Toward an integrated multi-gigahertz ionizing particle diagnostic.

Needs arising at both current and future accelerator facilities call for the development of radiation-hardened position-sensing diagnostics that can operate with multi-GHz repetition rates. Such instruments are likely to also have applications in the diagnosis of rapid plasma behavior. Building on the recent work of our Advanced Accelerator Diagnostics Collaboration, we are exploring the development of integrated multi-GHz ionizing particle detection systems based on chemical-vapor deposition diamond sensors, with the initial goal of producing a quadrant detector that can determine the intensity and centroid position of a particle beam at a repetition rate between 5 and 10 GHz. Results from our initial high-speed characterization work are presented, including those from a single-channel sensor with a GHz response. Approaches to achieving multi-GHz (5-10 GHz) rate capability, including the design of a dedicated Application Specific Integrated Circuit and the use of 3D RF-solver computer aided design software, are presented and discussed in more detail. 3D RF simulations suggest clean pulses of duration less than 250 ps (FWHM less than 125 ps) can be achieved with the approaches developed by this work.

Feasibility of implementing pulse oximetry screening for congenital heart disease in a community hospital.

OBJECTIVE: Pulse oximetry has been recognized as a promising screening tool for critical congenital heart disease (CCHD). The aim of this research was to study the feasibility of implementation in a community hospital setting. STUDY DESIGN: Meetings were conducted to determine an implementation plan. Pulse oximetry was performed on the right hand and foot after 24 h of age. Newborns with a saturation ≤ 95% or a ≥ 3% difference were considered to have a positive screen. Screening barriers, screening time and ability to effectively screen all eligible newborns were noted. RESULT: From January 2009 through May 2010, of 6841 eligible newborns, 6745 newborns (98.6%) were screened. Of the nine infants with positive pulse oximetry screens, one had CCHD, four had CHD and four others were determined to have false positive screens. Average screening time was 3.5 min (0 to 35 min). CONCLUSION: Pulse oximetry can be implemented successfully in community hospitals without an excessive number of false positives or additional nursing staff.

[Needs and wishes of healthy patients - how should physicians deal with them?]. / Anliegen und Wünsche gesunder Patienten - wie gehen Hausärzte damit um?

BACKGROUND: It is hardly known how physicians feel and act if patients complain about social damage, familial tragedies or problems at work instead of illnesses or diseases. METHODS: Seven general practitioners discussed this subject in a focus-group setting. Within two hours, the three female and four male practitioners described some typical needs and wishes of their healthy patients. They were also encouraged to relate their feelings, reactions and behaviour as doctors. We interpreted the transcript of the recorded discussion according to the rules of a content-analysis. RESULTS: Certificates, (non-medical) advice and information, general care and reducing expenses are the main reasons for healthy patients to see them, the doctors quoted. The doctor's feelings depend on the personality of the patient and the reported problems. As a result, the physician's acceptance of needs and wishes of healthy patients varies over a broad spectrum and the decisions differ and seem arbitrary, although reporting on similar situations. Her/his personal attributes and mood mainly determine their decision about the patient's wishes. DISCUSSION: The question of whether to refuse or to respect healthy patients' wishes was arbitrary in this focus-group setting. Because no specific medical curriculum exists, rules for doctors' reactions and decisions on social, familial or working problems of their patients could be helpful. In particular, specific problems should be dealt with by social workers and related professions.

Reducing psychological distress in patients with inflammatory bowel disease by cognitive-behavioural treatment: exploratory study of effectiveness.

