Suppression of Emittance Growth Using a Shaped Cold Atom Electron and Ion Source.

We demonstrate precise control of charged particle bunch shape with a cold atom electron and ion source to create bunches with linear and, therefore, reversible Coulomb expansion. Using ultracold charged particles enables detailed observation of space-charge effects without loss of information from thermal diffusion, unambiguously demonstrating that shaping in three dimensions can result in a marked reduction of Coulomb-driven emittance growth. We show that the emittance growth suppression is accompanied by an increase in bunch focusability and brightness, improvements necessary for the development of sources capable of coherent single-shot ultrafast electron diffraction of noncrystalline objects, with applications ranging from femtosecond chemistry to materials science and rational drug design.

Detailed observation of space-charge dynamics using ultracold ion bunches.

Control of Coulomb expansion in charged particle beams is of critical importance for applications including electron and ion microscopy, injectors for particle accelerators and in ultrafast electron diffraction, where space-charge effects constrain the temporal and spatial imaging resolution. The development of techniques to reverse space-charge-driven expansion, or to observe shock waves and other striking phenomena, have been limited by the masking effect of thermal diffusion. Here we show that ultracold ion bunches extracted from laser-cooled atoms can be used to observe the effects of self-interactions with unprecedented detail. We generate arrays of small closely spaced ion bunches that interact to form complex and surprising patterns. We also show that nanosecond cold ion bunches provide data for analogous ultrafast electron systems, where the dynamics occur on timescales too short for detailed observation. In a surprising twist, slow atoms may underpin progress in high-energy and ultrafast physics.

Levels of a subpopulation of platelets, but not circulating endothelial cells, predict early treatment failure in prostate cancer patients after prostatectomy.

BACKGROUND: Angiogenesis is one of the hallmarks of cancer driving tumour growth and ultimately metastasis. Circulating endothelial cells (CECs) and circulating endothelial progenitor (CEPs) cells have been reported as candidate surrogate markers for tumour vascularisation. Our aim was to investigate the potential use of these circulating cells levels as predictors of prostate cancer treatment failure and metastasis. METHODS: We examined the levels of CD31(+)CD45(-) cells (CECs) and CD31(+)CD45(-)CD117(+) (CEPs) in s.c. and orthotopic models of human prostate cancers and correlated measurements with tumour size, volume and microvessel density (MVD). We then performed a prospective cohort study in 164 men with localised prostate cancer undergoing prostatectomy. The CD31(+)CD45(-), CD31(+)CD45(-)CD146(+) (CECs) and CD31(+)CD45(intermediate)CD133(+) (CEPs) populations were quantified and subsequently enriched for further characterisation. RESULTS: In preclinical models, levels of CD31(+)CD45(-) cells, but not CEPs, were significantly elevated in tumour-bearing mice and correlated with tumour size, volume and MVD. In our human prospective cohort study, the levels of CD31(+)CD45(-) cells were significantly higher in men who experienced treatment failure within the first year, and on logistic regression analysis were an independent predictor of treatment failure, whereas neither levels of CECs or CEPs had any prognostic utility. Characterisation of the isolated CD31(+)CD45(-) cell population revealed an essentially homogenous population of large, immature platelets representing <0.1% of circulating platelets. CONCLUSION: Elevated levels of a distinct subpopulation of circulating platelets were an independent predictor for early biochemical recurrence in prostate cancer patients within the first year from prostatectomy.

Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older.

