Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer's disease patients.

Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition. This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25-59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively. The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).

A spherical crystal diffraction imager for Sandia's Z Pulsed Power Facility.

Sandia's Z Pulsed Power Facility is able to dynamically compress matter to extreme states with exceptional uniformity, duration, and size, which are ideal for investigating fundamental material properties of high energy density conditions. X-ray diffraction (XRD) is a key atomic scale probe since it provides direct observation of the compression and strain of the crystal lattice and is used to detect, identify, and quantify phase transitions. Because of the destructive nature of Z-Dynamic Material Property (DMP) experiments and low signal vs background emission levels of XRD, it is very challenging to detect a diffraction signal close to the Z-DMP load and to recover the data. We have developed a new Spherical Crystal Diffraction Imager (SCDI) diagnostic to relay and image the diffracted x-ray pattern away from the load debris field. The SCDI diagnostic utilizes the Z-Beamlet laser to generate 6.2-keV Mn-Heα x rays to probe a shock-compressed material on the Z-DMP load. A spherically bent crystal composed of highly oriented pyrolytic graphite is used to collect and focus the diffracted x rays into a 1-in. thick tungsten housing, where an image plate is used to record the data.

Design and raytrace simulations of a multilayer-coated Wolter x-ray optic for the Z machine at Sandia National Laboratories.

Recent breakthroughs in the fabrication of small-radii Wolter optics for astrophysics allow high energy density facilities to consider such optics as novel x-ray diagnostics at photon energies of 15-50 keV. Recently, the Lawrence Livermore National Laboratory, Sandia National Laboratories (SNL), the Smithsonian Astrophysical Observatory, and the NASA Marshall Space Flight Center jointly developed and fabricated the first custom Wolter microscope for implementation in SNL's Z machine with optimized sensitivity at 17.5 keV. To achieve spatial resolution of order 100-200 microns over a field of view of 5 × 5 × 5 mm3 with high throughput and narrow energy bandpass, the geometry of the optic and its multilayer required careful design and optimization. While the geometry mainly influences resolution and the field of view of the diagnostic, the mirror coating determines the spectral response and throughput. Here we outline the details of the design and fabrication process for the first multilayer-coated Wolter I optic for SNL's Z machine (Z Wolter), including its W/Si multilayer, and present results of raytrace simulations completed to predict and verify the performance of the optic.

A Wolter imager on the Z machine to diagnose warm x-ray sources.

A new Wolter x-ray imager has been developed for the Z machine to study the emission of warm (>15 keV) x-ray sources. A Wolter optic has been adapted from observational astronomy and medical imaging, which uses curved x-ray mirrors to form a 2D image of a source with 5 × 5 × 5 mm3 field-of-view and measured 60-300-µm resolution on-axis. The mirrors consist of a multilayer that create a narrow bandpass around the Mo Kα lines at 17.5 keV. We provide an overview of the instrument design and measured imaging performance. In addition, we present the first data from the instrument of a Mo wire array z-pinch on the Z machine, demonstrating improvements in spatial resolution and a 350-4100× increase in the signal over previous pinhole imaging techniques.

A new time and space resolved transmission spectrometer for research in inertial confinement fusion and radiation source development.

We describe the design and function of a new time and space resolved x-ray spectrometer for use in Z-pinch inertial confinement fusion and radiation source development experiments. The spectrometer is designed to measure x-rays in the range of 0.5-1.5 Å (8-25 keV) with a spectral resolution λ/Δλ ∼ 400. The purpose of this spectrometer is to measure the time- and one-dimensional space-dependent electron temperature and density during stagnation. These relatively high photon energies are required to escape the dense plasma created at stagnation and to obtain sensitivity to electron temperatures ≳3 keV. The spectrometer is of the Cauchois type, employing a large 30 × 36 mm2, transmissive quartz optic for which a novel solid beryllium holder was designed. The performance of the crystal was verified using offline tests, and the integrated system was tested using experiments on the Z pulsed power accelerator.

X-ray intensity and source size characterizations for the 25 kV upgraded Manson source at Sandia National Laboratories.

At Sandia National Laboratories, the x-ray generator Manson source model 5 was upgraded from 10 to 25 kV. The purpose of the upgrade is to drive higher characteristics photon energies with higher throughput. In this work we present characterization studies for the source size and the x-ray intensity when varying the source voltage for a series of K-, L-, and M-shell lines emitted from Al, Y, and Au elements composing the anode. We used a 2-pinhole camera to measure the source size and an energy dispersive detector to monitor the spectral content and intensity of the x-ray source. As the voltage increases, the source size is significantly reduced and line intensity is increased for the three materials. We can take advantage of the smaller source size and higher source throughput to effectively calibrate the suite of Z Pulsed Power Facility crystal spectrometers.

