Non-insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions.

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes-related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon-like peptide-1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium-glucose co-transporter-2 and dual sodium-glucose co-transporter-2 and -1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis-related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.

Efficient continuous synthesis of high purity deep eutectic solvents by twin screw extrusion.

Mechanochemical synthesis has been applied to the rapid synthesis of Deep Eutectic Solvents (DESs), including Reline 200 (choline chloride : urea, 1 : 2), in a continuous flow methodology by Twin Screw Extrusion (TSE). This gave products in higher purity and with Space Time Yields (STYs), four orders of magnitude greater than for batch methods.

Interactions between genetic background, insulin resistance and ß-cell function.

An interaction between genes and the environment is a critical component underlying the pathogenesis of the hyperglycaemia of type 2 diabetes. The development of more sophisticated techniques for studying gene variants and for analysing genetic data has led to the discovery of some 40 genes associated with type 2 diabetes. Most of these genes are related to changes in ß-cell function, with a few associated with decreased insulin sensitivity and obesity. Interestingly, using quantitative traits based on continuous measures rather than dichotomous ones, it has become evident that not all genes associated with changes in fasting or post-prandial glucose are also associated with a diagnosis of type 2 diabetes. Identification of these gene variants has provided novel insights into the physiology and pathophysiology of the ß-cell, including the identification of molecules involved in ß-cell function that were not previously recognized as playing a role in this critical cell.

Arm length is associated with type 2 diabetes mellitus in Japanese-Americans.

AIMS/HYPOTHESIS: The aim of the study was to examine the association of type 2 diabetes mellitus with arm length as a marker for early life environment and development. METHODS: This was a cross-sectional analysis of 658 second- and third-generation Japanese-Americans (349 men and 309 women). Different arm length (total, upper and forearm length) and leg length (total and lower leg length) measurements were performed. Type 2 diabetes was defined by the use of hypoglycaemic medication, fasting plasma glucose (FPG) ≥ 7 mmol/l or glucose at 2 h ≥ 11.1 mmol/l during an OGTT. Persons meeting the criteria for impaired glucose tolerance were excluded from these analyses (FPG <7 mmol/l and 2 h glucose during an OGGT <11.1 but ≥ 7.8 mmol/l). Multivariable logistic regression was used to estimate associations between prevalence of diabetes and limb length while adjusting for possible confounders. RESULTS: A total of 145 individuals had diabetes. On univariate analysis, arm and leg length were not associated with diabetes. After adjustment for age, sex, computed tomography-measured intra-abdominal fat area, height, weight, smoking status and family history of diabetes, total arm length and upper arm length were inversely related to diabetes (OR for a 1 SD increase 0.49, 95% CI 0.29, 0.84 for total arm length, and OR 0.56, 95% CI 0.36, 0.87 for upper arm length). Forearm length, height and leg length were not associated with diabetes after adjustment for confounding variables. CONCLUSIONS/INTERPRETATION: Our findings of associations between arm lengths and prevalence of type 2 diabetes supports a role for factors that determine bone growth or their correlates in the development of this condition.

EX SAIF SEREEA II--the field hospital clinical report.

This paper places on record the clinical activity of the hospital facilities run by 22 Field Hospital on Exercise SAIF SEREEA II in Oman from August to November 2001. There were 1322 episodes of illness resulting in a hospital admission. The mean rate of admission was 1.96 patients per thousand per day (SD 13.62). The main causes of admission were gastrointestinal illness, conditions related to the heat and injuries. The reporting of health service utilisation data is an important duty of medical personnel during overseas deployments in order to add to the dataset available for the estimation of medical workload for future operations.

Motility and binocularity outcomes in vitrectomy versus scleral buckling in retinal detachment surgery.

