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SUMMARY We have assessed the ability of interleukin-2 (IL-2) and interleukin-6 (IL-6) to augment the proliferative response of T lymphocytes from ‘common-variable’ hypogammaglobulinaemia (CVH) patients and from normal controls, to the mitogens phytohaemagglutinin (PHA) and OKT3. We show that with cells from the control group and from those patients whose T cells respond to PHA within the control range, both IL-2 and IL-6 will significantly augment the response to OKT3. However, in those patients with a T cell defect in which the PHA response is below the control range, neither IL-2 nor IL-6 could restore the PHA or OKT3 response to normal. Responses to IL-2 or IL-6 alone were always in or above the control range.

SummaryWe show that at least half of patients with common variable immunodeficiency (CVID) have circulating CD8+ T cells specific for epitopes derived from cytomegalovirus (CMV) and/or the Epstein–Barr virus (EBV). Compared to healthy age-matched subjects, more CD8+ T cells in CVID patients were committed to CMV. Despite previous reports of defects in antigen presentation and cellular immunity in CVID, specific CD4+ and CD8+ T cells produced interferon (IFN)-γ after stimulation with CMV peptides, and peripheral blood mononuclear cells secreted perforin in response to these antigens. In CVID patients we found an association between a high percentage of circulating CD8+ CD57+ T cells containing perforin, CMV infection and a low CD4/CD8 ratio, suggesting that CMV may have a major role in the T cell abnormalities described previously in this disease. We also show preliminary evidence that CMV contributes to the previously unexplained severe enteropathy that occurs in about 5% of patients.

NaSnN with the non-centrosymmetric layered structure type of KSnAs and featuring the new layered Zintl ion [SnN]− is the first example of a ternary nitride containing Sn–N bonds, and the first example of a nitride containing formally divalent tin.

SUMMARY The phenotype and function of monocyte derived dendritic cells (MdDC) were investigated in 25 patients with common variable immunodeficiency (CVID) to test for abnormalities that might help explain the failure of antibody production. Using MHC class II DR and CD86 as markers of maturation, DCs from the majority of CVID patients were normal. However 5 patients, the majority of whom had affected family members who had previously been shown to have a susceptibility genetic locus in the MHC region, expressed abnormally low levels of DR on repeated testing, in some cases associated with a reduced capacity to support antigen stimulated T cell proliferation; nevertheless costimulatory molecules for production of IL-13, IL-10 and IFN-γ from T cells were intact. In contrast to DCs from healthy donors, DCs from many CVID patients had high spontaneous production of IL-8 and lipopolysaccharide stimulation often caused a reduction in DR expression. Expression of other cytokines (IL-1a, IL-6 and IL-12), either before or after LPS stimulation, was normal. The data suggests there is a fundamental defect in the maturation of MdDCs in a subset of CVID patients that may compromise antigen presentation and subsequent antibody production.

The hemoglobins found in unicellular organisms show a greater chemical reactivity, protect cells against oxidative stress and hence have been implicated in a wider variety of potential functions than those traditionally associated with animal and plant hemoglobins. There are well-documented studies showing that bacteria expressing Vitreoscilla hemoglobin (VHb), the first prokaryotic hemoglobin characterized, have better growth and oxygen uptake rates than VHb counterparts.

The European research co-operation Lotus is presented. The main objectives of the project were i) to show the potential for a urea-based SCR system to comply with the EU standard of years 2005 and 2008 for heavy-duty Diesel engines for different driving conditions with optimal fuel consumption, ii) to reach 95 % conversion of NOx at steady state at full load on a Euro III. engine, iii) to reach 75 % NOx reduction for exhaust temperatures between 200-300°C, and 85 % average NOx reduction between 200-500°C. The energy content of the consumed urea should not exceed 1.0 %, calculated as specific fuel consumption. These targets were met in May 2003 and the Lotus SCR system fulfilled the Euro V NOx legislative objectives for year 2008. Copyright © 2004 SAE International.

The DEXA Cluster consisted of three closely interlinked projects. In 2003 the DEXA Cluster concluded by demonstrating the successful development of critical technologies for Diesel exhaust particulate after-treatment, without adverse effects on NO[x] emissions and maintaining the fuel economy advantages of the Diesel engine well beyond the EURO IV (2000) emission standards horizon. In the present paper the most important results of the DEXA Cluster projects in the demonstration of advanced particulate control technologies, the development of a simulation toolkit for the design of diesel exhaust after-treatment systems and the development of novel particulate characterization methodologies, are presented. The motivation for the DEXA Cluster research was to increase the market competitiveness of diesel engine powertrains for passenger cars worldwide, and to accelerate the adoption of particulate control technology.

