. Posterior portions of the cranium over the cerebellum and brain stem appear to have higher flow gray values than the cerebral cortex. Gray matter flow decreases with advancing age.

In baboons the right cerebral hemisphere was embolised by a shower of microemboli, immediately followed by one large embolus designed to occlude the middle cerebral artery (MCA). One hour after embolism a significant, though small, reduction in blood flow and oxygen consumption of the embolised hemisphere was recorded, at which time the animals were killed and brain monoamines measured. Dopamine was reduced in the ipsilateral caudate nucleus, the reported site of maximal ischaemic damage in this model. Dopamine levels were increased in frontal and occipital grey matter sampled from areas surrounding the occluded MCA territory and in similar brain areas of the opposite non-embolised hemisphere. Noradrenaline was increased in grey matter from both cerebral hemispheres, as well as subcortical structures bilaterally. Brain 5-hydroxytryptamine levels were unaltered, but increased 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid suggested transient alteration in 5-hydroxytryptamine metabolism after embolism. The effects of cerebral embolism on brain monoamine metabolism appear to be different from the effects of permanent surgical occlusion of major cerebral vessels. The bilaterality of effects after unilateral hemispheric embolism might be related to diaschisis. The mechanisms of the observed changes, as well as their relevance to the progression of cerebral ischaemia and the complications associated with cerebral embolism, still require to be established.

Taeniasis is a major public health problem among the aboriginal populations on Taiwan, and is highly prevalent and wide spread in the mountain areas of 10 Counties. Over 27,000 cases of tapeworm infection are estimated influencing the health and economy in the endemic areas. A treatment of taeniasis with mebendazole and praziquantel followed by a re-treatment with atabrine has been done in the field trial, and confirmed that praziquantel is highly effective agent against tapeworm infection, but mebendazole is not. Based upon experiments reported here praziquantel in a single dose of 150 mg, and 450 mg are highly effective against taeniasis and hymenolepiasis respectively.

One hundred and ten cases of hypertensive disorders in pregnancy were analyzed retrospectively. There were 16 cases of gestational hypertension, 36 cases of mild preeclampsia, 43 cases of severe preeclampsia, 6 cases of eclampsia, and 9 cases of chronic hypertension with superimposed severe preeclampsia. The principle of management was conservative in order to prolong pregnancy for patients remote from term. Corticosteroids were used to accelerate fetal lung maturity for patients with gestations of less than 36 weeks and magnesium sulfate was administered to prevent seizures. Fetal heart rate monitoring was done routinely and doppler blood flow velocity time wave form study of uterine and umbilical arteries was also performed in the latter part of the study. The cesarean section rate in gestational hypertension and mild preeclampsia was comparable to the general obstetric population in our institute (26.9% vs. 21.2%), but the rate of severe forms of the disease including severe preeclampsia, eclampsia, and chronic hypertension with superimposed severe preeclampsia was as high as 77.6%. Fetal distress was the main indication of section. There were 2 cases (6.9%) of mild respiratory distress syndrome, and all recovered uneventfully. The patients with severe forms of the disease had a higher incidence of small infants for gestational age (72%) and delivery at less than 36 weeks' gestation (48.2%). The corrected perinatal mortality rate was 5.4%. No maternal death was encountered. It was concluded that pregnancy could be prolonged in the interest of fetal lung maturity under meticulous maternal-fetal monitoring without endangering the mother.

Oral potassium citrate therapy was recently approved for treatment of urolithiasis based on results of experiments in a university research setting. However, no supporting studies from private practice have been published. The present study was undertaken to assess the response to one week of oral potassium citrate therapy (60 mEq/day), with respect to urinary risk factors for kidney stones, in a private practice setting. A significant rise in urinary pH, citrate, and potassium excretion, accompanying a significant fall in calcium excretion, were observed. Urinary saturation of calcium oxalate was significantly reduced, as some risk factors in urolithiasis were corrected with oral potassium citrate therapy. The response to therapy in private practice was comparable to that observed in a university research setting.

Our previous work has shown that low concentrations of 4-fluoro-3-nitrophenyl azide (FNPA) (0.01-1 microM) photodependently inhibited only the type B monoamine oxidase in rat brain [Biochem. Pharmacol. 34:781-785 (1985)]. Evidence is presented in this paper indicating that higher concentrations of FNPA (15 microM) photodependently inhibit type A monoamine oxidase (MAO-A) from human placenta. FNPA acted as a competitive inhibitor for human placental MAO-A in the dark (Ki = 10 microM) when [14C]serotonin was used as the substrate. The inhibition of MAO-A activity by FNPA was concentration dependent and also irradiation time dependent. The specificity of the photodependent incorporation of FNPA to MAO-A was shown by the protective effect of serotonin during the irradiation. The kinetic analysis showed that the Vmax was decreased whereas the Km was not changed after FNPA was photolyzed with MAO-A. Furthermore, there was no recovery of MAO-A activity upon washing of the photolyzed FNPA-enzyme mixture. These results suggest that FNPA may be covalently bound to the substrate-binding site. Thus, under the present experimental conditions, FNPA is a suitable photoaffinity labeling probe for human placental MAO-A. This is the first photoaffinity label for MAO-A, which may be useful for characterizing the substrate-binding site of this enzyme.

Voltage-controlled multicolor detection with a two-stack GaAs/AlGaAs superlattice structure is reported. Each stack contains a superlattice and current blocking layers. The responsivity of each stack has a voltage-tunable spectral range and can be turned on or off by controlling the bias polarity. In a back-to-back configuration of the two stacks, a variable detection range with peak wavelength at 5.5, 6.8, 8.5, and 10.8 μm is achieved by changing the applied voltage at 45 K.