BACKGROUND: This prospective study aimed to determine whether cognitive-behavioural group treatment accompanying medical standard care is effective in reducing psychological distress in patients with inflammatory bowel disease. METHODS: Twenty-eight outpatients with Crohn disease or ulcerative colitis completed the treatment programme. Psychological treatment consisting of 12 weekly sessions was conducted in a group setting. Medical and psychometric assessments were taken at the beginning of the 3-month pretreatment waiting period, at pretreatment, at post-treatment and at the 3, 6 and 9-month follow-ups. RESULTS: During baseline, no change was observed in psychological distress. Disease-related worries and concerns decreased significantly from pretreatment to the follow-ups. The disease groups differed in the decline of concerns between pre- and post-treatment, with a significant reduction of concerns in patients with ulcerative colitis but not Crohn disease. This difference did not occur at the follow-ups, indicating long-term improvement for both disease groups. Depressive coping decreased significantly in women and remained stable at the follow-ups, whereas depressive coping did not change in men. The same gender difference was found for depressive symptoms. CONCLUSIONS: The exploratory findings suggest that psychological group treatment for outpatients is a feasible and effective approach for the short- and long-term reduction of psychological distress for patients with inflammatory bowel disease. However, the revealed gender differences on coping and depression might indicate the necessity to consider gender-specific aspects of inflammatory bowel disease when designing and evaluating psychological interventions.

Cloning and molecular characterization of the novel human melanin-concentrating hormone receptor MCH2.

Using a genomics-based approach for screening orphan G-protein-coupled receptors, we have identified and cloned a novel high-affinity, melanin-concentrating hormone (MCH) receptor. This receptor, named S643b, displays the greatest overall identity (32%) with the previously reported human SLC-1 receptor (MCH1) and to a lesser extent with the somatostatin receptor subtypes. The gene encoding the S643b receptor spans more than 23 kilobase pairs (kb) and was mapped, by radiation hybrid experiments, on chromosome 6q14.3-q15. Comparison of the S643b cDNA with human genomic sequence reveals that the 340-amino-acid receptor is encoded by five exons. Its tissue distribution, as determined by Northern blot and reverse transcription-polymerase chain reaction analysis, indicates that a 4-kb transcript is predominantly expressed in the brain. When expressed in Chinese hamster ovary (CHO) cells, the S643b receptor displays a strong, dose-dependent, transient elevation of intracellular calcium in response to MCH (EC(50) = 9.5 nM). During the present study, we isolated a splice variant, designated S643a, encoding for a receptor that was not activated by MCH in a cellular calcium mobilization assay. Comparative pharmacological studies using CHO cells stably expressing either SLC-1 or S643b receptors demonstrated that similar structural features of MCH are required to stimulate intracellular Ca(2+) mobilization at both receptors. The identification and localization of this new MCH receptor (MCH2) provides further insight into the physiological implication of MCH in modulating behavioral responses, including food intake.

Genomic organization and characterization of splice variants of the human histamine H3 receptor.

In the present paper we report the genomic organization of the human histamine H3-receptor gene, which consists of four exons spanning 5.5 kb on chromosome 20. Using PCR, six alternative splice variants of the H3 receptor were cloned from human thalamus. These variants were found to be coexpressed in human brain, but their relative distribution varied in a region-specific manner. These isoforms displayed either a deletion in the putative second transmembrane domain (TM), H3(DeltaTM2, 431aa) or a variable deletion in the third intracellular loop (i3), H3(Deltai3, 415aa), H3(Deltai3, 365aa), H3(Deltai3, 329aa) and H3(DeltaTM5+Deltai3, 326aa). In order to determine the biological role of the H3 receptor variants compared with the 'original' H3(445aa) receptor, three isoforms, namely H3(445aa), H3(DeltaTM2, 431aa) and H3(Deltai3, 365aa), were expressed in CHO cells and their pharmacological properties were investigated. Binding studies showed that H3(DeltaTM2, 431aa) transiently expressed in CHO cells was unable to bind [125I]iodoproxyfan, whereas both the H3(445aa) and H3(Deltai3, 365aa) receptors displayed a high affinity for [125I]iodoproxyfan [K(d)=28+/-5 pM (n=4) and 8+/-1 pM (n=5) respectively]. In addition, H3(Deltai3, 365aa) possessed the same pharmacological profile as the H3(445aa) receptor. However, in CHO cells expressing H3(Deltai3, 365aa), H3 agonists did not inhibit forskolin-induced cAMP production, stimulate [35S]guanosine 5'-[gamma-thio]triphosphate ([35S]GTP[S]) binding or stimulate intracellular Ca(2+) mobilization. Therefore the 80-amino-acid sequence located at the C-terminal portion of i3 plays an essential role in H3 agonist-mediated signal transduction. The existence of multiple H3 isoforms with different signal transduction capabilities suggests that H3-mediated biological functions might be tightly regulated through alternative splicing mechanisms.