There are an increasing number of published reports of patients with acquired immunodeficiency without evidence of HIV infection, who have been labelled as having "idiopathic CD4+ lymphocytopenia". The case is reported here of a young man who presented with Pneumocystis carinii pneumonia (PCP), CD4+ lymphopenia, and hypogammaglobulinaemia attributable to common variable immunodeficiency (CVID). The presentation of this condition, with many of the clinical and laboratory features of AIDS, highlights CVID as a diagnosis to be considered in the differential diagnosis of CD4+ lymphocytopenia.

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Despite documented successes in the battle to clean up the coastal waters of Southern California, Los Angeles County residents continue to view the ocean more as a place of pollution than a vibrant and healthy place for bathing and swimming. This study shows that residents of Los Angeles County tend to hold perceptions of marine water quality that are at odds with data on bacteriological measures of water quality collected by local sanitation districts (and reported by not-for-profit Heal the Bay). Summary results of a survey of 400 randomly chosen households in Los Angeles County are given. Respondents were asked about their beach use and perceptions of environmental quality: both coastal water quality and air quality. The results suggest that perceptions of coastal water quality may be influenced less by "current coastal education campaigns" and more by the media and other factors.

Intracellular expression of several cytokines was assessed in lymphocytes and monocytes of children with transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). THI was characterized by an increased frequency of CD3+/CD4+ lymphocytes expressing tumour necrosis factor α (TNF-α), TNF-β and interleukin 10 (IL-10), while in SIgAD elevated numbers of these cells containing TNF-α and interferon γ (IFN-γ) were observed. No changes in the number of CD4+ T cells expressing IL-4 in both diseases were noted. The proportion of CD33+ monocytes containing TNF-α both in THI and SIgAD was unchanged. The secretion of IL-12 by peripheral blood mononuclear cells (PBMCs) of patients with THI and SIgAD was significantly elevated and associated with an increased frequency of IL-12 expressing monocytes in THI but not in SIgAD. IL-18 secretion was slightly, but not significantly, elevated in both diseases. Intracellular Th1 and Th2 type cytokines within CD3+/CD4+ lymphocytes were also determined in the normal blood donors that showed high or low production of IgG and IgA in vitro. In low producers of IgG an increased proportion of CD3+/CD4+ cells expressing TNF-α and IFN-γ was found, while in low IgA responders only elevated TNF-α positive CD3+/CD4+ cells were observed. These results suggest that THI and SIgAD may represent diseases with an excessive Th1 type response that is associated with an up-regulation of IL-12 secretion and, at least in THI, elevated numbers of monocytes expressing intracellular IL-12. Up-regulation of IL-12 may be the essential factor in the patomechanism(s) of these diseases as already described in common variable immunodeficiency (CVID).

BACKGROUND: Whilst sentinel node biopsy is being evaluated for optimising treatment of the axilla, axillary dissection remains the gold standard. Seroma formation, a common sequel to axillary dissection, has been shown to be associated with an increased incidence of wound infection, delayed healing, and lymphoedema. This study was conducted to evaluate the possible contributory role of obesity in axillary drainage following lymphatic dissection. PATIENTS AND METHODS: This study comprised a prospective review of all patients undergoing axillary dissection in conjunction with mastectomy or wide local excision. The total in-patient axillary drainage and the average daily drainage was correlated with various clinical parameters, including obesity, type of surgery, level of axillary dissection and nodal involvement. The body mass index (BMI) was used as a measure of obesity. RESULTS: During a 6-month period, axillary dissection was performed in 79 women. Nineteen patients were excluded. Patey mastectomy was performed on 33 (55%) and the remaining had breast conservation. The amount or duration of axillary drainage did not correlate with the type of operation, tumour histology, level of axillary dissection or the nodal status. Higher BMI correlated with increased mean daily axillary drainage and total volume drained, whilst in hospital. (Spearman correlation coefficient 0.42; P < 0.01). CONCLUSION: Obesity predisposes to increased axillary drainage following nodal clearance.

The obligate aerobic bacterium, Vitreoscilla, synthesizes elevated quantities of a homodimeric hemoglobin (VHb) under hypoxic growth conditions. Expression of VHb in heterologous hosts often enhances growth and product formation. A role in facilitating oxygen transfer to the respiratory membranes is one explanation of its cellular function. Immunogold labeling of VHb in both Vitreoscilla and recombinant Escherichia coli bearing the VHb gene clearly indicated that VHb has a cytoplasmic (not periplasmic) localization and is concentrated near the periphery of the cytosolic face of the cell membrane. OmpA signal-peptide VHb fusions were transported into the periplasm in E. coli, but this did not confer any additional growth advantage. The interaction of VHb with respiratory membranes was also studied. The K(d) values for the binding of VHb to Vitreoscilla and E. coli cell membranes were approximately 5-6 microm, a 4-8-fold higher affinity than those of horse myoglobin and hemoglobin for these same membranes. VHb stimulated the ubiquinol-1 oxidase activity of inverted Vitreoscilla membranes by 68%. The inclusion of Vitreoscilla cytochrome bo in proteoliposomes led to 2.4- and 6-fold increases in VHb binding affinity and binding site number, respectively, relative to control liposomes, suggesting a direct interaction between VHb and cytochrome bo.