Evidence of a possible role of altered angiotensin function in the treatment, but not etiology, of depression.

BACKGROUND: Angiotensin-converting enzyme inhibitors are reportedly effective in the treatment of depression; furthermore, antidepressants decrease angiotensin function. It appears therefore that reduced angiotensin function may be important in the treatment of depression. The aims of this study were to elucidate the actions of antidepressants on angiotensin receptors; to investigate the antidepressant potential of an angiotensin antagonist; and to study angiotensin receptors in depressed puerperal women. METHODS: The effects of antidepressant drugs on angiotensin receptors and the relationship between mood and platelet receptors in puerperal women were investigated using radioligand binding. The antidepressant potential of the angiotensin antagonist losartan was assessed using the mouse forced swim test. RESULTS: Desipramine, but neither fluoxetine nor tranylcypromine, displaced angiotensin from its receptor; however, there was no significant relationship between receptor number and depressed mood. In the forced swim test losartan was shown to possess antidepressant like activity. CONCLUSIONS: These findings indicate that antidepressants differ in the mechanism by which they reduce angiotensin function, but the link between antidepressants and angiotensin is reiterated by the demonstration that losartan possesses antidepressant like activity. There is, however, no evidence of abnormal angiotensin receptors in women with depressed mood postpartum.

Reduction of salbutamol-induced drinking by putative and proven antidepressants.

Salbutamol-induced drinking was determined in rats after 4 days of twice daily treatment with the conventional and putative antidepressants desipramine, clenbuterol or salbutamol. Drinking was also determined 21 h after a single dose of the abovementioned drugs. Both chronic and acute administration of the drugs resulted in a significant reduction in the salbutamol-induced fluid intake. The results suggest that these drugs decrease beta 2-adrenoceptor activity, but that repeated administration is not a prerequisite for the effect.

Reduction of responses to angiotensin II by antidepressant drugs.

The effects of the antidepressant drugs desipramine, fluoxetine and tranylcypromine and the non-antidepressant control cocaine on angiotensin II function were determined in vivo by use of angiotensin-induced drinking in rats and in vitro using contractile responses of the rat uterus. The results of the drinking studies showed that the three antidepressants, but not cocaine, reduced the dipsogenic effects of angiotensin II. In vitro, all of the drugs reduced the effects of not only angiotensin but also acetylcholine and oxytocin on the uterus. The inhibition appeared to be non-competitive in all cases. These results indicate that the antidepressant drugs reduced the activity of angiotensin II, albeit non-selectively, and suggest that the previously reported effects of antidepressants on isoprenaline-induced drinking in rats reflect an action on angiotensin activity rather than a reduction of beta-adrenoceptor activity as previously suggested.

In vitro cytotoxicity and teratogenicity of norethisterone and levonorgestrel released from hollow nylon monofilaments.

Direct delivery of progestogens to the uterus may be of use in the treatment of dysfunctional uterine bleeding and the sequelae of the menopause as it has the potential to overcome the problems of systemic administration. This study characterised the release of norethisterone and levonorgestrel into an aqueous medium from hollow nylon fibres with dimensions suitable for easy insertion through the post-menopausal cervix. Cell culture techniques were used to assess potential cytotoxic and teratogenic effects. The results demonstrated that the hollow fibres released norethisterone and levonorgestrel at mean rates of 0.5 and 0.6 micrograms/day over 14 days, respectively. There were indications, however, that both steroids were toxic to endometrial cells at concentrations of approximately 5 micrograms/ml, and both drugs showed signs of potential teratogenicity at 10 micrograms/ml. Delivery of the same doses of norethisterone using the hollow fibres reduced the effects on the endometrial and fetal cells. Delivery of levonorgestrel from the hollow fibres had no effect on the endometrial cell toxicity but potentiated the effects on the fetal cells. These results suggest that the hollow nylon fibres may be of use for the delivery of norethisterone to the uterus but that they are inappropriate for the delivery of levonorgestrel.

Strain differences in the anxiolytic effects of losartan in the mouse.

Anxiolytic effects of the angiotensin AT(1) receptor antagonist losartan were studied in the elevated plus maze (EPM) and the light/dark test (LDT) in different mouse strains as were responses to angiotensin II and acetylcholine in isolated ascending colon. There were no significant strain differences in behaviour on the EPM, and diazepam was anxiolytic in C57BL/6, DBA/2 and BKW mice. Losartan was anxiolytic in BKW only. In the LDT, there were significant strain differences, with BKW mice exhibiting greatest anxiety-like behaviour; losartan was ineffective in this test. In vitro responses to angiotensin II and acetylcholine were significantly smaller in BKW than in C57BL/6 and DBA/2. These results indicate that the mouse strain exhibiting least angiotensin receptor function is the most responsive to the anxiolytic effects, suggesting a possible relationship between angiotensin receptor function and anxiolytic response to losartan.