BACKGROUND: Ocular motility defects and loss of binocularity are well-recognised problems following retinal detachment surgery. It is presumed that scleral buckling is primarily responsible for these effects. The increasing use of vitrectomy in the management of retinal detachment might be expected to reduce the incidence of these defects. METHOD: Two groups of patients presenting with primary uncomplicated rhegmatogenous retinal detachments were examined following a single surgical repair. The first group underwent vitrectomy (n = 17), the second group, scleral buckling/external surgical techniques (n = 23). RESULTS: Heterotropia was present in 24% (n = 4) of the vitrectomy group and 30% (n = 7) of the "external" group, with suppression reported clinically in 8 of these and diplopia by the other 3. While ocular movements were frequently full (vitrectomy 59%, external 61%), restricted vertical movements were observed in 35% of the vitrectomy group and 26% of the external group, with horizontal and general restrictions being rare (6% and 13% respectively). True motor fusion was more common for the external group (44%) than the vitrectomies (24%), while superimposition was more frequent in the vitrectomies (64%; external 39%). The latter was achieved only with correcting prisms in 18% of vitrectomies and 9% of the external group. The remainder did not demonstrate any potential for binocularity. Visual symptoms were more frequent among the vitrectomy group, with aniseikonia and torsion significantly more common. CONCLUSIONS: The findings confirm that ocular motility problems are not exclusive to scleral buckling, with the incidence being similar in both groups. Slinging of the extraocular muscles and the accompanying dissection, resulting in the 'fat adherence syndrome', must be considered as contributory factors. The visual deficits which inevitably occur as the result of retinal detachment seem to play a more major role in the disruption of binocularity in these cases.

Morbidity surveillance in the British Army--the first 12 months.

This paper describes the data obtained during the first 12 months of the morbidity surveillance system used, world-wide, by the British Army in operational and non-operational settings and the economic impact of such morbidity in terms of estimated working days lost. Analysis is provided on primary health care and dental morbidity, the surveillance of patients undergoing physiotherapy and those Service personnel cared for by the NHS. The surveillance of the latter population shows a high burden of morbidity which, previously, has never been quantified. The most frequent cause of attendance within primary health care is injuries (all causes) with an annual total of 77,254--a rate per 1,000 personnel per month of 51.92. This leads to an annual loss of manpower, in terms of estimated working days lost of 127,839--a rate per 1,000 personnel per month of 85.91. Army Training Regiments (ATRs-5 sites), Infantry Training Centres (ITCs-2 sites) and the Royal Military Academy Sandhurst (RMAS) are grouped together as Selected Training Establishments (STEs) and show attendance rates higher than the mean for all causes. Summary results of Cochrane systematic reviews presenting up-to-date concise information on experimental evidence as to which preventive interventions should be used to diminish the notable impact of injuries on Army personnel are also given.

Ex vivo effects associated with the expression of a bcr-abl-specific ribozyme in a CML cell line.

The bcr-abl chimeric gene is found in 95% of chronic myeloid leukemia (CML) patients and is thought to be seminal to the etiology of the disease. The possibility of using ribozymes to suppress bcr-abl gene expression and subsequently alter the malignant phenotype of hematopoietic cells may provide an alternative therapeutic approach to current regimens. A series of hammerhead ribozymes targeted to a b3a2 bcr-abl transcript has been developed and previously shown to be capable of cleaving the desired sequence with varying degrees of specificity. This study investigated the ex vivo effects of endogenous expression of these ribozymes in a CML cell line, K562. We demonstrated a 53% decrease in bcr-abl mRNA levels in a clone induced to express Rz8, compared with its uninduced control. Phenotypic analysis of this clone also revealed a 63% decrease in colony-forming ability and a 43% inhibition of cell proliferation following ribozyme expression. Morphologic analysis of cells showed there was a slight increase (2.5% to 15%) in the number of cells undergoing apoptosis. These results suggest that Rz8 was effective in suppressing bcr-abl gene expression within a cellular environment and altering the leukemic nature of a CML cell line.

Proposed definitive methods for measurement of plasma testosterone and 17 alpha-hydroxyprogesterone.

OBJECTIVES: This report provides the results of the development and evaluation of definitive isotope dilution/mass spectrometry (ID/MS) methods for the determination of testosterone and 17 alpha-hydroxyprogesterone in human plasma at concentrations ranging from 1.4 to 37.9 nmol/L and 1.5 to 45.4 nmol/L, respectively. The internal standards were 16, 16, 17-2H-testosterone and 21,21,21, -2H-17 alpha-hydroxyprogesterone. The development of optimum extraction and derivatization procedures, and studies of storage time, temperature effects, accuracy, and precision are presented. RESULTS: The results indicate that the methods employing the TBDMS derivative of testosterone and MO-TMS derivative of 17 alpha-hydroxyprogesterone are capable of generating accurate and precise data at the inherently low concentrations given, with recovery greater than 95%. Accuracy of testosterone in the fortified steroid-free and pooled plasma by ID/MS measurement was good because the relative error ranged from +3.1% to -0.7, with a mean of 0.9% over the concentration levels of 1.4 to 37.9 nmol/L testosterone, and the imprecision ranged from 4.2% to 0.7% CV, with a mean of 1.9%. Accuracy of 17 alpha-hydroxyprogesterone in the fortified steroid-free and pooled plasma was also good, considering the inherently low concentrations. The relative error ranged from -2.1% to +1.5%, with a mean of 1.1%, and the imprecision ranged from 3.8% to 0.8% CV with a mean of 1.3% over concentration levels of 1.5 to 15.1 nmol/L. The high precision and accuracy and absence of statistically significant bias qualifies these methods as candidate definitive methods for plasma testosterone and 17 alpha-hydroxyprogesterone.