Growth and degradation of 2,4-dinitrotoluene (2,4-DNT) were compared in liquid cultures in shake flasks for Burkholderia sp. strain DNT and strain DNT engineered to produce Vitreoscilla (bacterial) hemoglobin (strain YV1). Parameters varied included aeration rate, initial 2,4-DNT concentration (50 and 200 ppm), and concentration and type of cosubstrate (yeast extract, succinate, casamino acids, and tryptic soy broth). 2,4-DNT degradation increased with increasing cosubstrate concentration and was greater for strain YV1 than strain DNT under most conditions tested; the greatest advantages of YV1 (up to 3.5-fold) occurred under limited aeration. A third strain (YV1m), derived from YV1 by repeated growth on 2,4-DNT-containing medium, demonstrated increased 2,4-DNT degradation (up to 1.3-fold compared to YV1) at 200 ppm 2,4-DNT. The growth profiles of the three strains with respect to each other were in general similar to those of the degradation patterns of 2,4-DNT.

A model of undergraduate education based on a one to one relationship between a student and a patient with cancer has become a core module within the University of Wales College of Medicine undergraduate curriculum. The project combines the powerful impact of a one to one interaction with an active investigative and reflective approach to issues triggered from that patient's cancer journey. The aim is to provide each medical student with an understanding of the impact of a malignant disease and its treatment on patients and their families through the experience of one patient with cancer. The benefits of the project cover the areas of attitudes, skills and knowledge. Students are assessed on their involvement with the patient, in tutorials and on their portfolio, in which they record all aspects of the project. Student evaluations indicate high levels of appreciation of the project, despite its potentially strong emotional content.

The objectives were to assess the prevalence of substance use among Dutch dental students and to determine their attitudes about substance use and its consequences.In association with a national study of drug use among US dental students, a questionnaire was translated from English into Dutch and administered to dental students at two dental schools in The Netherlands. Students received an anonymous 115-item questionnaire in the fall of 1996.Alcohol was the students' drug of choice for lifetime (95%), past year (94%) and past month (88%) use. No significant correlations were found between alcohol use and gender, schools, and years in dental education. In the past month, 58% of students reported drinking on 5 or more days; 53% had 5 or more drinks on the same occasion, 20% had 5 or more drinks on the same occasion on 5 or more days; and 17% reported getting drunk at least monthly. Prevalence rates for past month use of tobacco was 24% and marijuana, 4%. Male students smoked twice as much as females, with significant differences found for all three periods of use (X219.00, P0.01). When asked whether their schools offered policies and education programs on alcohol and other drugs, 52% of students reported that these were not available.Dental schools should develop effective programmes to educate students about responsible use of alcohol and other licit and illicit drugs. Schools should also inform students about their susceptibilities to substance abuse and dependency.

Patients whose test results are abnormal cannot make health behavior changes until the final phase of the laboratory testing process, patient notification, has been completed. Patients whose results are normal are often not notified at all. Few studies have examined the problematic aspects of patient notification, a crucial step in a complex and expensive process.To determine patient preferences for receiving laboratory test results.Patient survey by telephone.Forty-nine patients with hypercholesterolemia who had had a lipoprotein profile performed within the previous 6 months were asked whether or not they had been informed of the test result, how they were informed, how satisfied they were with the process, and how they would prefer to be notified of results. All patients attended a clinic in suburban Detroit. Questions were read from a prepared script.The majority of patients (94%) preferred to receive notification of all test results: both abnormal results accompanied by recommendations for health management changes, and normal results. Preferences for type of notification included mail (59%), phone (16%), office visit (12%), other or multiple response (6%).Notification of both normal and abnormal results is of great importance to patients. Further studies are needed to determine what form of notification is most effective and which method is most satisfactory to patients.

IgA deficiency (IgAD, MIM 137100) is the most frequent primary immunodeficiency in humans (for review see Burrows and Cooper, 1997; Hammarstrom et al., 2000). It is characterized by the absence of IgA in serum and mucosal secretions due to an as yet unidentified defect of terminal lymphocyte differentiation. Affected individuals may suffer from susceptibility to infections and autoimmune complications. While IgAD is defined by a laboratory measurement and is usually asymptomatic, common variable immunodeficiency (CVID, MIM 240500) is characterized clinically by overt susceptibility to infections and by frequent inflammatory and autoimmune symptomatology. In addition to the lack of IgA, CVID patients have decreased levels of additional isotypes in serum.