Several inhaled drugs for use by cystic fibrosis (CF) patients are formulated for nebulizer use only. This therapy is time consuming and includes the risk of contamination of the nebulizers. Dry powder inhalers (DPI) can be an attractive alternative for CF drugs. Inhaled flow rate and volume, and the device resistance are important determinants for optimal dispersion of drug from a DPI. It is important to understand how these variables interact in the CF population in order to properly design a new DPI formulation targeted for these patients. The objective of this study was to assess the inspiratory variables of a representative population of CF subjects 6 years and older with varying degrees of lung disease while inhaling through resistances that simulate DPI devices. Ninety-six stable CF patients were enrolled, ages 6-54 years, FEV(1) 19-126% predicted. Subjects inhaled forcefully through four different resistances (0.019, 0.024, 0.038, and 0.048 kP(0.5)/LPM, respectively), while inspiratory time (IT(DPI)), peak inspiratory flow (PIF(DPI)), and volumes (V(DPI)) were measured. For any resistance, inspired V(DPI) increased with the older age groups; PIF(DPI) was similar between adults and adolescents but lower in the children. Subjects with lower FEV(1) had lower V(DPI) and PIF(DPI). As resistance increased, PIF(DPI) decreased, IT(DPI) increased, with no significant change in V(DPI). At the lowest resistance mean PIF(DPI) was 105 LPM (range 45-163) for all patients; 112 LPM (range 75-163) in adults; and 89 LPM (45-126) in children. Mean inspired V(DPI) was 1.75 L for all patients; 2.2 L (0.8-3.7) in adults; and 1.2 L (0.5-1.8) in children. At the lowest resistance a minimal flow rate of 30, 45, and 60 LPM was attained in 100%, 99%, and 96% of all patients. Volumes of 1.0, 1.5, and 2.0 L were attained by 85%, 57%, and 30% of the patients. At the highest resistance mean PIF(DPI) was 52 LPM (range 26-70) for all patients; 55 LPM (40-70) in adults; and 47 LPM (26-62) in children. Mean inspired V(DPI) was 1.5 L in all patients; 1.9 L (0.9-3.5) in adults and 1.1 L (0.5-2.3) in children. At the highest resistance, a minimal flow rate of 30, 45, and 60 LPM was attained in 99%, 80%, and 22% of all patients. Volumes of 1, 1.5, and 2 L were attained in 84%, 45%, and 23% of the patients. We defined ranges for inspiratory variables in a diverse CF population for a range of device resistances that bracket those of current DPIs. The recorded inspiratory patterns can be used on the bench to design and test new dry powder formulations and devices to target the largest proportion of the CF population.

An improved cocaine hydrolase: the A328Y mutant of human butyrylcholinesterase is 4-fold more efficient.

Butyrylcholinesterase (BChE) has a major role in cocaine detoxication. The rate at which human BChE hydrolyzes cocaine is slow, with a kcat of 3.9 min(-1) and Km of 14 microM. Our goal was to improve cocaine hydrolase activity by mutating residues near the active site. The mutant A328Y had a kcat of 10.2 min(-1) and Km of 9 microM for a 4-fold improvement in catalytic efficiency (kcat/Km). Since benzoylcholine (kcat 15,000 min(-1)) and cocaine form the same acyl-enzyme intermediate but are hydrolyzed at 4000-fold different rates, it was concluded that a step leading to formation of the acyl-enzyme intermediate was rate-limiting. BChE purified from plasma of cat, horse, and chicken was tested for cocaine hydrolase activity. Compared with human BChE, horse BChE had a 2-fold higher kcat but a lower binding affinity, cat BChE was similar to human, and chicken BChE had only 10% of the catalytic efficiency. Naturally occurring genetic variants of human BChE were tested for cocaine hydrolase activity. The J and K variants (E497V and A539T) had k(cat) and Km values similar to wild-type, but because these variants are reduced to 66 and 33% of normal levels in human blood, respectively, people with these variants may be at risk for cocaine toxicity. The atypical variant (D70G) had a 10-fold lower binding affinity for cocaine, suggesting that persons with the atypical variant of BChE may experience severe or fatal cocaine intoxication when administered a dose of cocaine that is not harmful to others.

In vitro antimycobacterial activity of 5-chloropyrazinamide.

5-Chloropyrazinamide and 5-chloropyrazinoic acid were evaluated for in vitro activity against Mycobacterium tuberculosis, Mycobacterium bovis, and several nontuberculous mycobacteria by a broth dilution method. 5-Chloropyrazinamide was more active than pyrazinamide against all organisms tested. It is likely that this agent has a different mechanism of action than pyrazinamide.

Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide.

The mechanism of action of pyrazinamide (PZA) is not known. One hypothesis is that PZA functions as a prodrug of pyrazinoic acid. Susceptibility to PZA correlates with amidase activity of the Mycobacterium tuberculosis isolate in question. PZA-resistant isolates retain susceptibility in vitro to pyrazinoic acid and n-propyl pyrazinoate. Esters of pyrazinoic acid appear to circumvent the requirement for activation by mycobacterial amidase. The MICs of n-propyl pyrazinoate for M. tuberculosis isolates are lower than those of pyrazinoic acid. Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way. This may lead to a candidate compound with enhanced activity against both PZA-susceptible and PZA-resistant M. tuberculosis isolates suitable for clinical development.

Hyperventilation in the dental chair.