Improved specificity of ribozyme-mediated cleavage of bcr-abl mRNA.

Ribozyme-mediated cleavage of bcr-abl mRNA has been shown to be associated with the concomitant cleavage of bcr mRNA. The possible role of this ribozyme as a clinical therapeutic constrained us to improve its target specificity. Consequently, three modified ribozymes (Rz7-9) were created, each carrying a single base mismatch in the sequence immediately 5' of the cleavage site, while a fourth ribozyme (Rz10) was targeted to a nearby site. Each was compared with the parent ribozyme for its ability to cleave synthetic bcr-abl and bcr substrates, and it was shown that alteration of the second base 5' of the cleavage site created a ribozyme with significantly improved specificity for its substrate. Rz10 was shown to exclusively act on bcr-abl, but the efficiency of cleavage was reduced compared to that shown by ribozymes 6, 8, and 9.

Nocturnal asthma and exercise-induced bronchospasm. Why they occur and how they can be managed.

Asthma is increasing in prevalence and morbidity worldwide. Worsening of asthma symptoms during sleep and following exercise is an important component of this morbidity. Better recognition and management of nocturnal asthma and exercise-induced broncho-constriction should lead to improved outcomes. Measures to alleviate nocturnal asthma include elimination of exposure to allergens, use of measures to control contributing factors (rhinitis, sinusitis, gastroesophageal reflux, sleep apnea), maximization of the dosage of daytime asthma medications, and appropriately timed use of medications such as a long-acting inhaled beta 2 agonist, a once-daily sustained-release theophylline product, and an oral corticosteroid. Bronchoconstriction after exercise can be decreased by physical conditioning, warm-up exercises, wearing of a face mask in cold weather, postponement of exercise until at least 2 hours after a meal, and pretreatment with an inhaled beta agonist. Pretreatment with inhaled cromolyn sodium (Intal), nedocromil sodium (Tilade), or ipratropium bromide (Atrovent) may be added if necessary.

Magnesium-DNA interactions from interpretation of 25Mg-nmr relaxation rates: field and coion dependence.

We have used 25Mg-nmr to investigate the binding of magnesium ions to double-stranded DNA. We have measured line shapes for 25Mg in the presence of monodisperse calf thymus DNA (160 base pairs; b.p.) (magnesium: phosphate = 2.0) at two different field strengths, 11.75 T and 7.05 T, and used the isotropic model of two-site exchange developed by Westlund and Wennerstrom to simultaneously fit the line shapes at both field strengths. This model does not reproduce the observed field dependence. This is in contrast to a previous study [E. Berggren, L. Nordenskiold, and W.H. Braunlin (1992), Biopolymers, Vol. 32, pp. 1339-1350] in which a similar model of isotropic two-site exchange qualitatively reproduced the temperature dependence of the line widths. Relaxation rates were also measured as a function of magnesium: phosphate ratio and coion type. These measurements were used to assess the sensitivity of magnesium relaxation measurements to small changes in DNA structure induced by changes in the solvent environment. The temperature dependence of the line shape varies with the type of coion (chloride or sulfate) present. This coion dependence of the line shape is consistent with the coion dependence of the aggregation midpoint temperature reported by Bloomfield and co-workers [O.A. Knoll, M.G. Fried, and V.A. Bloomfield (1988) in Structure and Expression, Vol. 2, R.H. Sarma and M. H. Sarma, Eds., Adenine Press, New York] and attributed to a lyotropic effect. These results suggest that even at low magnesium: phosphate ratios, relaxation parameters are specific to each magnesium-coion-DNA system.