Comparison of amoxycillin and clarithromycin as initial treatment of community-acquired lower respiratory tract infections.

BACKGROUND: Numerous new oral antibiotics have been produced over the last few years with the aims of improving treatment for lower respiratory tract infections. AIM: The aim of the study was to compare the efficacy of an established drug, amoxycillin, with a new macrolide, clarithromycin, for initial treatment of adults with community-acquired lower respiratory tract infection. METHOD: Consecutive adults fulfilling a standard definition of lower respiratory tract infection presenting to 14 general practitioners in two neighbouring practices were allocated to antibiotic therapy in a random, single-blind manner. The outcome of treatment was assessed by the time taken by the patient to return to normal activities or work, the speed of resolution of symptoms, number of repeat consultations and side effects. RESULTS: The profile of the 221 patients receiving amoxycillin was very similar to that of the 221 receiving clarithromycin. The two groups did not differ greatly in requirement to visit the general practitioner again within either 4 weeks (20% amoxycillin group; 25% clarithromycin group) or 3 months (31% compared with 36%) of the original infection, in time taken to return to normal activities (6 days for group taking amoxycillin; 5 days for those on clarithromycin) or work (5 days for both groups), or in speed of resolution of symptoms. Compliance was good and the side-effects reported were similar for both groups. No increase in gastrointestinal complaints was noted for patients taking the macrolide. CONCLUSION: Amoxycillin and clarithromycin appear to be equally effective as initial therapy and to be tolerated in similar ways. Use of the newer drug appears to have no advantages over use of the accepted standard treatment.

Marketing issues in continuing medical education.

Marketing is an important component of continuing medical education (CME). However, marketing is more than the identification of methods to recover costs of delivering programming. It focuses on meeting the needs and desires of physician participants, identifying an appropriate location, satisfying the goals of a sponsoring institution, and making an effect on the quality of care given by receivers and deliverers of CME. This paper discusses these issues as well as describes results of a survey designed to gather opinions on CME activities from alumni of training programs of a large, referral-based, multispecialty group practice. The data suggest that CME programs should be targeted to certain specialty groups as determined by field of training rather than practice specialty. Physicians' preferences for CME activities held at resort settings should be considered. Finally, participation in CME may itself be a marketing tool for a sponsoring institution to increase referrals.

Cytotoxicity and teratogenicity of chlorhexidine diacetate released from hollow nylon fibres.

Intra-uterine contraceptive devices are associated with an increased incidence of pelvic infections, possible due to the introduction of vaginal bacteria into the uterus at insertion. One potential means to overcome this problem is the use of a device which releases the antimicrobial agent chlorhexidine although such an approach carries with it the risk of adverse effects on the endometrium and, possibly, teratogenic effects. Cultured monolayers of endometrial cells were used to assess the cytotoxicity of both chlorhexidine and chlorhexidine-releasing devices. The results indicated that the agent is toxic at concentrations of 1 microg mL(-1) and that the devices potentiated the toxicity. When the devices were tested in a guinea-pig model, endometrial damage was seen only at the high dose of chlorhexidine, suggesting that there is greater distribution of chlorhexidine in-vivo. Assessment of the teratogenic effects of chlorhexidine in rat embryonic limb bud tissue cells in-vitro showed that the foetal cells were highly susceptible to the toxic effects of chlorhexidine, but that there was no evidence of teratogenicity. Overall, the findings suggest that chlorhexidine-releasing devices may be a safe means of reducing infections related to intra-uterine devices, but that the chlorhexidine may have a toxic effect on foetal cells.

The effects of transcervical monofilament insertion on the microbial status of the uterus in guinea-pigs.

The monofilament marker tail attached to intra-uterine contraceptive devices (IUCDs) has been implicated in the development of pelvic infection because it acts as a substrate for bacterial adhesion, and facilitates the transmission of vaginal bacteria into the uterus. A guinea-pig model was used to investigate the role of transcervical monofilaments in the transmission of vaginal bacteria into the uterus. By 21 days the degree of uterine contamination was significantly lower than after 24 h (P < 0.05), but was still significantly greater than control values (P < 0.01). Coating the monofilaments with poly (2-hydroxyethyl-methacrylate) (polyHEMA) had no effect on uterine bacterial counts at 24 h. After 21 days, however, contamination within the uteri fitted with polyHEMA-coated monofilaments had significantly increased from levels observed at 24 h (P < 0.01). These counts were also significantly greater than those recorded for the uncoated and control groups at the same time interval. In animals fitted with monofilaments, in which chlorhexidine had been incorporated into the polyHEMA coating, the level of uterine contamination after 24 h was significantly lower than that observed with uncoated threads at the same time interval (P < 0.02). After 21 days there was no significant difference between uterine bacterial counts from the chlorhexidine group and control animals. It is concluded that the use of such drug-loaded monofilaments offers the potential to minimize infections associated with the transcervical insertion of IUCDs.

