Intrauterine growth retardation leads to the development of type 2 diabetes in the rat.

Intrauterine growth retardation has been linked to the development of type 2 diabetes in later life. The mechanisms underlying this phenomenon are unknown. We have developed a model of uteroplacental insufficiency, a common cause of intrauterine growth retardation, in the rat. Bilateral uterine artery ligation was performed on day 19 of gestation (term is 22 days) in the pregnant rat; sham-operated pregnant rats served as controls. Birth weights of intrauterine growth-retarded (IUGR) animals were significantly lower than those of controls until approximately 7 weeks of age, when IUGR rats caught up to controls. Between 7 and 10 weeks of age, the growth of IUGR rats accelerated and surpassed that of controls, and by 26 weeks of age, IUGR rats were obese (P < 0.05 vs. controls). No significant differences were observed in blood glucose and plasma insulin levels at 1 week of age. However, between 7 and 10 weeks of age, IUGR rats developed mild fasting hyperglycemia and hyperinsulinemia (P < 0.05 vs. controls). At age 26 weeks, IUGR animals had markedly elevated levels of glucose (P < 0.05 vs. controls). IUGR animals were glucose-intolerant and insulin-resistant at an early age. First-phase insulin secretion in response to glucose was also impaired early in life in IUGR rats, before the onset of hyperglycemia. There were no significant differences in beta-cell mass, islet size, or pancreatic weight between IUGR and control animals at 1 and 7 weeks of age. However, in 15-week-old IUGR rats, the relative beta-cell mass was 50% that of controls, and by 26 weeks of age, beta-cell mass was less than one-third that of controls (P < 0.05). The data presented here support the hypothesis that an abnormal intrauterine milieu can induce permanent changes in glucose homeostasis after birth and lead to type 2 diabetes in adulthood.

Combined intralesional interferon alpha 2B and oral vitamin E in the treatment of Peyronie's disease.

It has been recently reported that intralesional therapy with alpha interferon 2B resulted in significant improvement of both objective and subjective complaints (penile curvature, pain, plaque size, sexual function) associated with Peyronie's disease. Vitamin E, with its antioxidant properties, may play a role in reducing the inflammatory response. This study was designed to determine the safety and effectiveness of a high dose of alpha INF-2B injected weekly into the Peyronie's plaque combined with oral Vitamin E therapy. Twenty-nine patients with Peyronie's disease were evaluated with penile duplex Doppler for degree of penile curvature, deformity, and plaque size both prior to and after treatment. Each patient then received 4.0 x 10(6) units of alpha INF-2B in 10 cc of normal saline after appropriate local anesthesia. Injections were given once per week directly into the Peyronie's plaque for a period of 10 weeks. Patients also received 400 units of Vitamin E by mouth twice a day. Subjective data was obtained via a questionnaire prior to and at the conclusion of the study. Preliminary results demonstrated improvement of penile curvature in 39% of patients, with one patient experiencing complete resolution. Significant decreases in plaque sizes were noted in 11 of these patients, with softening of the plaques noted in all patients completing the study. Seven patients dropped out of the study prior to completing the 10 weeks: three with severe disease proceeded to surgery, two were lost to follow-up, one had exascerbation of his arthritis symptoms, and one quit secondary to flu-like symptoms. Subjective data from questionnaires revealed improvement in sexual function in those men with decreased curvature and plaque size. Weekly intralesional injections with 4.0 x 10(6) units improved plaque consistency and decreased curvature and plaque size (P < 0.5). Overall subjective sexual performance was reportedly improved. Increased dosage of alpha INF-2B resulted in increased severity of flu-like symptoms when compared to the lower (1 x 10(6) units) biweekly dosage. No significant difference was noted with the addition of oral Vitamin E therapy.

DNA microarray-mediated transcriptional profiling of the Escherichia coli response to hydrogen peroxide.

