Rationalizing the solution properties of zwitterions by means of computational chemistry

This short review describes our computational studies of carnitine, acetylcarnitines, and betaines over the past two decades. Interspersed among the three computational studies--a molecular mechanics study of the conformer population of carnitine and acetylcarnitine, an AM1 study of the energetics of hydrolysis of acetylcarnitine, and an HF 6-31G* study of the solvation energies and structures of a homologous series of betaines--are brief overviews of our research in designing and testing new therapeutic agents for non-insulin dependent diabetes and for protection against sexually transmitted diseases. The three studies also show how computational chemistry has evolved during this time to enable an evaluation of the structure and energetics of zwitterions in aqueous solution.     

Verbal Intercourse and Sexual Communication: Impediments to STD Prevention

This article explores the problems of risky sexual behavior by examining the ways people verbally negotiate sexual interaction regarding sexually transmitted diseases. Based on in-depth interviews with 124 adults (ages 21–63) who are infected with genital herpes, the article shows that knowledge about sexually transmitted diseases is not necessarily related to the action needed for their prevention. People are more afraid of being rejected by a partner than they are of contracting an STD (except, of course, AIDS). By examining difficulties people have with sexual health discourse and showing how these difficulties are related to both the problem of communicating politeness and the problem of representing the self and the sexual other, this article demonstrates that STD prevention programs overlook a very important emotional and communicative issue: the lack of a culturally sanctioned language with which to discuss sexual health with partners, [genital herpes, STD prevention, STD communication, sexually transmitted diseases, STD risk]     

How informed is patients' consent to release of medical information to insurance companies?

A study was conducted to assess how informed the consent of patients is to the release of confidential information to insurance companies. Questionnaires were sent to 226 consecutive patients from four practices whose general practitioners had received requests to complete a personal medical attendant''s report for an insurance company. In total 195 patients returned the questionnaire, whose six questions required only a yes or no answer. More than half of the patients (102 (52%] could not recall having given their consent and 79 (40%) had one or more objections to the questions commonly asked by insurance companies. Questions about sexually transmitted diseases and AIDS led to the greatest proportion of objections (85% (67/79) and 80% (63/79) respectively). Over half (111 (57%) of the 195 respondents expected their doctor to withhold sensitive information. Of the 93 patients who gave their informed consent, 63 (68%) did not expect that their doctor would be asked to answer one or more of the common questions. In most cases the consent of patients to the release of confidential information to insurance companies is neither knowingly given nor informed.     

Integrated care for diabetes: clinical,psychosocial, and economic evaluation. Diabetes Integrated Care Evaluation Team.

OBJECTIVES--To evaluate integrated care for diabetes in clinical, psychosocial, and economic terms. DESIGN--Pragmatic randomised trial. SETTING--Hospital diabetic clinic and three general practice groups in Grampian. PATIENTS--274 adult diabetic patients attending a hospital clinic and registered with one of three general practices. INTERVENTION--Random allocation to conventional hospital clinic care or integrated care. Integrated care patients seen in general practice every three or four months and in the hospital clinic annually. General practitioners were given written guidelines for integrated care. MAIN OUTCOME MEASURES--Metabolic control, psychosocial status, knowledge of diabetes, beliefs about control of diabetes, satisfaction with treatment, disruption of normal activities, numbers of consultations and admissions, frequency of metabolic monitoring, costs to patients and NHS. RESULTS--A higher proportion of patients defaulted from conventional care (14 (10%)) than from integrated care (4 (3%), 95% confidence interval of difference 2% to 13%). After two years no significant differences were found between the groups in metabolic control, psychosocial status, knowledge, beliefs about control, satisfaction with treatment, unscheduled admissions, or disruption of normal activities. Integrated care was as effective for insulin dependent as non-insulin dependent patients. Patients in integrated care had more visits and higher frequencies of examination. Costs to patients were lower in integrated care (mean 1.70 pounds) than in conventional care (8 pounds). 88% of patients who experienced integrated care wished to continue with it. CONCLUSIONS--This model of integrated care for diabetes was at least as effective as conventional hospital clinic care.     