The objective of this study was to determine the effects of a workshop on the sexual harassment perceptions of students at the University of Kentucky College of Dentistry. Responses to a twenty-six-item questionnaire were elicited from 147 first-through fourth-year students before and after they attended a two-hour sexual harassment workshop. Five questions explored students' personal experiences with sexual harassment; twenty-one questions addressed students' attitudes about sexual harassment. The repeated measures option of the SPSS General Linear Model statistical program was used to individually analyze the Likert-type scale response to the twenty-one attitude items for the following variables: gender, year in dental education, and whether respondents had been sexually harassed or had observed harassment of others. Workshop participation significantly changed some student attitudes about sexual harassment regardless of gender, year in dental education, or whether they had been harassed personally or had witnessed harassment of someone else (p.05). There were also significant gender-related differences in the direction and magnitude of change in pre- versus post-workshop responses to several attitude items (p.05). Workshop participants were better informed about and more sensitive to a wide range of sexual harassment issues. The workshop empowered students, especially females, to help create an environment that minimizes the probability of sexual harassment. This may be possible because, after the workshop, participants better understood institutional policies and procedures to handle complaints, including provisions for protection from retaliation if they do file a grievance. This knowledge and sensitivity may result in an environment that facilitates the education of beginning general practitioners who are competent, empathetic, and sensitive.

The description of X-linked agammaglobulinaemia (XLA) 48 years ago provided the catalyst for a fruitful interaction between basic immunologists and clinicians, and was the beginning of Clinical Immunology as practised in the UK today. Over the subsequent 40 years many more immunodeficiency syndromes were described and partially characterized at a functional level, but it has been the ability to clone genes in the past decade that has led to a dramatic increase in our understanding at a molecular level of most of these disorders. There are now about 75 characterized single gene defects causing primary immunodeficiency, with about another 20 expected to be discovered in the current decade. Most are associated with a predisposition to infection with either a broad or selective range of organisms, and most affected patients would die from infection without antibiotics. However, a few patients with loss of an apparently crucial protein involved in host defence surprisingly survive into adulthood with only minimal infection, suggesting the presence of unknown back-up systems. Furthermore, complicated clinical phenotypes, with immune dysregulation and autoimmunity, may result from inherited defects allowing partial expression of some of these proteins. Clinical and Experimental Immunology will be publishing a series of reviews on most of the primary immunodeficiency syndromes over the next 12 months, appropriately leading up to the 50th anniversary of the discovery of XLA. The first of these is the review by Gaspar & Conley on XLA that appeared in the March 2000 issue of the Journal [1]. These reviews will not only highlight the most recent advances in our understanding of the molecular mechanisms of specific disorders, but will also discuss new developments in clinical management. This field has pioneered the correction of disease by bone marrow grafting and gene therapy, and is likely to set the precedent for a complete cure by gene replacement in the next few years.

Sequences from the coat protein cistron of five ryegrass mosaic virus (RgMV) isolates indicated the presence of two distinct strains in New Zealand. The nucleotide differences between the strains, and their distribution, suggested that both strains were introduced recently, either as a mixed infection or as two independent introductions. The relationship between these New Zealand strains and other strains and isolates of RgMV, and their potential severity is discussed.

The objective of this study was to describe the sexual harassment experiences and attitudes of students at the University of Kentucky College of Dentistry. A twenty-six-item questionnaire was developed and administered to 170 dental students in years one through four of the curriculum. Five questions explored students' personal experiences with sexual harassment--whether they had been harassed or had observed harassment; twenty-one questions addressed students' attitudes about sexual harassment. Computations of mean differences in Likert-type scale responses for the twenty-one attitude items were completed using independent t-tests for the following variables: gender, whether respondents had been sexually harassed or had observed harassment of others, and years in dental education. Almost 15 percent of the students reported being sexually harassed at least once in dental college. Females were sexually harassed more often than males (p.01), and second, third, and fourth year students more often than first year students (p.05). Additionally, 30 percent of the students reported witnessing sexual harassment in the college. Harassers included faculty (88 percent), dental students (8 percent), and others (4 percent). Differences (p.05) in sexual harassment attitudes were found when responses were analyzed by gender, by whether students had been sexually harassed, by whether they had witnessed harassment, and by years in dental education. The data show that sexual harassment occurs in the college. Dental faculty and students could benefit from programs to educate them about sexual harassment, how to prevent it from occurring, and how to respond if they are sexually harassed.