The African Caribbean Eye Survey: risk factors for glaucoma in a sample of African Caribbean people living in London.

The purpose of the study was to estimate the prevalence of and risk factors for chronic glaucoma in a sample of African Caribbean people over 35 years of age living in the London Borough of Haringey. A cross-sectional voluntary sample of persons were subjected to detailed ophthalmic assessment including automated tangent screen suprathreshold visual field testing, applanation tonometry and stereoscopic disc evaluation in 50 community-based survey clinics over an 8 month period. Cases and suspects were referred to Moorfields Eye Hospital for more detailed assessment and confirmation of the diagnosis. Of 873 eligible persons examined (out of a total of 1022), 32 definite cases of glaucoma were identified, a prevalence of 3.9%; 42% of these had been previously diagnosed. Approximately 10% of the sample required further assessment and follow-up when ocular hypertensives and glaucoma suspects were included. An age-standardised comparison with the findings of the Roscommon survey revealed a relative risk for glaucoma for Haringey blacks compared with Irish whites of 3.7. Significant risk factors for glaucoma included age, African birthplace and darker skin colour. Neither diabetes nor hypertension reached significance. Despite the lack of a population base, this study provides strong evidence that the 4 times greater risk of glaucoma estimated for American blacks compared with whites applies equally to the United Kingdom population. Community-based facilities are required to raise awareness of the risk among this ethnic minority in this country and case-finding resources should be provided to meet local needs.

The African Caribbean eye survey: risk factors for glaucoma in a sample of African Caribbean people living in London

The purpose of the study was to estimate the prevalence of and risk factors for chronic glaucoma in a sample of African Caribbean people over 35 years of age living in the London Borough of Haringey. A cross-sectional voluntary sample of persons were subjected to detailed ophthalmic assessment including automated tangent screen suprathreshold visual field testing, applanation tonometry and stereoscopic disc evaluation in 50 community-based survey clinics over an 8 month period. Cases and suspects were referred to Moorfields Eye Hospital for more detailed assessment and confirmation of the diagnosis. Of 873 eligible persons examined (out of a total of 1022), 32 definite cases of glaucoma were identified, a prevalence of 3.9 percent; 42 percent of these had been previously diagnosed. Approximately 10 percent of the sample required further assessment and follow-up when ocular hypertensives and glaucoma suspects were included. An age-standardised comparison with the findings of the Roscommon survey revealed a relative risk for glaucoma for Haringey blacks compared with Irish whites of 3.7. Significant risk factors for glaucoma included age, African birthplace and darker skin colour. Neither diabetes nor hypertension reached significance. Despite the lack of a population base, this study provides strong evidence that the 4 times greater risk of glaucoma estimated for American blacks compared with whites applies equally to the United Kingdom population. Community-based facilities are required to raise awareness of the risk among this ethnic minority in this country and case-finding resources should be provided to meet local needs (Summary)

Essential fatty acids, plasma cholesterol, and fat-soluble vitamins in subjects with age-related maculopathy and matched control subjects.

A matched-control study of plasma retinol, alpha-tocopherol, carotenoid, and cholesterol concentrations and the polyunsaturated fatty acid content of plasma and erythrocyte phospholipids was undertaken in 65 elderly patients with age-related maculopathy and 65 control subjects matched for age and sex. Despite the high statistical power of the study and large variations between subjects in the variables under consideration, no significant differences were noted between patients and control subjects. However, several statistically significant differences were noted between male and female subjects independent of their classification with maculopathy or as controls and age: plasma cholesterol, total phospholipids, alpha-tocopherol, and beta-cryptoxanthin concentrations were higher in females than in males. The mean plasma cholesterol concentration for the upper tertile of the whole sample was 7.6 mmol/L. Plasma concentrations of total carotenoids, alpha-carotene, and beta-carotene, but not alpha-tocopherol, were significantly lower in smokers than in non-smokers. The results of this study do not provide any evidence in favor of changing the dietary intake of polyunsaturated fatty acids or fat-soluble vitamins to protect against age-related maculopathy.

Visual problems in the elderly population and implications for services.