An anxious patient may experience an uncontrollable increase in ventilatory effort, far in excess of the body's metabolic needs, to such a degree that profound changes are induced in the cardiovascular and neurological systems. This abnormal drive to breathe rapidly leads to a reduction in the tension of carbon dioxide in alveolar gas and arterial blood and to mild alkalosis. The outward expression of these disturbances can be alarming for both patient and dentist, but for the physiologist searching for underlying mechanisms it is intriguing. The cursory coverage of this subject in some textbooks and lecture courses is regrettable when one considers that hyperventilation is not uncommon in a dental patient. This article examines the causes, signs, symptoms and management of acute hyperventilation.

One counsellor, two practices: report of a pilot scheme in Cambridgeshire.

BACKGROUND: Despite limited evidence of their effectiveness, counsellors are increasingly being employed as part of the primary health care team. Evaluation of counsellor services is therefore important. AIM: In 1990 the Cambridgeshire Family Health Services Authority initiated a pilot scheme to evaluate the role of counsellors in general practice and to help the authority determine its policy towards claims by general practitioners for reimbursement through the ancillary staff scheme. METHOD: Two group practices were identified and an external evaluator appointed. The evaluator and the general practitioners developed their aims and objectives for counselling in the general practice context, the number of counsellor hours per week and the type and process of referral. An experienced counsellor was appointed to work in both practices. Information was gathered over two years about doctors' reasons for referral, counsellor's initial assessment, patient outcome at the end of treatment, the patients' and practice teams' opinions about the counselling service, and patient outcome a year after counselling. RESULTS: A total of 293 patients were referred in the first two years of the scheme, of whom 75% were women. The main reasons for referral were that the general practitioners considered the patients to be suffering from anxiety/stress (33%), interpersonal difficulties (33%) and depression (20%). Almost all referrals (98%) were considered by the counsellor to be appropriate. The counsellor was able to provide an assessment for the 248 patients who attended and either take on the case for short-term counselling (69%) or suggest referral to a more appropriate service (25%) (6% withdrew). The expected maximum of six sessions of 45 minutes duration per referral was achieved in 87% of cases. The service was valued by patients and doctors. It coped effectively with a high proportion of patients with problems who did not reappear as demand elsewhere in the practice, and achieved a reduction in dose of psychotropic drugs among those seen. CONCLUSION: This study has shown the value of clarifying referral criteria and the intended role of the counsellor prior to the counsellor's introduction. This ensures effective use of a scarce resource and a high level of satisfaction among doctors and patients.

Stress and the immune system.

The centuries-old belief that stressed individuals are more susceptible to disease has gained scientific respectability in recent years. A new interdisciplinary science, psychoneuroimmunology (or as it is now more appropriately named, psychoneuroendocrinimmunology) has been born and, judging from the number of articles appearing annually, is thriving. In essence, stressors activate the neuroendocrine axis, which in turn influences the immune system. This is a bidirectional process, since chemicals are released by activated immunological cells which alter the functioning of the endocrine and autocrine nervous systems and influence our behaviour. This article examines these interactions.

Food and oral health: 2. Periodontium and oral mucosa.

Dental schools tend to teach only the rudiments of this subject and this does not provide a good basis for dentists to advise patients and combat the misinformation surrounding the topic. The first article in the two-part series examined nutrition as it applies to dental caries, while part two discusses some of the general principles of nutrition in relation to oral health, periodontal disease and the oral mucosa.

Food and oral health: 1. Dental caries.

Dental schools tend to teach only the rudiments of this subject and this does not provide a good basis for dentists to advise patients and combat the misinformation surrounding the topic. The first article in the two-part series examines nutrition as it applies to dental caries, while part two will discuss some of the general principles of nutrition in relation to oral health, periodontal disease and the oral mucosa.

Haemostasis.

Normal haemostasis depends on a balance between coagulation and fibrinolytic processes. Because of this concept of balance between coagulation and fibrinolysis, drugs which retard or inhibit the breakdown of fibrin encourage haemostasis. Such drugs are used in patients undergoing dental extractions and as prophylactic agents to prevent spontaneous bleeding. Blood clotting factors produced by genetic engineering are now becoming available and these offer exciting prospects for the management of patients with bleeding disorders.

Effects of phosphoprotein moieties on the remineralization of human root caries.