Association of low birth weight with beta cell function in the adult first degree relatives of non-insulin dependent diabetic subjects.

OBJECTIVE--To examine the relation between birth weight and beta cell function in the first degree relatives of non-insulin dependent diabetic subjects. DESIGN--Cross sectional study of 101 adults of known birth weight from 47 families which had at least one member with non-insulin dependent diabetes. SUBJECTS--101 white adults aged mean 43 (SD 7) years. SETTING--Oxfordshire, England. MAIN OUTCOME MEASURES--Glucose tolerance was measured by continuous infusion glucose tolerance test. beta cell function and insulin sensitivity were calculated from the fasting plasma glucose and insulin concentrations with homeostasis model assessment. beta cell function was standardised to allow for the confounding effects of age and obesity. RESULTS--Twenty seven subjects had non-insulin dependent diabetes, 32 had impaired glucose tolerance, and 42 were normoglycaemic. Birth weight correlated with the beta cell function of the complete cohort (rs = 0.29, p = 0.005), the non-insulin dependent diabetic subjects (rs = 0.50, p = 0.023), and the non-diabetic subjects (rs = 0.29, p = 0.013). The non-insulin dependent diabetic (n = 27) and the non-diabetic (n = 74) subjects had similar mean (inter-quartile range) centile birth weight 50% (19%-91%), and 53% (30%-75%) respectively. Non-insulin dependent diabetic subjects had significantly lower beta function than the non-diabetic subjects: 69% (48%-83%) v 97% (86%-120%), p < 0.001. CONCLUSIONS--The cause of the association between low birth weight and reduced beta cell function in adult life is uncertain. Impaired beta cell function in non-insulin dependent diabetic subjects was not accounted for by low birth weight, and genetic or environmental factors are likely to be necessary for development of diabetes.     

Nijmegen breakage syndrome (NBS)

Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alstr?m disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses.     

Diabetes,driving, and the general practitioner.

The medical fitness of drivers who have diabetes is assessed primarily by general practitioners. A survey was made of the knowledge of driving and diabetes of 105 general practitioners in Glasgow. Ninety four (90%) knew that people who were insulin dependent were required by law to declare their condition to the Driver and Vehicle Licensing Centre in Swansea, but most were unaware that people with diabetes should not hold a "till 70" driving licence. Seventy one doctors (69%) claimed that patients were recalled individually for fitness to drive. The minimum visual acuity for driving was stated correctly by 37 (35%). Only eight respondents knew that a hypoglycaemic diabetic driver can be charged with driving under the influence of a drug (Road Traffic Act 1972), and the practical advice that was given to patients about hypoglycaemia and driving was unsatisfactory. As a group the general practitioners showed deficiencies in knowledge regarding diabetes and driving, suggesting a need for further postgraduate education.     

Delta aminolevulinate dehydratase (ALA-D) activity in human and experimental diabetes mellitus

The haem pathway is impaired in porphyrias and a frequent coexistence of diabetes mellitus and porphyria disease has been reported. We have therefore decided to investigate delta-aminolevulinate dehydratase, one of the more sensitive enzymes in the haem pathway, in both human diabetic patients and diabetic rats. We have studied 131 diabetes mellitus patients, 32 insulin dependent and 99 non-insulin dependent. The latter group was further subdivided according to treatment: diet alone (n = 24), diet plus oral hypoglycemic agents (n = 28) and diet plus insulin (n = 47). We have also performed similar studies in the rat model of diabetes mellitus, induced in 11 Wistar rats by streptozotocin. Control groups of both humans and animals were used. Erythrocytic aminolevulinate dehydratase activity was reduced in both insulin dependent and non-insulin dependent diabetic patients as compared to their controls (p < 0.001). This activity was only partially restored by addition of zinc and thiols to the incubation media. In insulin-dependent diabetes mellitus, reduction of enzyme activity was related to the glycosilated hemoglobin concentration (p < 0.05) and in non-insulin dependent diabetes mellitus to the glycemia (p < 0.01). In the diabetic rat, aminolevulinate dehydratase activity was diminished on both erythrocytes (p < 0.01) and hepatic tissue (p < 0.01) when compared to the control group. The decrease in activity of erythrocyte aminolevulinate dehydratase observed in diabetic patients, may represent an additional and useful parameter for the assessment of the severity of carbohydrate metabolism impairment.     

