Mega-electron-volt ultrafast electron diffraction at SLAC National Accelerator Laboratory.

Ultrafast electron probes are powerful tools, complementary to x-ray free-electron lasers, used to study structural dynamics in material, chemical, and biological sciences. High brightness, relativistic electron beams with femtosecond pulse duration can resolve details of the dynamic processes on atomic time and length scales. SLAC National Accelerator Laboratory recently launched the Ultrafast Electron Diffraction (UED) and microscopy Initiative aiming at developing the next generation ultrafast electron scattering instruments. As the first stage of the Initiative, a mega-electron-volt (MeV) UED system has been constructed and commissioned to serve ultrafast science experiments and instrumentation development. The system operates at 120-Hz repetition rate with outstanding performance. In this paper, we report on the SLAC MeV UED system and its performance, including the reciprocal space resolution, temporal resolution, and machine stability.

Remote two-color optical-to-optical synchronization between two passively mode-locked lasers.

Using balanced detection in both the radio frequency (RF) and the optical domain, we remotely synchronize the repetition rate of a Ti:sapphire oscillator to an Er-doped fiber oscillator through a 360 m length-stabilized dispersion compensated fiber link. The drift between these two optical oscillators is 3.3 fs root mean square (rms) over 24 hours. The 68 MHz Er-doped fiber oscillator is locked to a 476 MHz local RF reference clock, and serves as a master clock to distribute 10 fs-level timing signals through stabilized fiber links. This steady remote two-color optical-to-optical synchronization is an important step toward an integrated femtosecond fiber timing distribution system for free-electron lasers (FELs); it does not require x-ray pulses, and it makes sub-10-fs optical/x-ray pump-probe experiments feasible.

Multiple myeloma: the bone marrow microenvironment and its relation to treatment.

Multiple myeloma is the most common haematological malignancy yet currently it remains incurable. For decades the mainstay in therapy has been non-targeted approaches including genotoxic agents and immunosuppressants. With myeloma predominantly affecting an elderly population, who are vulnerable to aggressive therapy, these non-specific approaches have resulted in poor survival. However, in recent years an explosion of collaborative research into myeloma has identified molecular interactions between myeloma cells and the bone marrow microenvironment as promoting myeloma development and associated complications such as bone lesions due to osteolysis. At the same time, a better understanding of the adhesion molecules, cytokines and signalling pathways involved in myeloma has led to the development of new targeted therapies, which are improving the quality of life for patients and significantly extending median patient survival. This review explores the current understanding of molecular pathways that promote myeloma progression and lead to bone destruction, with particular reference to the influence of interactions with the bone marrow microenvironment. It describes molecular targets for therapy with reference to the new therapeutics and their improved efficacy. While the outlook for myeloma patients has improved in recent years as a result of these new approaches, drug resistance remains a problem and future therapies will also need to address the molecular mechanisms of resistance in order to improve further the outcome for patients with this disease.

Role of botulinum toxin A injection into the submandibular salivary glands as an assessment for the subsequent removal of the submandibular glands in the management of children with sialorrhoea.

Sialorrhoea is caused by an excessive production of saliva or a lack of muscular coordination at the initiation of the swallowing reflex during the voluntary phase. In children with neuromuscular disorders it can cause excoriation and social embarrassment. In adults, repeated injections of botulinum have been shown to be beneficial in the control of sialorrhoea, but in children, lack of cooperation necessitates general anaesthesia, and repeated injections would not be appropriate. We aimed to assess outcome after injection of botulinum into the submandibular glands to find out whether subsequent removal of the glands would reduce salivary flow to an acceptable level. We assessed 30 children with various neuromuscular disorders that caused a lack of muscular coordination when swallowing. Under general anaesthesia, they all had injection of 1 unit/kg/gland of botulinum toxin A (Dysport™, Ipsen Ltd., Slough, UK) into each submandibular gland either by bimanual palpation or under ultrasound guidance. They were reassessed at 6 weeks to find out whether the flow had reduced adequately or whether the mouth was too dry. Twenty-one had improved and of these, 20 went on to have the glands removed successfully with no neurological or surgical complications. The mouth of one patient had become too dry after injection and the parents declined further surgery. The remaining 9 did not improve noticeably and continued to be managed medically. Injection of botulinum into the submandibular glands gives a reliable assessment of how much the salivary flow will be reduced after the submandibular gland has been removed.