The genome-wide transcription profile of Escherichia coli cells treated with hydrogen peroxide was examined with a DNA microarray composed of 4,169 E. coli open reading frames. By measuring gene expression in isogenic wild-type and oxyR deletion strains, we confirmed that the peroxide response regulator OxyR activates most of the highly hydrogen peroxide-inducible genes. The DNA microarray measurements allowed the identification of several new OxyR-activated genes, including the hemH heme biosynthetic gene; the six-gene suf operon, which may participate in Fe-S cluster assembly or repair; and four genes of unknown function. We also identified several genes, including uxuA, encoding mannonate hydrolase, whose expression might be repressed by OxyR, since their expression was elevated in the DeltaoxyR mutant strain. In addition, the induction of some genes was found to be OxyR independent, indicating the existence of other peroxide sensors and regulators in E. coli. For example, the isc operon, which specifies Fe-S cluster formation and repair activities, was induced by hydrogen peroxide in strains lacking either OxyR or the superoxide response regulators SoxRS. These results expand our understanding of the oxidative stress response and raise interesting questions regarding the nature of other regulators that modulate gene expression in response to hydrogen peroxide.

Encapsulation in biodegradable microparticles enhances serum antibody response to parenterally-delivered beta-amyloid in mice.

Poly(lactide-co-glycolide) (PLG) microspheres were tested as a parenteral delivery system for human beta-amyloid (1-42) (Abeta), a potential immunotherapeutic undergoing assessment in Phase 1 studies for Alzheimer's disease (AD). Abeta was successfully encapsulated in PLG microspheres of average sizes of 3 or 15 microm diameter. Swiss Webster (SW) mice were injected by the sub-cutaneous (s.c.) or intra-peritoneal (i.p.) routes with 3-33 microg Abeta. Abeta-PLG microparticles (3 microm) induced dose-dependent antibody responses, which were maximal at 33 microg Abeta, while Abeta in phosphate-buffered saline (PBS) produced weak antibody responses at the same doses by both routes. Significantly increased antibody responses were seen for both small and large particle formulations given by the i.p. route in comparison to the s.c route. It was previously reported that passive immunisation with Abeta-specific antibodies cleared amyloid plaques in a mouse model of AD (Bard F, Cannon C, Barbour R, et al. Peripherally administered antibodies against amyloid beta-peptide enter the nervous system and reduce pathology in a mouse model of Alzheimer disease. Nature Med 2000;6:916-19), an indication that induction of serum antibody is a prerequisite for efficacy.

A tale of two representations: the misinformation effect and children's developing theory of mind.

The present research investigates representational ability as a cognitive factor underlying the suggestibility of children's eyewitness memory. The misinformation effect is used as an index of children's suggestibility, and performance on the false belief task is used as an assessment of children's representational abilities (N = 117). Analyses that considered the effect of representational ability and general memory ability on children's susceptibility to misleading information showed that differences in representational ability and general memory ability predicted participants' susceptibility to misleading information. These results demonstrate that the eyewitness memory of children who lack either multirepresentational abilities, sufficient general memory abilities, or both (i.e., most 3- and 4-year-olds) is less accurate than the eyewitness memory of children with both multirepresentational abilities and sufficient memory abilities (i.e., most 6-year-olds and adults). Thus, it appears that the earliest age at which children's eyewitness memory can be considered to be similar to that of adults is 6 years of age, when children's mental representational abilities are similar to those of adults. These results suggest that one factor underlying children's vulnerability to misleading information is the number of representations of an event that they can simultaneously hold and compare.

Health-related problems and proposed solutions identified by women in Ivory Park, Midrand. A participatory research approach.

People living in informal settlements do not realise that they could make a significant change in their circumstances by first engaging in introspection and secondly identifying their intellectual resources. In this study, participatory research was done, whereby emphasis was placed on the importance of active participation by all concerned in the project. The participants were women from the community who were able to identify the problems they encountered in their daily living that threatened their health and that of their families. After reflecting on their intellectual resources, an awareness of the power they had over their current situation surfaced. This awareness enabled them to find solutions to their problems. Participatory research is a means of community participation that ultimately leads to empowerment of the community as a whole.