Metabolic abnormalities in children of non-insulin dependent diabetics.

Non-insulin dependent diabetes appears to be an inherited condition. A study of young offspring of non-insulin dependent diabetics was conducted to determine whether metabolic abnormalities could be found at a young age before clinical diabetes developed. Thirteen patients with non-insulin dependent diabetes were selected who fulfilled the following criteria: they had a sibling who also had non-insulin dependent diabetes, their spouse was non-diabetic, and the offspring were aged between 12 and 45 years, not diabetic, and available for study. All 32 offspring had a 75 g oral glucose tolerance test, and results in 13 of them, one randomly selected from each family, were compared with 13 controls of similar age, sex, and weight. The offspring had significantly higher fasting concentrations of glucose, higher proportions of haemoglobin A1, and higher concentrations of insulin, C peptide, and glucagon. After glucose challenge the increases in both glucose and C peptide concentrations were significantly greater in the offspring. These differences were maintained in all 32 offspring when compared with 18 controls of similar age, sex, and weight; seven of the 32 offspring had impaired glucose tolerance. These results indicate that young offspring of selected non-insulin dependent diabetics can show extensive metabolic changes including impaired glucose tolerance. These changes are associated with hyperinsulinaemia and hyperglucagonaemia.     

Diabetes in prison: can good diabetic care be achieved?

OBJECTIVE--To investigate the clinical characteristics and metabolic control of diabetic patients given structured diabetic care in prison. DESIGN--Survey of diabetic men serving prison sentences during a 22 month period in a large British prison. SETTING--HM Prison, Walton, Liverpool. SUBJECTS--42 male diabetic prisoners, of whom 23 had insulin dependent and 19 non-insulin dependent diabetes. MAIN OUTCOME MEASURES--Episodes of diabetic instability, glycated haemoglobin concentrations, body mass index. RESULTS--No serious diabetic instability occurred. Between the initial assessment by the visiting consultant diabetologist and a second assessment 10 weeks later glycated haemoglobin concentrations had fallen from 10.8 (SD 2.9)% to 9.8 (2.4)% (p less than 0.05) in prisoners with insulin dependent diabetes and from 8.7 (1.9)% to 7.6 (1.2)% (p less than 0.05) in those with non-insulin dependent diabetes. Good glycaemic control continued, a mean glycated haemoglobin concentration of 7.6 (1.5)% being recorded in seven men remaining in prison for six to 18 months. Mean body mass index (weight (kg)/(height(m))2) did not change during the study (insulin dependent prisoners 23.3 (SD 2.1), non-insulin dependent prisoners 27.9 (3.8)). CONCLUSIONS--Good diabetic metabolic control is usual in prison, probably due to the rigid dietary regimen, no alcohol, and compliance with treatment. Many younger men had defaulted from their home diabetic clinics, and imprisonment allowed screening for diabetic complications and reassessment of treatment. Structured diabetic care should be offered in all prisons.     