Genetic control of peripheral TCRAV usage by representation in the preselection repertoire and MHC allele-specific overselection.

TCRAV segments contribute significantly to MHC restriction as illustrated by their general preference for either the CD4 or CD8 T cell subset and additional, MHC allele-specific overselection during T cell differentiation. The 10-fold over-representation of the TCRAV8S2 (VA8S2) segment in CD8 over CD4 T cells by the RT1(f) haplotype of LEW.1F rats provides the most striking example of MHC allele-specific overselection of a VA segment reported so far. Also in alloreactivity, VA8S2(+) CD8 cells from RT1(f-) rats are preferentially expanded by RT1(f+) stimulators. We have identified the class I molecule, A(f), mediating VA8S2 overselection and report that it differs only in four amino acids at the MHC-TCR interface from the class I molecule A(a), which is neutral with regard to selection of VA8S2. We also provide an extensive survey of the TCRAV8 family and show that among 14 functional VA8 segments in LEW rats, the dramatic A(f)-dependent overselection is unique for VA8S2. Surprisingly, VA8S2 expression in CD8 T cells of RT1(f+) rats derived from a Sprague-Dawley stock was only 3% as compared to the 12% observed in LEW.1F. The VA8S2 segment of Sprague-Dawley (VA8S2(SD)) differs from VA8S2 of the LEW background (VA8S2(l)) in only two amino acids, one of which is located in CDR2 and could thus participate in allele-specific recognition of A(f). However, analysis of the pre- and postselection thymic repertoires of Sprague-Dawley and LEW.1F rats and of the repertoire of CD8 cells from both strains expanded in the alloreactive response to RT1(f) revealed that the difference in VA8S2 representation between the two backgrounds is explained by differential availability in the preselection repertoires and not by a difference in overselection. Sequence comparisons of A(f) and A(a) and of both VA8S2 segments suggest a predominant role of CDR1 in hyper-reactivity to A(f). Thus, the VA composition of the mature TCR repertoire is influenced by TCRA: locus polymorphisms at two levels: the regulation of VA usage in the preselection repertoire and the composition of structural elements which contribute to specific VA-MHC interactions during thymic selection.

Thymic development and repertoire selection: the rat perspective.

This review summarizes our current knowledge of T-cell maturation and repertoire selection in the rat thymus. Some unique features of early thymocyte development and of CD4/CD8 lineage decision are described. A detailed analysis of lineage progression through the CD4, CD8 "double positive" compartment and T-cell receptor-induced CD8 T-cell maturation in cell culture is provided. A second emphasis is placed on interactions between germline-encoded T-cell receptor elements with MHC molecules in thymic repertoire selection and alloreactivity

Dimorphism and inclusion compounds of N,N'-di(benzenesulfonyl)-p-phenylenediamine

Crystal structures of a new polymorph of N,N'-(p-phenylene)bis(benzenesulfonamide) (C18H16N2O4S2) and of two inclusion compounds with acetone [(CH3)2CO] and dimethyl sulfoxide [2(CH3)2SO], respectively, have been determined at 150 K. For a more reliable comparison, the structure of the already known polymorph of N,N'-di(benzenesulfonyl)-p-phenylenediamine has been redetermined under identical conditions. In addition, the phase transformation behavior has been examined by differential scanning calorimetry and the crystallization conditions of both polymorphs including their formation by weathering of the inclusion compounds were investigated.

Differential CD4/CD8 subset-specific expression of highly homologous rat Tcrb-V8 family members suggests a role of CDR2 and/or CDR4 (HV4) in MHC class-specific thymic selection.