Toxicity testing: the search for an in vitro alternative to animal testing.

Prior to introduction to the clinic, pharmaceuticals must undergo rigorous toxicity testing to ensure their safety. Traditionally, this has been achieved using in vivo animal models. However, besides ethical reasons, there is a continual drive to reduce the number of animals used for this purpose due to concerns such as the lack of concordance seen between animal models and toxic effects in humans. Adequate testing to ensure any toxic metabolites are detected can be further complicated if the agent is administered in a prodrug form, requiring a source of cytochrome P450 enzymes for metabolism. A number of sources of metabolic enzymes have been utilised in in vitro models, including cell lines, primary human tissue and liver extracts such as S9. This review examines current and new in vitro models for toxicity testing, including a new model developed within the authors' laboratory utilising HepG2 liver spheroids within a co-culture system to examine the effects of chemotherapeutic agents on other cell types.

A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro.

1. In the CA1 region of hippocampal slices prepared from juvenile (12- to 18-day-old) rats, activation of group I metabotropic L-glutamate (mGlu) receptors by the specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) induces a form of long-term depression (LTD) of excitatory synaptic transmission. 2. We have used a variety of electrophysiological techniques applied to CA1 neurones in hippocampal slices and from pyramidal cells in dissociated hippocampal cultures to investigate the Ca2+ dependence and locus of expression of DHPG-induced LTD. 3. In patch-clamp experiments from hippocampal slices, bath application of DHPG induced a depression of synaptically evoked responses that persisted for the duration of the recording (up to 2 h after commencing washout of DHPG) in 27 of 29 neurones investigated. 4. DHPG-induced LTD was associated with an increase in both the paired-pulse facilitation ratio and the coefficient of variation of EPSCs. 5. Using dendritic recording, there was a decrease in EPSC success rate (number of trials that elicited a detectable response) but no change in potency (mean EPSC amplitude excluding failures) associated with DHPG-induced LTD. 6. In experiments using dissociated hippocampal cultures, application of DHPG elicited a persistent decrease in the frequency of tetrodotoxin-resistant miniature EPSCs but no change in the amplitude of such events. 7. DHPG-induced LTD was not blocked by intracellular application of the calcium chelator BAPTA. It was also unaffected when intracellular calcium stores were depleted by perfusion with thapsigargin. Furthermore, when synaptic transmission was blocked by perfusing with Ca2+-free medium, DHPG application reliably induced LTD. 8. These data suggest that DHPG-induced LTD is Ca2+ independent and is expressed presynaptically.

The effect of additional shots on the vaccine administration process: results of a time-motion study in 2 settings.

CONTEXT: The introduction of combination vaccines to the pediatric regimen offers the possibility of reducing the number of injections required to reach full vaccination status. Fewer injections benefit the patient/child and the parent/caregiver, and the healthcare provider may benefit from savings in personnel time associated with vaccine administration. To date, however, these savings have not been quantified. OBJECTIVE: To study the vaccine administration process in a managed care environment. STUDY DESIGN: We studied 2 settings in which vaccinations were administered: (1) a devoted injection room and (2) the examination room as part of the well-child examination. For each setting, we documented the vaccine administration process, identified vaccine-related activities, and quantified the time savings in each activity by reductions in the number of shots. PATIENTS AND METHODS: For vaccine recipients younger than 2 years, time-motion data on vaccine-related activities in 2 managed care settings were collected by a professional industrial engineering consultant. Activity time data by the number of shots administered were analyzed using linear regression adjusting for patient age. RESULTS: We observed 276 vaccination visits (137 in an examination room, and 139 in an injection room). Total nurse time associated with vaccine administration decreased by 2.4 and 1.7 minutes per shot eliminated in the examination room setting (P = .006) and in the injection room setting (P < .001), respectively. Significant time savings were realized for activities associated with vaccine preparation, vaccine injection, and administrative duties. In addition, infant crying time decreased by 1.0 and 0.4 minutes per shot eliminated in the examination room and injection room settings, respectively (P < or = .001 for both). CONCLUSIONS: Significant reductions in vaccine administration time could be achieved by eliminating injections during a well-child regimen.