Case-control study of self reported genitourinary infections and risk of gastroschisis: findings from the national birth defects prevention study, 1997-2003

Objective To assess the association between genitourinary infections in the month before conception to the end of the first trimesterand gastroschisis.Design Case-control study with self reported infections from a computer assisted telephone interview.Setting National birth defects prevention study, a multisite, population based study including 10 surveillance systems for birth defects in the United States.Participants Mothers of 505 offspring with gastroschisis and 4924 healthy liveborn infants as controls.Main outcome measure Adjusted odds ratios for gastroschisis with 95% confidence intervals.Results About 16% (n=81) of case mothers and 9% (n=425) of control mothers reported a genitourinary infection in the relevant time period; 4% (n=21) and 2% (n=98) reported a sexually transmitted infection and 13% (n=67) and 7% (n=338) reported a urinary tract infection, respectively. Case mothers aged <25 years reported higher rates of urinary tract infection alone and in combination with a sexually transmitted infection compared with control mothers. In women who reported both types of infection, there was a greater risk of gastroschisis in offspring (adjusted odds ratio 4.0, 95% confidence interval 1.4 to 11.6).Conclusion There is a significant association between self reported urinary tract infection plus sexually transmitted infection just before conception and in early pregnancy and gastroschisis.     

Why blind diabetics with renal failure should be offered treatment.

During May 1978 to April 1983 this renal dialysis unit treated 65 patients by continuous ambulatory peritoneal dialysis. Of these, 24 had type I (insulin dependent) diabetes, of whom 20 were blind; eight had type II (non-insulin dependent) diabetes, of whom three were blind; and 33 did not have diabetes and were not blind. The cumulative actuarial survival rates of these patients at five years were 60% for blind diabetics, 40% for sighted diabetics, and 46% for the non-diabetics. Of the 23 blind patients, 22 successfully achieved self care, including the self administration of insulin into the peritoneal dialysis solution. Blind patients had the least peritonitis and fewest complications of continuous ambulatory peritoneal dialysis, and none objected to the treatment or requested to be taken off it or be allowed to die. It was concluded that blind diabetic patients with renal failure showed both the will and the ability to stay alive and that their treatment was worth while.     

Differences in mortality and morbidity in African Caribbean and European people with non-insulin dependent diabetes mellitus: results of 20 year follow up of a London cohort of a multinational study.

OBJECTIVE: To examine differences in morbidity and mortality due to non-insulin dependent diabetes in African Caribbeans and Europeans. DESIGN: Cohort study of patients with non-insulin dependent diabetes drawn from diabetes clinics in London. Baseline investigations were performed in 1975-7; follow up continued until 1995. PATIENTS: 150 Europeans and 77 African Caribbeans with non-insulin dependent diabetes. MAIN OUTCOME MEASURES: All cause and cardiovascular mortality; prevalence of microvascular and macrovascular complications. RESULTS: Duration of diabetes was shorter in African Caribbeans, particularly women. African Caribbeans were more likely than the Europeans to have been given a diagnosis after the onset of symptoms and less likely to be taking insulin. Mean cholesterol concentration was lower in African Caribbeans, but blood pressure and body mass index were not different in the two ethnic groups. Prevalence of microvascular and macrovascular complications was insignificantly lower in African Caribbens than in Europeans. 59 Europeans and 16 African Caribbeans had died by the end of follow up. The risk ratio for all cause mortality was 0.41 (95% confidence interval 0.23 to 0.73) (P = 0.002) for African Caribbeans v Europeans. This was attenuated to 0.59 (0.32 to 1.10) (P = 0.1) after adjustment for sex, smoking, proteinuria, and body mass index. Further adjustment for systolic blood pressure, cholesterol concentration, age, duration of diabetes, and treatment made little difference to the risk ratio. Unadjusted risk ratio for cardiovascular and ischaemic heart disease were 0.33 (0.15 to 0.70) (P = 0.004) and 0.37 (0.16 to 0.85) (P = 0.02) respectively. CONCLUSIONS: African Caribbeans with non-insulin dependent diabetes maintain a low risk of heart disease. Management priorities for diabetes developed in one ethnic group may not necessarily be applicable to other groups.     

Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years.

OBJECTIVE: To establish whether the relation between size at birth and non-insulin dependent diabetes is mediated through impaired beta cell function or insulin resistance. DESIGN: Cohort study. SETTING: Uppsala, Sweden. SUBJECTS: 1333 men whose birth records were traced from a cohort of 2322 men born during 1920-4 and resident in Uppsala in 1970. MAIN OUTCOME MEASURES: Intravenous glucose tolerance test at age 50 years and non-insulin dependent diabetes at age 60 years. RESULTS: There was a weak inverse correlation (r=-0.07, P=0.03) between ponderal index at birth and 60 minute insulin concentrations in the intravenous glucose tolerance test at age 50 years. This association was stronger (r=-0.19, P=0.001) in the highest third of the distribution of body mass index than in the other two thirds (P=0.01 for the interaction between ponderal index and the body mass index). Prevalence of diabetes at age 60 years was 8% in men whose birth weight was less than 3250 g compared with 5% in men with birth weight 3250 g or more (P=0.08; 95% confidence interval for difference -0.3% to 6.8%). There was a stronger association between diabetes and ponderal index: prevalence of diabetes was 12% in the lowest fifth of ponderal index compared with 4% in the other four fifths (P=0.001; 3.0% to 12.6%). CONCLUSION: These results confirm that reduced fetal growth is associated with increased risk of diabetes and suggest a specific association with thinness at birth. This relation seems to be mediated through insulin resistance rather than through impaired beta cell function and to depend on an interaction with obesity in adult life.     

Insulinopenic Diabetes in Africa

The high proportion of unrefined carbohydrates (maize meal) in the diet of Africans could be responsible for their low insulin secretion. The consequent insulinopenia in the general African population may explain the comparative rarity of typical non-insulin dependent diabetes mellitus, and also the virtual absence of coronary heart disease. Changes in growth hormone secretion and in serum lipids, known to be associated with diabetes in Europeans, are also found in African patients.     

Adolescent health care in a large multispecialty prepaid group practice. Who provides it and how well are they doing?

Adolescents are at risk for pregnancy, sexually transmitted diseases, suicide, homicide, accidents, and substance abuse. Adolescent medicine involves an overlap of many skills needed to provide routine medical care, as well as care for those conditions that require psychosocial assessment. We report the results of a mail survey covering care of this age group by practitioners of pediatrics, internal medicine, obstetrics and gynecology, family practice, and adolescent medicine in a large, multispecialty, prepaid group practice. The mail survey covered 10 areas of adolescent care. Adolescent medicine physicians expressed the highest level of perceived knowledge and competence in these areas, with family practitioners ranked second. More than 50% of internists and pediatricians felt only fair to poor competence for a variety of adolescent conditions, whereas a third of internists and pediatricians reported that they liked to care for adolescents. Physicians in all 4 of the primary care specialties reported a need for a teen health center for both consultation and education. These results are similar to those reported for pediatricians and primary care physicians in private practice and for residents in internal medicine.     

Cost effectiveness of self monitoring of blood glucose in patients with non-insulin treated type 2 diabetes: economic evaluation of data from the DiGEM trial