Different rat Tcrb haplotypes express either TCR beta variable segment (Tcrb-V) 8.2l or 8.4a. Both V segments bind the mAb R78 but differ by one conservative substitution (L14V) and clusters of two and four substitutions in the complementarity-determining region (CDR) 2 and CDR4 [hypervariable loop 4 (HV4)]. Independently of MHC alleles numbers of R78+ CD4+ cells are lower in Tcrb-V8.2l-expressing than in Tcrb-V8.4a-expressing strains. Expression of R78+ TCR during T cell development, analysis of backcross populations and generation of a Tcrb congenic strain [LEW.TCRB(AS)] define two mechanisms how Tcrb haplotypes affect the frequency of R78+ cells, one acting prior to thymic selection leading to up to 2-fold higher frequency of Tcrb-V8.4a versus Tcrb-V8.2l in unselected thymocytes and another occurring between the TCRlow and the CD4/CD8 single-positive stage. The latter leads to a 50% reduction of frequency of Tcrb-V8.4a CD8+ cells but not CD4+ cells and does not affect either subset of Tcrb-V8.2l cells. A comparison of rat classical class I MHC (RT1.A) sequences and current models of TCR-MHC-peptide interaction suggests that this reduction in frequency of Tcrb-V8.4a CD8 cells may be a consequence of differential selection of Tcrb-V8.2l versus Tcrb-V8.4a TCR by differential binding of CDR2beta to highly conserved areas of C-terminal parts of the alpha helices of class I MHC molecules.

Opposite CD4/CD8 lineage decisions of CD4+8+ mouse and rat thymocytes to equivalent triggering signals: correlation with thymic expression of a truncated CD8 alpha chain in mice but not rats.

Unselected CD4+8+ rat thymocytes, generated in vitro from their direct precursors, are readily converted to functional TCRhigh T cells by stimulation with immobilized TCR-specific mAb plus IL-2. Lineage decision invariably occurs toward CD4-8+, regardless of the timing of TCR stimulation after entry into the CD4+8+ compartment or the concentration of TCR-specific mAb used for stimulation. CD4-specific mAb synergizes with suboptimal TCR-specific mAb in inducing T cell maturation, but lineage decision remains exclusively CD4-8+. These results contrast with those obtained in mice, in which Abs to the TCR complex were shown to promote CD4+8- T cell maturation from CD4+8+ thymocytes. Surprisingly, when rat and mouse CD4+8+ thymocytes were stimulated with PMA/ionomycin under identical conditions, the opposite lineage commitment was observed, i.e., mouse thymocytes responded with the generation of CD4+8- and rat thymocytes with the generation of CD4-8+ cells. It thus seems that CD4+8+ thymocytes of the two species respond with opposite lineage decisions to strong activating signals such as given by TCR-specific mAb or PMA/ionomycin. A possible key to this difference lies in the availability of p56lck for coreceptor. supported signaling. We show that in contrast to mouse CD4+8+ thymocytes, which express both a complete and a truncated CD8 alpha-chain (CD8 alpha') unable to bind p56lck, rat thymocytes only express full-length CD8 alpha molecules. Mice, but not rats, therefore may use CD8 alpha' as a "dominant negative" coreceptor chain to attenuate the CD8 signal, thereby facilitating MHC class II recognition through the higher amount of p56lck delivered, and rats may use a different mechanism for MHC class distinction during positive selection.

Control of TCR V alpha-mediated positive repertoire selection and alloreactivity by differential J alpha usage and CDR3 alpha composition.