The sequences of the 3'-terminal 1.8 kb of the genomes of three Australian and three Welsh isolates of ryegrass mosaic rymovirus (RGMV) were determined, as too were the virion protein genes of two New Zealand isolates of RGMV. They were compared with each other and with the published sequences of a Danish and a South African isolate by distance and maximum likelihood methods, and found to be very closely related (mean nucleotide difference 5.5%). All three Australian isolates and one from North Island of New Zealand formed one consistent cluster, and the Danish and South African isolates formed another. However the relationships between these two clusters and the other isolates were not consistent; they depended on the method of comparison used, and on the protein, gene or codon position compared. Nonetheless the European (Welsh and Danish) sequences were 2-4 times more different from one another than those from the Antipodes, suggesting that the European RGMV population may be older than the Antipodean. The Danish isolate has 39 nucleotides of the 5'-terminal region of its virion protein gene frameshifted -1 relative to the 'common' sequence. Interestingly the South African isolate has a similar frameshift, but sequence comparisons indicate that this frameshift must have occurred independently; a possible example of 'convergent frameshifting'.

The bacterial hemoglobin from Vitreoscilla has been shown to increase growth yield and yield of genetically engineered product in Escherichia coli. To test the generality of this phenomenon, the approximately 560-bp bacterial (Vitreoscilla) hemoglobin gene (vgb) (including the native promoter), cloned into the vector pUC8 in two constructs containing about 1650 and 850 bp, respectively, of Vitreoscilla DNA downstream of vgb, was transformed into Serratia marcescens. After several transfers of the transformants on selective media, both plasmids became stable in this host and the resulting strains produced hemoglobin. Both transformants were compared, regarding growth in liquid Luria-Bertani (LB) medium, with untransformed S. marcescens and S. marcescens transformed with pUC8. The vgb-bearing strains had about 5 times lower maximum viable cell numbers than the strains without hemoglobin, but the former also had late log or early stationary phase cells that were 5-10 times larger than those of the latter. Further, on a dry cell mass basis the presence of vgb inhibited cell growth in liquid media. In contrast, growth of the vgb-bearing strains on LB plates based on cell mass (determined from colony size) was markedly enhanced compared with that of the pUC8 transformant. Respiration of the vgb-bearing strains was lower than that of the strains without vgb on a cell mass basis. These results show that the presence of vgb can have idiosyncratic effects and is not always an aid to cell growth so that its use for genetic engineering must be tested on a case by case basis.

Serratia marcescens was transformed with plasmid vector pUC8 or pUC8 containing the bacterial (Vitreoscilla) hemoglobin gene (vgb) on either a 2.3-kb fragment (pUC8:15) or 1.4-kb fragment (pUC8:16) of Vitreoscilla DNA. The vgb-bearing strains were compared with the pUC8 transformant and untransformed S. marcescens with respect to growth in Luria-Bertani (LB) broth supplemented with glucose or casein acid hydrolysate. Growth (on a viable cell basis) was similar to that in unsupplemented LB. Total acid excretion (as estimated by medium pH) was similar for all strains in both LB plus 2% casein acid hydrolysate and LB without additions. Acid excretion in LB plus 2% glucose was somewhat greater at up to 10 h in culture for the two vgb-bearing strains; from 10 to 26 h in culture, the pHs of these cultures continued to decrease (to 4.1-4.2), whereas those of the non-vgb-bearing strains returned to near the starting pH (7.4-7.8). Concomitantly, after 26 h of culture in LB plus 2% glucose, the non-vgb-bearing strains had produced about 15 times as much acetoin and about three to four times as much 2,3-butanediol as the vgb-bearing strains. In general, for all strains, much more acetoin and 2,3-butanediol were produced in LB plus 2% glucose than in unsupplemented LB. The exception was acetoin production by the strain bearing vgb on plasmid pUC8:15; after 26 h of culture in LB without supplementation it was between three and four times that of the other strains, and about 50% higher than its level in LB plus 2% glucose. When grown with the 2% casein acid hydrolysate supplement, the strain bearing vgb on plasmid pUC8:15 produced much more acetoin and 2,3-butanediol than the other strains after 26 hours in culture. The results confirm that vgb can significantly alter carbon metabolism and suggest that the use of vgb technology for directed metabolic engineering may be a complicated process, depending in part on medium composition.

Synthesis and excretion of alpha-amylase is investigated in batch cultures of Escherichia coli JM103[pMK57] (vgb-) and E. coli JM103[pMK79] (vgb+). While total production and excretion of alpha-amylase were promoted in Luria broth (LB) (excretion being as high as 87%), cell-mass-specific production of the enzyme was promoted in M9 in bioreactor cultures and in LB in shake flask cultures. Low aeration and agitation rates and presence of starch were conducive to alpha-amylase synthesis in E. coli JM103[pMK79]. Two-stage bioreactor operating strategies that will improve alpha-amylase production are proposed. The potential of these strategies is demonstrated via two-stage shake flask cultures.