Are practice nurses an unexplored resource in the identification and management of alcohol misuse? Results from a study of practice nurses in England and Wales in 1995.

Changes in the health promotional work undertaken in primary care, including the work needed to meet the 'Health of the Nation' alcohol targets, have led to a rapid expansion of the number of practice nurses in England and Wales. However, there has been little evaluation of this role. This study provides data, for the first time at a national level, about practice nurses' work in identifying and managing patients drinking above recommended sensible guidelines. Data were collected by postal questionnaire from all nurses in a 50% random sample of 1852 practices (drawn from a general practitioner (GP) national study, undertaken at the same time). 43% of nurses responded from 62% of the targeted practices. Respondents reported identifying a mean of 3.1 patients per month who were drinking above recommended sensible guidelines. These patients tended to be male, above 40 years of age and in contact with the nurse for the first time about this problem. Most patients were categorized as having a potential alcohol problem; few were classified as currently dependent. Very little intervention work was undertaken by nurses except for referral to the GP. If real progress is to be made in meeting the 'Health of the Nation' targets on population alcohol consumption, then primary care work in identifying alcohol misusing patients needs to be developed as a matter of urgency. The patients identified by practice nurses are those patients relevant to the 'Health of the Nation' alcohol targets. More emphasis needs to be placed on the valuable contribution practice nurses can make, particularly through the use of screening instruments and brief interventions.

How do general practitioners manage alcohol-misusing patients? Results from a national survey of GPs in England and Wales.

The appropriateness of the primary care setting to undertake health promotional activities has been emphasized, but little is known about the clinical work of GPs with patients misusing alcohol. This study examines how GPs managed alcohol-misusing patients. A 20% random sample of all general practitioners in England and Wales were surveyed using a postal questionnaire. A 44% response rate was achieved. GPs reported managing different levels of severity of drinking problems differently. Basic interventions, such as reporting the alcohol misuse diagnosis and the provision of advice and information, were routine. Health promotion leaflets were not used uniformly, even with the less severe problem drinkers. Detoxification, prescribing of drugs and the management of medical complications were undertaken mainly with dependent patients. Dependent drinkers were the most likely group to be referred to specialist services, while internal practice referrals occurred with all drinking status categories. Anti-depressants were the drugs most usually prescribed to alcohol-misusing patients. The data point to a need for basic guidelines, not only on how to manage and refer dependent drinkers, but also on how to detect and manage those who are not yet manifesting problems but are drinking above recommended guidelines. One of the most evident areas in which there appears to be a need for guidelines is that of prescribing within primary care.

Low detection rates, negative attitudes and the failure to meet the "Health of the Nation" alcohol targets: findings from a national survey of GPs in England and Wales.

The appropriateness of the primary care setting to undertake the health promotional activities needed to meet 'Health of the Nation' alcohol targets has been acknowledged in UK government policy and the scientific literature. However, the latest data suggest these targets are not being met. A 20% random sample of all general practitioners in England and Wales were surveyed by postal questionnaire to examine their work in detecting alcohol misuse and their attitudes towards the work. Four mailing waves produced a 44% response rate. GPs had identified a mean of 3.2 patients per month drinking above recommended 'sensible' guidelines. These patients were mostly male (73%) and above 40 years of age (45%), with nearly half (45%) already dependent drinkers. Most GPs perceived alcohol misuse patients as a difficult group with whom to work. None the less, over half the respondents believed general practice was an appropriate setting for the detection of the problem. However, most did not feel trained or supported in this area of their work. More emphasis needs to be placed on the valuable contribution GPs can make with the larger number of patients who are drinking regularly above 'sensible' levels but not yet suffering adverse affects. Our findings point towards not an unwilling profession, but a profession lacking confidence. The provision of support and basic training are major factors in how GPs perceive alcohol misusers and their own role in this work. Twenty years after the Maudsley Alcohol Pilot Project research it is disappointing that, despite greater recognition by GPs of their potential impact, lack of training and lack of support are still so central to their continued low levels of therapeutic commitment.