Prevalence of dyskinesia and related movement disorders in a developmentally disabled population.

The prevalences and inter-relationships of five types of movement disorders were evaluated in a large, developmentally disabled (DD) population (n = 1227); prevalence was evaluated with regard to severity, age, gender and antipsychotic-drug (APD) exposure. Dyskinesia was found in 48% of the sample, dystonia in 29%, akathisia in 13%, Parkinsonism in 3% and paroxysms in 4%. Many persons had more than one symptom so that 72% had one or more of the five target symptoms. Although the five movement-disorder categories were not mutually exclusive, analysis supported the individuality of the categories as defined in this study. The prevalences of dyskinesia and Parkinsonism were considerably greater than those in the general population. On the other hand, the prevalence of dyskinesia was similar to that reported for psychiatric and institutionalized geriatric populations. Parkinsonism increased with age and male gender, while dyskinesia increased with age and female gender. APD-exposure was significantly correlated only with akathisia.

Dyskinesia, antipsychotic-drug exposure and risk factors in a developmentally-disabled population.

The relation between antipsychotic drug (APD) exposure and the prevalence of dyskinesia (DK) was examined in a large, developmentally-disabled (DD) population. Using qualitative data in a cross-sectional, retrospective design, the drug-exposed group was systematically compared with a non-drug-exposed group, controlling for age and gender. When the population was evaluated with no regard to APD-exposure, age and female gender were significant risk factors, as in many prior studies. When APD-exposure was considered, it proved to be a complex variable dependent on the recency of exposure to APD, and the outcome depended on the method of analysis: when APD-exposure was considered as a binomial variable (yes/no), the relationship between APD and DK was not significant; when APD-exposure was controlled for recency of exposure, however, a significant relationship between APD and DK was demonstrated (p less than 0.01) although the relationship accounted for less than 3% of the variance. Analysis of the relation between DK-prevalence and recency-of-APD-exposure revealed a pattern of diminished prevalence during APD use and increased prevalence during early withdrawal.

Carcinoma of the lung: a clinical review.

Records of 702 patients with carcinoma of the lung seen from 1960 through 1970 were reviewed. The efficacy of various diagnostic and therapeutic procedures was assessed. Salient findings were as follows: Biopsy of nonpalpable ipsilateral supraclavicular lymph nodes was positive for carcinoma in 63 of 286 patients (22%). Even more surprising, biopsy of nonpalpable contralateral supraclavicular lymph nodes was positive for carcinoma in 9 of 38 patients (24%). Accordingly, the importance of biopsy of nonpalpable supraclavicular nodes is to be stressed. Squamous cell carcinoma was the most common type, but adenocarcinoma was more common in women and nonsmokers. Among the 702 patients, 48 (6.8%) were nonsmokers. The 5-year survival for 92 patients treated by lobectomy was 21%; the 5-year survival for 77 patients treated by pneumonectomy was 19%; the 5-year survival among 18 patients have resection of the chest wall in addition to resection of the primary lesion was 22%. Of 12 patients with small cell carcinoma of the lung treated by resection, there was 1 5-year survivor. The overall 5-year survival in the 702 patients was 6.6%.

Urachal remnants: benign or malignant?

Two cases are presented with cystoscopically visible cystic urachal remnants. The initial clinical findings, including bladder biopsies, were remarkably similar. Partial cystectomy with removal of the urachal cord alone clarified the actual disease. The inability to separate the malignant and the benign urachal lesion by other means suggests the necessity of total surgical extirpation. Perhaps this approach may result in an improvement in the generally poor prognosis for urachal carcinoma.

Studies of the biologic effects of selective C4 deficiency.

The role of the several pathways of complement activation in mediating a number of the biologic activities of complement has been examined in an animal model, the C4-deficient guinea pig. It has been shown that the presence of an intact classic pathway (C1, 4, 2) is requisite for damage of antibody-sensitized mammalian cell membranes and for the development of thrombocytopenia and the hypercoagulable state following in vivo endotoxin administration. Both the classic and alternate pathways participate in defense against the lethal effects of endotoxin, in opsonization and lysis of bacteria and in mediation of the events of inflammation.