In rats expressing the f allele of the rat MHC (RT1f), CD8 T cells utilizing the V alpha 8.2 segment are 10-fold overselected during thymic development, resulting in V alpha 8.2 expression by 14% of mature CD8 T cells as compared to 1-2% in MHC congenic strains. In the alloreactive responses of CD8 T cells from RT1f-negative rats against RT1f, V alpha 8.2+ CD8 T cells are also preferentially expanded. Neither overselection nor alloreactivity of V alpha 8.2+ TCR require selective V beta pairing. However, RT1f alloreactive V alpha 8.2+ TCR preferentially use a related set of J alpha segments which contribute short homogeneous CDR3 alpha loops, with features suggesting peptide promiscuity, and little N additions. In contrast, only few overselected V alpha 8.2+ CD8 T cells showed an imprint of positive selection on J usage or CDR3 composition. The results demonstrate that a single V alpha segment can promote both MHC allele-specific positive selection and alloreactivity, and that the latter is more dependent on an additional contribution of CDR3 alpha, possibly by promoting reactivity with a diverse set of MHC-bound peptides or by providing additional MHC contacts.

The canonical T cell receptor of dendritic epidermal gamma delta T cells is highly conserved between rats and mice.

Two monoclonal antibodies with specificity for rat gammadelta T cell receptor (TCR) were generated. One, called V65, reacts with all CD3+ alphabeta TCR- rat Tcells and thus recognizes a constant determinant of the rat gammadelta TCR (Kühnlein et al., Journal of Immunology 1994, 153: 979). The other, called V45, reacts with approximately 80% of gammadelta T cells in peripheral lymphoid organs. In rat epidermis, V65 but not V45 detects a dense network of the dendritic epidermal Tcells (DETC). Analysis of epidermal RNA by polymerase chain reaction (PCR) indicated that Vgamma3 and Vdelta1 are the predominant, if not exclusive TCR V transcripts present at this site. Sequence analysis of cDNA clones obtained by reverse transcription-PCR with Vgamma3- and Vdelta1-specific primers revealed that the variable domains of rat DETC gamma and delta chains are very homologous to those described in mice (92% and 95% identity at the protein level). The complete conservation between the two species of the amino acid sequences at the V-(D)-J transitions of this monomorphic receptor indicates that the interaction of the DETC TCR with its as yet unknown ligand must be of central importance for DETC function.

Evaluations of retinopathy in the VA Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM). A feasibility study.

OBJECTIVE: The main goal of the study of 153 male veterans was to determine whether a statistically and clinically significant difference in HbA1c could be achieved between a standard therapy and an intensively treated group of patients with type II diabetes. A second major goal was to assess the feasibility of collecting reliable high-quality endpoint data, including microvascular and macrovascular events. Retinopathy was defined as a key microvascular endpoint. RESEARCH DESIGN AND METHODS: This was a randomized prospective trial of 153 men between the ages of 40 and 69 years, with type II diabetes for 15 years or less. Of the patients, 78 were assigned to the standard therapy arm and 75 to the intensive therapy arm. The goal of standard therapy was good general medical care and well-being and avoiding excessive hyperglycemia, glycosuria, ketonuria, or hypoglycemia. This was generally accomplished with one shot of insulin per day. The goal of intensive therapy was to obtain an HbA1c within two standard deviations of the mean of nondiabetic subjects (4.0-6.1%). This was obtained by a four-step management technique, with patients moving to the next step only if operational goals were not met. The steps were as follows: step 1: evening intermediate or long-acting insulin only; step 2: evening insulin with daytime glipizide; step 3: insulin, twice a day, no glipizide; and step 4: more than two injections of insulin, no glipizide. Retinopathy was assessed at baseline, 12, and 24 months by seven-field stereo fundus photography done at each of the five participating VA medical centers and read at the Central Reading Center at the Department of Ophthalmology, University of Wisconsin Medical School, Madison. Visual acuity was determined by ophthalmologists at each of the participating hospitals. RESULTS: After the 6th month of the 24-month study, an average HbA1c of approximately 7.1% in the intensively treated group was sustained for the full study and was significantly lower than that seen in the standard group (9.2%, P < 0.001). Compliance in obtaining fundus photographs was excellent. Near normalization of glycemia did not cause transient worsening of retinal morphology nor did it prevent the onset or delay the progression of retinopathy. There was no effect on visual acuity. CONCLUSIONS: 1) A glycemic control intervention study in people with type II diabetes is feasible and safe; 2) intensive control did not cause transient deterioration of retinopathy; and 3) although no improvement was seen in retinopathy, the follow-up was 24 months, an interval shorter than the 3 years or more of intensive therapy before improvement is seen in type 1 diabetic studies. This does not rule out the possibility that longer periods of intensive therapy would have improved retinopathy. A full-scale intervention trial in type II diabetes is needed to resolve this issue.