Comparison of Fy(b) status as determined serologically and genetically.

Comparison of the serologically determined phenotype and the genotype of samples as defined by PCR-RFLP indicated a significant percentage of discrepancies on analysis of serologically defined Fy(a + b-) samples. An investigation of these discrepancies has shown that the serologically determined phenotype of the samples varies with respect to the reagent used but that the PCR-RFLP assay gives reliable results for all the samples investigated. The samples which yielded the discrepant results were further investigated and the results indicated weakened expression of the Fyb antigen. This may arise by a method similar to the expression of Fyx although we found the incidence of these samples to be much higher than that reported for Fyx. These results may have important implications for the routine testing of blood donations, particularly in situations where the unit is to be transfused to a patient who has previously formed an anti-Fyb.

Polarized dispersion of X-rays in pyrite.

Diffraction of synchrotron radiation in a crystal of FeS2 reveals dipolar anisotropy of anomalous scattering by Fe near its K-absorption edge, in spite of the almost-regular octahedral geometry of the nearest S neighbors. At 7121 eV, the magnitude of f changes with polarization direction by as much as 0.7 electron units. No effects of quadrupolar anisotropy were detected.

The effect of cash and other financial inducements on the response rate of general practitioners in a national postal study.

BACKGROUND: Low response rates are acknowledged as a potential source of bias in survey results. Response rates are a particular problem in surveys of GPs. Thus, the methods used to encourage response to mailed surveys and the influence of inducements in maximizing response rates are fundamental issues to be examined when addressing the problem of response bias. AIM: To increase the overall response rate to a national study of GPs and to explore the effects of financial and non-financial inducements on response rates. METHODS: Two mailing waves of a postal questionnaire to a 20% random sample of all GPs in England and Wales had achieved a 33% response rate. For the third mailing wave, the non-responding GPs were then divided into a control group, a group who were offered a donation to charity to complete the questionnaire and a group who were offered cash. The charity and cash groups were further subdivided into 5 pounds and 10 pounds groups to assess the effect of the size of the inducement offered. For the control group, a fourth wave was sent the offer of a 5 pounds or 10 pounds incentive. RESULTS: Response was positively affected by the offer of an inducement. Cash, however, had a more substantial effect than the offer of a donation to charity. Older GPs were less likely to participate overall, whereas male GPs were more likely to respond to a cash inducement. Doctors who had seen more patients were less likely to reply earlier and were more likely to respond to the offer of cash. CONCLUSIONS: Primary care is going through many changes, some of which have increased the workload of the GP. It may now be that, to achieve the response rates needed to validate policy-related research, the offer of inducements will become a necessary part of the research process.

Surveying general practitioners: does a low response rate matter?

BACKGROUND: Primary care has long been of interest to policy research. Recently, there is evidence to suggest that it is becoming more difficult to encourage GPs (general practitioners) to participate in surveys. As low response rates can introduce bias into survey results, it is important to study the effects of non-response. AIM: To assess the validity of a response rate of 44% obtained in a national postal study of GPs surveyed about their work with alcohol-misusing patients by assessing the extent of any non-response bias. METHOD: A telephone survey of 148 GPs who had not responded to repeated mailings of a postal questionnaire was undertaken. In addition to personal and practice structure characteristics, the GPs were asked three questions taken from the original questionnaire about their work with alcohol-misusing patients. RESULTS: Of the 148 GPs telephoned, 64 responded to the telephone questionnaire in full; all had previously failed to respond to the postal questionnaire. Younger GPs were more likely to respond to both the national postal and telephone surveys, but more so to the latter. Telephone responders were more likely to be GPs in a single-handed practice. The work of GPs with alcohol-misusing patients highlighted differences between the two response groups. Male telephone responders were found to be identifying a significantly higher average of alcohol misusers than male postal responders. Telephone responders were more likely to feel trained in treating alcohol misuse and to feel better supported to deal with this patient group. CONCLUSION: Some significant differences were identified, indicating the presence of non-response bias. A low response rate need not affect the validity of the data collected, but it is still necessary to test for non-response effects and make corrections to the original data in order to maximize validity.