Objective To assess the cost effectiveness of self monitoring of blood glucose alone or with additional training in incorporating the results into self care, in addition to standardised usual care for patients with non-insulin treated type 2 diabetes.Design Incremental cost utility analysis from a healthcare perspective. Data on resource use from the randomised controlled diabetes glycaemic education and monitoring (DiGEM) trial covered 12 months before baseline and 12 months of trial follow-up. Quality of life was measured at baseline and 12 months using the EuroQol EQ-5D questionnaire.Setting Primary care in the United Kingdom.Participants 453 patients with non-insulin treated type 2 diabetes.Interventions Standardised usual care (control) compared with additional self monitoring of blood glucose alone (less intensive self monitoring) or with training in self interpretation of the results (more intensive self monitoring).Main outcome measures Quality adjusted life years and healthcare costs (sterling in 2005-6 prices).Results The average costs of intervention were £89 (€113; $179) for standardised usual care, £181 for less intensive self monitoring, and £173 for more intensive self monitoring, showing an additional cost per patient of £92 (95% confidence interval £80 to £103) in the less intensive group and £84 (£73 to £96) in the more intensive group. No other significant cost difference was detected between the groups. An initial negative impact of self monitoring on quality of life occurred, averaging −0.027 (95% confidence interval−0.069 to 0.015) for the less intensive self monitoring group and −0.075 (−0.119 to −0.031) for the more intensive group.Conclusions Self monitoring of blood glucose with or without additional training in incorporating the results into self care was associated with higher costs and lower quality of life in patients with non-insulin treated type 2 diabetes. In light of this, and no clinically significant differences in other outcomes, self monitoring of blood glucose is unlikely to be cost effective in addition to standardised usual care.Trial registration Current Controlled Trials ISRCTN47464659.     

Islet-cell,thyroid, and gastric autoantibodies in diabetic identical twins.

Sera from 54 pairs of identical twins, 29 discordant and 25 concordant for insulin-dependent diabetes, and 11 pairs of concordant non-insulin dependent identical twins were examined for pancreatic islet-cell antibodies (ICAs). ICAs were found in 10 of the 29 diabetic discordant and eight of the 50 concordant twins (difference not significant P greater than 0-05). Six out of nine twins tested within one year of onset of diabetes were positive, whereas nine out of 29 tested after one to 10 years and three out of 41 tested after 10 years were positive. Only one of the 22 non-insulin-dependent twins had ICAs. Repeat ICA testing in five pair of insulin-dependent twins and in the siblings of one pair showed that ICAs may be present in people with normal glucose tolerance'' may precede clinical diabetes by several years; and may decline in titre or disappear with increasing duration of disease. Thyroid or gastric autoantibodies, or both, were found in 36 out of 108 insulin-dependent twins and three out of 22 non-insulin dependent twins (difference not significant P less than 0-05). Only four twins had both ICAs and thyrogastric antibodies. There were no significant associations between autoantibodies and HLA histocompatibility types. As ICAs are more common in the diabetic than the non-diabetic twins of the discordant pairs they must be associated with juvenile onset diabetes. ICAs may appear some years before the onset of diabetes, but their prevalence declines with increasing duration of diabetes. The factors determining the production of ICA differ from those for thyroid and gastric autoantibodies.     

Include or exclude? A review on the role and suitability of aquatic invertebrate neozoa as indicators in biological assessment with special respect to fresh and brackish European waters

This paper reviews published knowledge on how to deal with invasive species during biological quality assessments in European river systems for water management and assessments of ecological quality required, for example, by the European Water Frame Work Directive. The papers studied included international papers and some standards for water assessment. An overview of the current state of neozoa research showed that many different topics are treated, comprising biogeography and fauna records, species replacements and effectiveness of colonisation, life cycles, competition between native and invasive species, habitat quality and pathways of migration. Additionally, some papers have been published recently on the integration of neozoa in index-based assessment systems. Although the decline or increase of alien species populations and the corresponding impacts on indigenous populations were frequently observed, the mechanisms behind the invasions often remain hypothetical. In the reviewed papers, issues such as possible reasons for coexistence, tolerances, quality of habitat or water, life history traits and introduction of diseases were rarely covered. Few neozoa are sufficiently investigated to be categorised as indicators. After discussing the advantages and disadvantages of inclusion or exclusion, inclusion of invaders in assessments of both biodiversity (all species) and human impact (only species classified in their specific tolerance) is suggested. Further research is required to (1) update and assign ecological profiles of the non-indigenous species currently and (2) assess the effects of new invaders on native communities.