A top loading balance can be used to monitor and record drainage from a soil core. Possible applications of the apparatus are discussed. Key words: Tension apparatus, real-time weight loss, soil core

Portfolio learning has not previously been reported for clinical undergraduate teaching. This open randomized study aimed to assess the effect of portfolio learning in the teaching of oncology to medical students. The project aimed to provide the student with a holistic understanding of the impact of the disease and its treatment on the patient and family, and the natural history of malignant disease, through long-term personal experience of a cancer patient. All undergraduate medical students entering Clinical Studies in October 1992 at the University of Wales College of Medicine were randomized to a study or control group. Both groups continued with the standard curriculum. Each study-group student followed a patient with cancer for 9 months, supported by bi-monthly small-group tutorials. Tutors were either general practitioners or hospital consultants, not necessarily oncologists; each was supplied with a tutor's resource pack of key oncology review papers. Students recorded triggers to learning and key items in a personal learning portfolio. Students' performances in clinical examinations and the contents of their portfolio was assessed. Final assessment was by hidden questions in the objective structured clinical examination (OSCE) in the final degree examination, when students in the study group showed higher marks in factual knowledge of oncology, particularly amongst the weaker students (P = 0.01). Those submitting portfolios for formative assessment had higher overall marks than those in the study group who did not (P = 0.04), representing the more motivated students. The whole study group showed a beneficial trend in their knowledge of oncology.

We have measured by flow cytometry the ability of subsets of CD8+ CD3+ lymphocytes within mononuclear cell preparations to make intracellular cytokines (IL-2, tumour necrosis factor-alpha (TNF-α) and IFN-γ) on stimulation in vitro with phorbol myristate acetate (PMA) and ionomycin for 16 h. These CD8+ subsets were defined by the presence or absence of CD28 or HLA-DR. Subsets of normal CD8+ cells were compared with cells from the antibody deficiency disease common variable immunodeficiency (CVID). In CVID there was a significant increase in the production of IFN-γ in the CD8+ CD28+ subset (‘cytotoxic’). This reflects a shift in this disease towards an excessive Th1 response away from B cell help. Paradoxically, some CVID patients also showed a reduction in IFN-γ production in the CD8+ CD28− subset (‘suppressor’) which was associated with a failure of these cells to maintain a state of activation after a stimulus in vitro. The B cell problem in this disease is known to be related to a failure of T cell help shown by an inability to produce the antigen-specific CD4+ memory T cells needed for successful B cell maturation. The two pathological CD28 subsets of CD8+ cells we have found in CVID may both be detrimental to a normal CD4-dependent immune response. The CD28− suppressor subset expands and is unable to maintain activation and cytokine secretion, and the CD28+ cytotoxic subset is over-producing the Th1 cytokine IFN-γ.

Graduate nursing students in a required course on concepts and processes of health and healing had the option to do an experiment in self-care. Included were exercises related to biofeedback, aesthetics, diet/nutrition, dreams, ethnicity, fairytales, values, physical exercise, ultradian rhythms, journaling, and a self-care practice of choice. Feedback on the exercises indicated that, based on group means, the values exercise was the most difficult. Students reported they would be most likely to continue using aesthetics and physical exercise, awareness of ultradian rhythms, and their personally preferred self-care activity. These exercises were also the ones they would be most likely to suggest to clients.

Firearms are a consumer product responsible for 38500 deaths in the United States in 1994. Like other products, firearms are advertised. In the absence of rules governing the design of firearms, regulating the way guns are advertised may be a useful public health intervention. Some gun advertisements include messages suggesting that bringing a handgun into the home is generally protective for the occupants of the home. The best available scientific information contradicts this message. Given this disjunction, regulating those advertisements may be an appropriate response. Under federal law, the Federal Trade Commission (FTC) has authority to prohibit advertisements that are "deceptive" or "unfair." Under the FTC's deception analysis, the focus is on whether consumers are misled by an advertisement. For a finding of unfairness, the FTC looks for advertisements that may cause substantial injury to consumers. Under either analysis, a strong argument can be made that firearm advertisements promising home protection are unlawful. On February 14, 1996, several organizations sent separate petitions to the FTC asking it to consider the issues raised by firearm advertisements that promise home protection. The FTC is still reviewing the information presented. There are no First Amendment or Second Amendment impediments to FTC regulation of deceptive firearm advertising under the US Constitution.

Two experiments examined the impact of the motivation for cognitive closure on the abstractness of linguistic communications in intergroup contexts. Participants described positive and negative behaviors attributed to either an in-group or an out-group member. Individuals high (vs. low) in need for closure exhibited greater linguistic abstraction when describing positive behaviors of in-group members and negative behaviors of out-group members. These differences disappeared for descriptions of negative behaviors of out-group members. The discussion relates these results to the interface of motivation, language, and social cognition.