Baseline characteristics of participants in the Appropriate Blood Pressure Control in Diabetes trial.

The ABCD (Appropriate Blood Pressure Control in Diabetes) trial is a large, prospective, randomized clinical trial designed to compare the effects of intensive with moderate blood pressure control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and neuropathy in non-insulin-dependent diabetes (NIDDM). The secondary objective is to determine equivalency of the effects of a calcium channel blocker (nisoldipine) and of an angiotensin-converting enzyme inhibitor (enalapril) as a first-line antihypertensive agent in the prevention and/or progression of these diabetic vascular complications. The study consists of two study populations: a hypertensive one (diastolic blood pressure of > or = 90.0 mm Hg at the time of randomization) and a normotensive one (diastolic blood pressure of 80.0-89.0 mm Hg at the time of randomization). A total of 950 men and women aged 40-74 years were randomized and are being followed for 5 years at a single center. There were 470 randomized participants in the hypertensive population and 480 randomized participants in the normotensive population. This report summarizes the demographic, biochemical, and clinical characteristics of the randomized patients at the time of entry into the trial and evaluates the balance between the treatment groups within each population.

The inhibition of human immunodeficiency virus proteases by 'interface peptides'.

The active human immunodeficiency virus type 1 (HIV-1) protease has a homodimeric structure, the subunits are connected by an 'interface' beta-sheet formed by the NH2- and COOH-terminal amino acid segments. Short peptides derived from these segments are able to inhibit the protease activity in the range of micromolar IC50 values. We have further improved the inhibitory power of such peptides by computer modelling. The best inhibitor, the palmitoyl-blocked peptide Pam-Thr-Val-Ser-Tyr-Glu-Leu, has an IC50 value of less than 1 microM. Some of the peptides also showed very good inhibition of the HIV-2 protease. The C-terminal segment of the HIV-1 matrix protein, Acetyl-Gln-Val-Ser-Gln-Asn-Tyr, also inhibits HIV-1 protease. Kinetic studies confirmed the 'dissociative' mechanism of inhibition by the peptides. Depending on the peptide structure and ionic strength, both dimerization inhibition and competitive inhibition were observed, as well as synergistic effects between competitive inhibitors and interface peptides.

Microanalysis of serotonin by high pressure liquid chromatography with electrochemical detection.

Serotonin (5-HT) analysis by high pressure liquid chromatography with electrochemical detection (HPLC-ED) has been designed to perform micro assays below the picogram range. We demonstrated that the oxidation potential of 5-HT was tightly linked to the pH of the buffer used as eluent phase. The electrochemistry of 5-HT in pH 4.00 acetate buffer and in pH 6.80 phosphate buffer allowed quantification down to 2 x 10(-18) g. The oxidization current was linked to the 5-HT amount added. The electrochemical response of 5-HT was different for low amounts in the 10(-18) g range and for amounts above the picogram range. Two curves were obtained according to the electrochemical response of 5-HT: the first one was for the 10(-18) g range and the second one was for the picogram range and above. It thus appeared between concentration ranges that assays are not be feasible. This method has been used to analyse 20 microns frozen slices of rat spinal cord. These data open new insights into scarce quantification of 5-HT without the use of radio-elements.

Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes.