Functional health status of older women.

By the year 2000 in the United States, there will be 32 million adults age 65 or over, representing 12% of the population, with the majority being women. Older women are experiencing greater longevity but worse overall health than men. The assessment of functional health status in older women is often neglected yet is the major contributor to independent living. Functional health status includes the dimensions of physical health, independent health, and psychosocial health. Studies of two different groups of non-institutionalized older women who reside in the same Southwestern state are discussed in relation to national study samples and implications for nurse practitioners.

Polarized Dispersion for X-rays Scattered by an Aromatic Bromide.

Second-rank tensors describing how the real and imaginary dispersion terms f' and f'' depend on photon polarization for Br atoms substituted on a benzene ring have been measured at six energies near the Br K absorption edge in diffraction experiments with synchrotron radiation and crystals of homocubanecarboxylic acid p-bromoanilide. Resonance with a sigma antibonding orbital causes f' to change with polarization as much as 4.3 and f''' as much as 7.5. The tensors for two independent Br atoms are equal, uniaxial and aligned with the respective Br-C bond. Absorption spectra show the average effect of two tensors with different orientations. Atomic coordinates from a new refinement of the structure are listed.

Polarized dispersion, glide-rule-forbidden reflections and phase determination in barium bromate monohydrate.

Reflections forbidden by a glide-plane rule are observed in diffraction experiments with a crystal of barium bromate monohydrate using linearly polarized synchrotron radiation with wavelength near the bromine K-absorption edge. Their intensities change with azimuth in agreement with equations derived using a tensor model of the anomalous scattering of the bromate ion and are consistent in scale with earlier measurements of that tensor in sodium bromate. The intensity of each forbidden h0l reflection gives the magnitude and phase of the bromine part of the structure factor of the allowed 2h,0,2l reflection. The x and z coordinates of the Br atom determined from such data for 11 reflections are within 0.02 A of those from two crystal structure determinations.

Phase determination by polarized dispersion in vanadyl sulfate pentahydrate.

Anomalous-scattering tensors for V measured with linearly polarized synchrotron radiation in VOSO4. 5H2O near the K-absorption edge exhibit anisotropy as much as 4 units in f" and +/- 2 units in f'. This polarized dispersion causes the diffraction intensity to change when a crystal is turned around a diffraction vector and is the basis of a new way to obtain phases of structure factors.

Use of an in vitro haemolysis test to predict tissue irritancy in an intramuscular formulation.

As part of a drug development program, an in vitro haemolysis test has been used to predict the in vivo muscle tissue irritancy of intramuscular (i.m.) formulations of a new drug entity. Solutions of lactic acid, polyvinylpyrrolidone (PVP) 12PF and two commercial injections were also included in the study. The results indicated that the test was able to differentiate formulations in terms of haemolytic potential and the correlation between the haemolysis test results and in vivo intramuscular irritancy studies indicated that the test may be used to screen formulations for potential tissue irritancy prior to in vivo evaluation.

Biaxial tensors for anomalous scattering of X-rays in selenolanthionine.

X-ray pleochroism is observed near the Se K absorption edge in a monoclinic crystal of selenolanthionine monohydrate using linearly polarized synchrotron radiation and is explained by a simple molecular-orbital model. The complex anomalous-scattering tensor of selenium, measured by diffraction in a tetraronal crystal of the anhydrous compound, exhibits anisotropy nearly 6 for f' and 7 for f", the most yet found for a K edge. The crystal structure was determined for D-(-)-selenolanthionine, space group P4(3)2(1)2, a = 6.651 (2), c = 21.758 (5) A, Z = 4, R = 0.027 for 304 unique reflections.