The effects of antibiotics and steroids on the carriage of vaginal bacteria into the uterus during insertion of intra-uterine monofilaments in the guinea-pig.

The effects of systemic norethisterone acetate and oxytetracycline hydrochloride on the levels of vaginal microorganisms found in the uterus after the insertion of transcervical, intra-uterine monofilaments in the guinea-pig were determined. The results indicated that bacteria were transferred to the uterus from the vagina during the insertion process and, in the presence of an intra-uterine substrate, persisted for up to 6 months. Daily treatment with norethisterone acetate or oxytetracycline hydrochloride whilst the monofilament was in-situ failed to reduce the bacterial numbers in the uterus. Similarly, daily treatment with oxytetracycline hydrochloride for the 5 days before monofilament insertion had no effect on these bacteria.

The effects of bromhexine hydrochloride and S-carboxymethyl-L-cysteine on guinea-pig uterine microflora.

This study used guinea-pigs as a mammalian model to investigate the effects of bromhexine hydrochloride and S-carboxymethyl-L-cysteine on the integrity of the cervical mucus plug. It was shown that under normal circumstances the uterus is sterile, but following drug administration microorganisms began to appear in the uterus with no significant effect on the vaginal microbial population. It therefore appears that these two mucolytic agents may reduce cervical mucus viscoelasticity. After the animals had been mated, microorganisms were isolated from the uterus even in the absence of drug treatment.

Predisposition to uterine microbial contamination in the guinea-pig following administration of mucolytic drugs and steroid hormones.

Using guinea-pigs as a mammalian model, the effects of bromhexine hydrochloride, ethinyloestradiol, norethisterone acetate and prednisolone acetate on uterine microbial status were determined. Those drugs known to decrease mucus viscoelasticity predisposed to the entry of vaginal bacteria into the uterus, probably due to reduction of the cervical mucus barrier. Norethisterone acetate, which increases cervical mucus viscoelasticity, reduced these effects. The effects produced by the steroid hormones were independent of their immunosuppressive effects. The results also suggest that prednisolone acetate may exert oestrogen-like actions on cervical mucus.

Prospective case-control study of role of infection in patients who reconsult after initial antibiotic treatment for lower respiratory tract infection in primary care.

OBJECTIVE: To assess direct and indirect evidence of active infection which may benefit from further antibiotics in adults who reconsult within 4 weeks of initial antibiotic management of acute lower respiratory tract infection in primary care. DESIGN: Observational study with a nested case-control group. SETTING: Two suburban general practices in Arnold, Nottingham, over 7 winter months. SUBJECTS: 367 adults aged 16 years and over fulfilling a definition of lower respiratory tract infection and treated with antibiotics. 74 (20%) patients who reconsulted within 4 weeks for the same symptoms and 82 "control" patients who did not were investigated in detail at fallow up. MAIN OUTCOME MEASURES: Direct and indirect evidence of active infection at the time of the reconsultation or the follow up visit with the research nurse for the controls. Investigations performed included sputum culture, pneumococcal antigen detection, serial serology for viral and atypical pathogens and C reactive protein, throat swabs for detecting viral and atypical pathogens by culture and polymerase chain reaction, and chest radiographs. RESULTS: Demographic and clinical features of the groups were similar. Two thirds of the 74 patients who reconsulted received another antibiotic because the general practitioner suspected continuing infection. Any evidence of infection warranting antibiotic treatment was uncommon at reconsultation. The findings for the two groups were similar for the occurrence of identified pathogens; chest x ray changes of infection (present in 13%); and C reactive protein concentrations, which had nearly all fallen towards normal. Only three patients in the reconsultation group had concentrations > or = 40 mg/l. Pathogens identified at follow up in the 156 patients in both groups included ampicillin sensitive bacteria in six. Atypical infections diagnosed in 27 (Chlamydia pneumoniae in 22) and viral infections in 54 had probably been present at the initial presentation. CONCLUSION: Our study suggests that active infection, which may benefit from further antibiotics, is uncommon in patients who reconsult after a lower respiratory tract infection, and a repeat antibiotic prescription should be the exception rather than the rule. Other factors, such as patients' perception of their illness, may be more important than disease and infection in their decision to reconsult.