OBJECTIVE: To determine the prevalence of visual disability and common eye disease among elderly people in inner London. DESIGN: Cross sectional random sample survey. SETTING: Inner London health centre. SUBJECTS: Random sample of people aged 65 and over taken from practice's computerised age-sex register. MAIN OUTCOME MEASURES: Presenting binocular Snellen 6 m distance acuity and best monocular 3 m Sonksen-Silver acuity to classify prevalence of blindness by World Health Organisation criteria (less than 3/60 in better eye) and American criteria for legal blindness (better eye equal to 6/60 or less) and of low vision by WHO criteria (best acuity 6/18) and visual impairment by American criteria (less than 6/12 or 20/40 but greater than 6/60 or 20/200 in better eye). Principal cause of visual loss by diagnosis, referral indication by cause to hospital eye service, and proportion of cases known to primary care. RESULTS: 207 of 288 (72%) eligible people were examined. 17 (8%) housebound subjects were examined at home. The prevalence of blindness was 1% by WHO criteria and 3.9% by American criteria. The prevalence of low vision (WHO criteria) was 7.7%. The prevalence of visual impairment (American criteria) was 10.6%. Cataract accounted for 75% of cases of low vision. Only eight out of 16 patients with low vision were known by their general practitioner to have an eye problem. 56 subjects (27%) would probably have benefited from refraction. Comparisons with studies in the United States and Finland suggested higher rates in this sample, mainly due to the prevalence of disabling cataract. CONCLUSION: There seems to be a considerable amount of undetected ocular disease in elderly people in the community.

Stereopsis and ageing.

This study reports the prevalence of defective stereopsis in an elderly population. Of 728 individuals over the age of 65 who attempted a Frisby stereotest, only 27% had full stereopsis and 29% had no stereopsis. In the elderly population defective stereopsis is a common finding in the absence of any other ocular morbidity. The prevalence of defective stereopsis increased with age. This finding was noted as a part of a survey of eye health of elderly people living in an inner city. The finding was not associated with any symptoms. The significance of this finding is discussed.

Ocular responses in healthy subjects to topical bunazosin 0.3%--an alpha 1-adrenoceptor antagonist.

The ocular effects of the alpha-adrenoceptor blocking drug bunazosin, administered as eyedrops, have been measured in a placebo-controlled double-blind single-dose study in 15 healthy volunteers. The drug significantly reduced intraocular pressure over 10 hours, and there was no associated change in pulsatile ocular blood flow. Characteristic effects of alpha-adrenoceptor blockade were observed--miosis, ptosis, and conjunctival hyperaemia. The miosis alone persisted for more than 24 hours in nine out of 15 subjects.

Development of a preformulation lipophilicity screen utilizing a C-18-derivatized polystyrene-divinylbenzene high-performance liquid chromatographic (HPLC) column.

Alkane/water partition coefficients have been predicted from the retention times of solutes using a C-18-derivatized polystyrene-divinylbenzene HPLC column (Act-I). Several classes of compounds, with molecular weights from 78 to 379 and partition coefficients ranging over several orders of magnitude, were included in the present study. A high correlation coefficient (0.953) was obtained from log-log plots of alkane/water partition coefficients versus capacity factor. A poor correlation was observed for octanol/water partition coefficient, presumably due to the hydrogen-bonding capability of octanol. The alkane/water correlation suggests that the system is devoid of significant specific solute-stationary phase interactions which are known to impart anomalous retention behavior to traditional reverse phase columns. Deviations of calculated alkane/water partition coefficients (and Hansch II alkane coefficients) from observed values could not be explained in terms of solute (or substituent) polarizability, dipole moment, sigma para, or pKHB values, further suggesting that specific interactions between the stationary phase and the solute are not significant. A molecular weight dependence that was independent of lipophilicity was observed. Thermodynamic and extra-thermodynamic parameters of retention were obtained in order to investigate retention mechanisms for the Act-I column. The molecular weight dependence does not appear to be due to size exclusion or entropic expulsion of the solute from the stationary phase. Hansch II substituent coefficients calculated from retention times were found to be similar for benzene and steroid derivatives. Thus, the Act-I column may be utilized as a rapid lipophilicity screen for drug candidates of similar molecular weight.

Otrivine-antistin-pupil, corneal and conjunctival responses to topical administration.

The ocular effects of Otrivine-Antistin eyedrops have been measured in a placebo controlled single-blind study in sixteen healthy volunteers. The drops produced mild sympathomimetic responses in the eye but had no effect on corneal sensitivity or on intraocular pressure. The evidence indicates that use of Otrivine-Antistin imposes no risk to the subject.