OBJECTIVE: It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus (NIDDM). The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined. Accordingly, we designed a feasibility study that compared standard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia. RESEARCH DESIGN AND METHODS: A prospective trial was conducted in five medical centers in 153 men of 60 +/- 6 years of age who had a known diagnosis of diabetes for 7.8 +/- 4 years. They were randomly assigned to a standard insulin treatment group (one morning injection per day) or to an intensive therapy group designed to attain near-normal glycemia and a clinically significant separation of glycohemoglobin from the standard arm. A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose: 1) an evening insulin injection, 2) the same injection adding daytime glipizide, 3) two injections of insulin alone, and 4) multiple daily injections. Patient accrual and adherence, glycohemoglobin (HbA1c), side effects, and measurements of endpoints for a prospective long-term trial were assessed. RESULTS: Accrual goals were met, mean follow-up time was 27 months (range 18-35 months), and patients kept 98.6% of scheduled visits. After 6 months, the mean HbA1c in the intensive therapy group was at or below 7.3% and remained 2% lower than the standard group for the duration of the trial. Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin, alone or with daytime glipizide. By the end of the trial, 64% of the patients had advanced to two or more injections of insulin a day, aiming for normal HbA1c. However, only a small additional fall in HbA1c was attained. Severe hypoglycemia was rare (two events per 100 patients per year) and not significantly different between the groups, nor were changes in weight, blood pressure, or plasma lipids. There were 61 new cardiovascular events in 40 patients and 10 deaths (6 due to cardiovascular causes). CONCLUSIONS: Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia, weight gain, hypertension, or dyslipidemia. Cardiovascular event rates are high at this stage of NIDDM. A long-term prospective trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin.

Prevention and treatment of Lewis rat experimental allergic encephalomyelitis with a monoclonal antibody to the T cell receptor V beta 8.2 segment.

The predominance of T cell receptor (TCR) V beta 8.2 utilization by encephalitogenic T cells induced in Lewis rats by immunization with myelin basic protein (MBP) is controversial. Thus, both an almost exclusive usage of V beta 8.2 [Burns, F. R., Li, X., Shen, N., Offner, H., Chou, Y. K., Vandenbark, A. A. and Heber-Katz, E., J. Exp. Med. 1989, 169: 27; Chluba, J., Steeg, C., Becker, A., Wekerle, H. and Epplen, J. T., Eur. J. Immunol. 1989. 19: 279] and a quite diverse V beta composition of CD4 T cells causing experimental autoimmune encephalomyelitis (EAE) [Sun, D., Gold, P. D., Smith, L., Brostoff, S. and Coleclough, C., Eur. J. Immunol, 1992. 22: 591; Sun, D., Le, J. and Coleclough, C., Eur. J. Immunol. 1993. 23: 494] have been reported. Using a recently developed monoclonal antibody (mAb) specific for TCR V beta 8.2, we show that postnatal treatment effectively eliminates V beta 8.2-bearing cells and prevents MBP-induced EAE in the majority of Lewis rats. Moreover, treatment of adult Lewis rats with V beta 8.2-specific mAb as late as on day 12 after MBP immunization suppressed the development of neurological symptoms. Thus, V beta 8.2-bearing cells do play a decisive role in Lewis rat EAE, and suppression of the small (5%) V beta 8.2-expressing T cell subset provides an effective therapeutic strategy.

Clinical factors associated with urinary albumin excretion in type II diabetes.

Clinical factors associated with urinary albumin excretion (UAE) in type II diabetes are less well known than in type I diabetes. To examine the factors associated with UAE in type II diabetes, 933 Appropriate Blood Pressure Control in Diabetes Trial patients were classified according to UAE status: normoalbuminuria (< 20 micrograms/min), microalbuminuria (20 to 200 micrograms/min), and macroalbuminuria (> 200 micrograms/min). The class of UAE was then correlated with various clinical factors. Using univariate analyses, Hispanic ethnicity, African-American race, male gender, poor glycemic control, insulin use, long duration of diabetes, dyslipidemia, diastolic and systolic hypertension, smoking, and obesity were significantly correlated with microalbuminuria and macroalbuminuria. Using multivariate logistic regression analyses controlling for diabetes duration, glycosylated hemoglobin, gender, and race, the most significant predictors of microalbuminuria and macroalbuminuria were systolic hypertension, body mass index, high-density lipoprotein cholesterol, insulin use, and smoking pack-years. Of these factors, several are potentially reversible with aggressive intervention.