The six papers presented here all point out the grave difficulties associated with the management of international fisheries. Each also provides some perspective on the potential for change in the system. Webster recommends that proponents of ecosystem-based management need to propose specific measures that may appeal to powerful fishing countries rather than broad goals that are difficult to implement. Kalfagianni and Pattberg propose that the Marine Stewardship Council could substantially improve its impact on global fisheries management by paying attention to structural effects, particularly trade barriers that may exacerbate the North–South divide. Sakaguchi similarly sees NGO involvement in fisheries regulation as a double-edged sword and warns about the potential for alienation of societies that resist the forceful imposition of new norms. In contrast, both Schiffman and Tiller show how domestic interests can shape new and future regional fisheries management organisations (RFMOs) into more effective regimes. Finally, Barkin and DeSombre propose that a new, global RFMO could reduce fishing capacity around the world, thereby bursting the balloon problem.

alpha-tubulin subunits within microtubules (MTs) can be post-translationally detyrosinated by a tubulin-specific carboxypeptidase (TCP) activity to form biochemically distinct MTs. Attempts to characterize and purify TCP have suffered from the inability to detect low levels of activity and to distinguish TCP from other, competing enzyme activities. We recently developed an assay for TCP [Webster et al. (1992) Biochemistry 31:5849] that uses taxol-stabilized MTs as the substrate. In this study, we exploited the increased sensitivity and specificity of this new assay to explore the effects of various agents that might act to either stimulate or inhibit this enzyme in vitro. We tested a variety of both monovalent and divalent cations for their ability to affect TCP, and tested whether the cations were affecting the enzyme, the substrate, or both. We found that TCP displayed salt-sensitive binding to MTs, characteristic of other, more well characterized MT-associated proteins. While both calcium and magnesium stimulated TCP activity over a narrow concentration range (2-10 mM), they inhibited activity at higher concentrations. Other divalent cations tested, including zinc, copper, and cobalt, inhibited TCP at virtually all concentrations tested, but to different levels (zinccoppercobalt). Most of the zinc-induced TCP inhibition was attributed to the interference with the normal binding of TCP to MTs. In addition, we examined the involvement of free sulfhydryl groups (which are important for the activities of many types of enzymes) in TCP activity by the addition of sulfhydryl-modifying compounds during the assay, and found that their addition reduced TCP activity mainly (but not solely) by their action on the extract that contained the TCP. Finally, we tested the ability of DL-benzylsuccinic acid, a potent inhibitor of carboxypeptidase A, to inhibit TCP. While carboxypeptidase A has been found, in other studies, to be inhibited by micromolar concentrations, TCP was affected only at concentrations above 20 mM, adding another proof that carboxypeptidase A and TCP are distinct enzyme activities.

The neurological features of 13 patients with primary hypogammaglobulinaemia are described. Seven patients had X-linked agammaglobulinaemia (XLA) and six had common variable immunodeficiency (CVID). Three clinical pictures emerged: (i) a progressive myelopathy (one case); (ii) a myelopathy progressing to an encephalopathy (four cases); (iii) a pure encephalopathy (eight cases). In four patients the encephalopathy was temporarily reversible; the relationship of this to immunoglobulin therapy is unclear. Additional features occurred in some patients. Three had retinopathy interpreted as retinitis pigmentosa, in one of whom the retinopathy resolved. Two patients had a sensori-neural hearing loss and three had features of dermatomyositis; a variable pleocytosis was found in the CSF of nine patients. Imaging revealed atrophic changes in the cerebral hemispheres in eight cases. Ten patients have died, 1-11 years after the onset of the CNS manifestations, and in four autopsies were obtained. Two patients had encephalopathy, one with XLA had evidence of end-stage encephalitis and the other with CVID had a multi-focal leucoencephalopathy. The other two with XLA had leptomeningitis without evidence of encephalitis. Enteroviral infection is probably an important cause of neurological disease in these patients as CSF from seven patients was either positive by polymerase chain reaction (PCR) or by culture for enteroviruses. Other possible mechanisms are discussed.

Xanthomonas maltophilia was transformed with the gene encoding Vitreoscilla (bacterial) hemoglobin, vgb, and the growth of the engineered strain was compared with that of the untransformed strain using benzoic acid as the sole carbon source. In general, growth of the engineered strain was greater than that of the untransformed strain; this was true for experiments using both overnight cultures and log phase cells as inocula, but particularly for the latter. In both cases the engineered strain was also more efficient than the untransformed strain in converting benzoic acid into biomass.

SUMMARY Concern over sporadic hepatitis C virus (HCV) infection from treatment with contaminated immunoglobulin in patients with immunodeficiency prompted us to screen serum from 44 patients for HCV RNA. We found no evidence of either horizontal or iatrogenic infection in our Clinic, except in two patients known to have received contaminated batches, and in one who had had regular plasma infusions. Thus, common variable immunodeficiency (CVID) patients in England do not have a high incidence of HCV infection despite exposure to various immunoglobulin products. This contrasts with the recently reported high prevalence in similar patients in Italy. Although our data reinforce the impression that both intramuscular and current licensed i.v. preparations in the UK are safe, manufacturers should be encouraged to PCR screen all batches of immunoglobulin for HCV.