The noncollagenous proteins, especially phosphoprotein, have been shown to modulate biomineralization. The objective of this study was to investigate the remineralization potential of human tooth root organic matrices which did or did not contain soluble non-collagenous proteins including phosphoprotein. Human tooth roots were completely demineralized using conditions that either removed or did not remove soluble phosphoprotein and were then subjected to remineralization conditions. Removal of soluble phosphoprotein resulted in remineralization while no remineralization occurred in tooth roots that still contained soluble phosphoprotein. Transmission electron microscopy and microradiography demonstrated that demineralized cementum did not remineralize under any of the conditions used in this study. Collagenase digestion of demineralized and salt-reextracted tooth root organic matrices revealed that a nonsoluble phosphoprotein was present in the matrices. Amino acid analysis and SDS-PAGE showed that this nonsoluble phosphoprotein was similar in composition to the soluble phosphoprotein. This work suggests that the removal of soluble, noncollagenous proteins, especially phosphoprotein from root caries lesions, may enhance their remineralization potential.

Tongue skills and clearance of toffee in two age-groups and in children with problems of speech articulation.

If children use the same tongue skills in swallowing and clearing remnants of sticky foods from the mouth as they do in articulating during speech, it could then be hypothesized that those with impaired articulation might have poorer tongue skills and, consequently, slower rates of food clearance. Does age alter these skills and rates of clearance? Measurements were made of oral stereognosis, tongue-tip manipulation skill, control of tongue protrusion, and the time taken to chew and swallow a standardized piece of toffee and to clear it from the mouth. A statistically significant improvement in tongue skills with age was observed when results for twenty-three 19- to 23-year-old students were compared with those for twenty-nine 6 to 11-year-old children, but no distant differences in clearance rates were noted. Results for thirty-nine 5- to 8-year old children with impaired articulation and forty normal age-matched children showed the former group to have delayed chewing times and clearance rates, and poorer oral stereognosis and tongue protrusion control. Although these tests have shown significant differences between relatively large groups, the value of such tests on individuals is limited.

Phosphoprotein extraction from the dentine/cementum complex of human tooth roots.

Root shards were placed in dialysis tubing and demineralized to completion in either 10% disodium EDTA, pH 7.4, 0.6 M HCl, 0.1 M HCl, 0.5 M acetic or 75 mM-25 mM lactic-acetic acids. The demineralized shards were then re-extracted with 0.05 M tris-HCl, 1.0 M NaCl. DEAE chromatography revealed that the major peak of the 0.6 M CHl and EDTA extracts contained organic phosphorus, whereas much less organic phosphorus was found in the major peak of the 0.1 M HCl extract. Analysis of the re-extracts gave a pattern opposite to that obtained from the initial extractions. Measurements of protein and organic phosphorus released during extraction and re-extraction confirmed these results. Staining of SDS-PAGE gels for phosphoprotein with Stains-All resulted in a blue smear in fractions containing organic phosphorus. Thus the extraction of phosphoproteins from human tooth roots differed depending upon the demineralizing conditions. This ability to remove phosphoprotein differentially will allow further investigation of the role of phosphoprotein in mineralization and remineralization.

Ultrasound findings in diffuse granulomatous cystitis in chronic granulomatous disease of childhood.

Chronic granulomatous disease (CGD) is a genetically inherited disease of childhood, which is characterized by repeated bacterial and/or fungal infections. The genitourinary tract is rarely involved. We report a case of CGD with involvement of the urinary bladder. Pertinent clinical and sonographic findings of this disease are described.

Toffee clearance and lingual sensory and motor activities in normal children and in children with articulation problems of speech.

The rate at which a standardized mouthful of toffee containing technetium (99mTc) tin colloid was cleared from the mouth during and after chewing was measured by counting the residual radioactivity in the mouth at short time intervals by external gamma counting. The clearance curve was resolved into three phases for each subject--chewing time (1), which coincided with the time to reach 10% of the initial counting rate, scavenging time (2), and a final slow diffusion phase (3). Although the mean chewing time was only 1.9 min, the technique allowed the pattern of clearance during this phase to be assessed for each of 10 normal children (mean age 11.1 yr) and 7 children (mean age 11.0 yr) diagnosed as having delayed articulation. Two measurements of sensory and motor functions of the tongue were made on the same subjects. These measurements were of oral stereognosis and tongue-tip manipulation. Within the control group, only the correlation between stereognosis error scores and the duration of phase 1 or phases 1 and 2 combined was statistically significant. The mean stereognosis and tongue manipulation scores were significantly lower in the poor articulation group than in normal children but, with one notable exception, the clearance curves were similar.