Leflunomide is a novel immunosuppressive compound that is effective in the treatment of animal models of autoimmune disease and human rheumatoid arthritis. The mechanism of action is unknown. Here we show that leflunomide blocked 1) increases in nucleolar size and number, 2) upregulation of the nuclear protein antigens (PCNA and Ki-67), 3) increases in uridine incorporation and total RNA and DNA content, 4) cell cycle progression and 5) proliferation in mitogen-stimulated rat spleen mononuclear cells and human peripheral blood mononuclear cells (HPBMC). Exogenous uridine reversed the leflunomide-dependent inhibition of the normal increase in total RNA and DNA content in mitogen-stimulated HPBMC and rat spleen cells. Uridine reversed the leflunomide-dependent inhibition of cell cycle progression in stimulated rat cell cultures. Either uridine or cytidine, which can be converted to uridine by cytidine deaminase, reversed the antiproliferative effect of leflunomide in HPBMC. Dihydroorotate accumulated in leflunomide-treated human T-lymphoblastoid cells, suggesting that the compound inhibited the fourth enzyme in the pyrimidine biosynthetic pathway, dihydroorotate dehydrogenase. The results support the hypothesis that the in vitro effects of leflunomide on T-lymphocytes are due to inhibition of de novo pyrimidine synthesis.

To determine the kinds of self-care used by women with interstitial cystitis and to find effective ways to manage symptoms of acute attack.One hundred thirty-eight women with interstitial cystitis completed a survey indicating how often they used and how effective they found strategies in four physical self-care subdomains (medication, treatment, diet, and body comfort) and three psychologic self-care subdomains (cognitive/stress reduction, distraction, and help-seeking).Descriptions of symptoms during an "acute attack" are more consistent with symptoms described "at onset" than symptoms experienced "currently." Physical strategies most used for acute attack included use of narcotics, antidepressants, and bladder analgesics, in addition to limiting the diet to bland or starchy foods, wearing loose clothing, taking hot baths, and using a heating pad over the pubis. Psychologic strategies most used included watching television, prayer, and seeking support from a significant other, family members, friends, and other patients with interstitial cystitis.Some psychologic and physical strategies found to be effective for other chronic pain conditions, such as biofeedback, alternating use of heat/cold, self-hypnosis, and redefining pain sensations were seldom used. Other nonmedical interventions such as massage and imagery, when used, were found to be more moderately to highly effective. Information about self-care and access to support groups may increase exposure to multiple ways of handling acute attacks.

It has been suggested that tryptophan 563 is sandwiched between residues R562 and A582 in Bruton's agammaglobulinemia tyrosine kinase (Btk). Mutations of the surrounding residues have been shown to cause X-linked agammaglobulinemia. Substitutions R562P and A582V were noticed to have impaired kinase activity. However, based on Western blot analysis, the mutant proteins were expressed at normal levels. Molecular modeling of the kinase domain has previously indicated that these residues presumably govern the position of the W563 side chain, which is thought to interact with the catalytic loop. W563 is inside the molecule and too far away from the catalytic center to interact directly with the substrate or cofactors. To prove these model-based conclusions, a conservative substitution with phenylalanine for W563 was made, and the resultant mutant lacked kinase activity. These results confirm our previous assumption that the side chain of W563, invariant in protein tyrosine kinases, is crucial for Btk kinase activity. Mutations in the surrounding residues seem to inactivate Btk by affecting the location of W563.

SUMMARY T cells from patients with CVID have defects that may relate to the failure in vivo of B cell production of antibodies. Antigen-driven responses of T cells from CVID patients and normal subjects have been assessed by measuring DNA synthesis in vitro. Low density cells enriched for antigen-presenting dendritic cells were pulsed with purified protein derivative (PPD) and cultured with autologous T cells. Overall, T cells from CVID patients showed a significantly low mean response to PPD, although non-specific DNA synthesis induced in CVID T cells by IL-2 was within the normal range. However, mean PPD-specific T cell responses in CVID were not restored by IL-2 irrespective of the presence of monocytes. Depletion of CD8+ cells also failed to restore the mean PPD response of CVID CD4+ T cells. Limiting dilution analysis showed that in CVID there was a reduced frequency of antigen-specific cells within the T cell preparations. The mean frequency of the PPD-specific T cells in cultures from patients vaccinated with bacille Calmette-Guérin (BCG) was reduced to 1 in 109000 T cells compared with 1 in 18 600 T cells in BCG-vaccinated normal donors. These data show that the reduced PPD-specific response in CVID is due to a partial peripheral loss of antigen-specific cells.