Randomized controlled trial to assess the impact of continuous glucose monitoring on HbA(1c) in insulin-treated diabetes (MITRE Study).

AIMS: To determine whether continuous glucose information provided through use of either the GlucoWatch G2 Biographer or the MiniMed continuous glucose monitoring system (CGMS) results in improved glycated haemoglobin (HbA(1c)) for insulin-treated adults with diabetes mellitus, relative to an attention control and standard care group. METHODS: Four hundred and four adults taking at least two daily insulin injections and with two consecutive HbA(1c) values > or = 7.5% were recruited to this randomized controlled trial (RCT). All were trained at baseline to use the same monitor for traditional capillary glucose testing throughout the 18-month study. The CGMS group were asked to wear the device three times during the first 3 months of the trial and on another three occasions thereafter. The GlucoWatch group wore the device a minimum of four times per month and a maximum of four times per week during the first 3 months and as desired for the remainder of the trial. Trained diabetes research nurses used downloaded data to guide therapy adjustments. Proportional reduction in HbA(1c) from baseline to 18 months was the primary outcome measure. RESULTS: Neither an intention-to-treat nor per-protocol analysis showed improvement in HbA(1c) in the device groups compared with standard care. For the intention-to-treat analysis, when the standard care group was compared with each of the other groups, this equated to differences in mean relative HbA(1c) reduction (95% confidence interval) from baseline to 18 months of 3.5% (-1.3 to 8.3; GlucoWatch), 0.7% (-4.1 to 5.5; CGMS), and -0.1% (-4.6 to 4.3; attention control). CONCLUSIONS: The additional information provided by these devices did not result in improvements in HbA(1c) in this population.

A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

OBJECTIVES: To evaluate whether the additional information provided by minimally invasive glucose monitors results in improved glycaemic control in people with poorly controlled insulin-requiring diabetes, and to assess the acceptability and health economic impact of the devices. DESIGN: A four-arm randomised controlled trial was undertaken. SETTING: Participants were recruited from secondary care diabetes clinics in four hospitals in England. PARTICIPANTS: 404 people aged over 18 years with insulin-treated diabetes mellitus (types 1 or 2) for at least 6 months who were receiving two or more injections of insulin daily were eligible. Participants had to have had two glycosylated haemoglobin (HbA1c) values > or = 7.5% in the last 15 months. INTERVENTIONS: Participants were randomised to one of four groups. Two groups received minimally invasive glucose monitoring devices [GlucoWatch Biographer or MiniMed Continuous Glucose Monitoring System (CGMS)]. These groups were compared with an attention control group (standard treatment with nurse feedback sessions at the same frequency as those in the device groups) and a standard control group (reflecting common practice in the clinical management of diabetes in the UK). MAIN OUTCOME MEASURES: Change in HbA1c from baseline to 3, 6, 12 and 18 months was the primary indicator of short- to long-term efficacy in this study. Perceived acceptability of the devices was assessed by use and a self-report questionnaire. A health economic analysis was also performed. RESULTS: At 18 months all groups demonstrated a decline in HbA1c levels from baseline. Mean percentage changes in HbA1c were -1.4 for the GlucoWatch group, -4.2 for the CGMS group, -5.1 for the attention control group and -4.9 for the standard care control group. At 18 months the relative percentage reduction in HbA1c in each of the intervention arms was less than that in the standard care control group. In the intention to treat analysis no significant differences were found between any of the groups at any of the assessment times. There was no evidence that the additional information provided by the devices resulted in any change in the number or nature of treatment recommendations offered by the nurses. The health economics analysis indicated no advantage in the groups who received the devices; a lower cost and higher benefit were found for the attention control arm. Assessment of device use and acceptability indicated a decline in use of both devices, which was most marked in the GlucoWatch group by 18 months (20% still using GlucoWatch versus 57% still using the CGMS). The GlucoWatch group reported more side effects, greater interference with daily activities and more difficulty in using the device than the CGMS group. CONCLUSIONS: Continuous glucose monitors do not lead to improved clinical outcomes and are not cost-effective for improving HbA1c in unselected individuals with poorly controlled insulin-requiring diabetes. On acceptability grounds the data suggest that the GlucoWatch will not be frequently used by individuals with diabetes because of the large number of side effects.

A spectrum of behaviour in silent corticotroph pituitary adenomas.

Silent corticotroph adenomas (SCA) are pituitary tumours positive on immunohistochemical staining for ACTH but without clinical evidence of Cushing's disease in the patient. Previous reports suggest that these tumours may behave in a more aggressive way then other pituitary adenomas. We have followed the natural history of SCA and assessed whether histopathological indices predict tumour behaviour. We identified 22 patients in whom trans-sphenoidal surgery was performed for a non-functioning adenoma (NFA) with positive immunostaining for ACTH between 1990 and 2000 and examined the history of their disease. Patients were followed up for a mean of 4.8 years. A total of 86.7% of patients had documented visual deficits at presentation. In four cases hypercortisolaemia was observed later in the course of the disease. Two patients died as a result of their SCA and 33.3% of tumours recurred. Recurrence was more frequent in patients treated with adjuvant radiotherapy. Pathological indices (increased mitotic range and Ki-67) did not predict recurrence or malignant transformation. We suggest that certain 'silent' corticotroph tumours may have the potential for ACTH secretion leading to hypercortisolaemia at a later stage in the disease. The possibility of transformation to a more aggressive tumour needs to be considered in all SCA.

Acromegaly or chronic renal failure: a diagnostic dilemma.

Uraemic patients may have markedly elevated serum GH concentrations yet, for hitherto unknown reasons, they do not develop acromegaly. We discuss the diagnostic dilemma presented by a 33-year-old Caucasian male with chronic renal failure (creatinine clearance 10 ml/min) secondary to polycystic kidney disease, elevated GH concentrations (fasting concentration of 22.6 rising to 77.9 mU/l 30 minutes after a 75-g oral glucose load) as well as acromegalic features. Review of the patient's relatives and the findings of a normal serum IGF-I concentration and a normal pituitary fossa on magnetic resonance imaging, suggest that the patient's acromegalic appearance is a familial trait and his abnormal GH dynamics a result of his renal failure rather than acromegaly. The patient's normal GH bioactivity and reduced GH binding protein concentration supports the current belief that chronic renal failure leads to an increase in peripheral tissue resistance to GH due to decreased GH receptor numbers. These changes, together with reduced IGF-I bioactivity, may explain why patients with chronic renal failure do not develop acromegaly in the presence of abnormally elevated levels of GH.

Oral dimercaptosuccinic acid and ongoing exposure to lead: effects on heme synthesis and lead distribution in a rat model.

Lead (Pb) exposure and subsequent toxicity continues to be a significant problem in the United States. Treatment with meso-2,3-dimercaptosuccinic acid (DMSA) has been reported to be effective in reducing the body's Pb burden, with fewer adverse side effects than other chelating agents. The oral availability and relative safety of DMSA presents the controversial option of treating patients with Pb poisoning on an outpatient basis. Despite recommendations that children be removed from the Pb contaminated environment, some children will inevitably be exposed to environmental Pb while receiving oral DMSA therapy. The study hypothesized that oral DMSA chelation therapy is beneficial even when faced with continued dietary Pb. Sprague-Dawley rats were exposed to Pb in water for 35 days and then placed in various treatment groups, including groups administered oral DMSA with and without concurrent Pb exposure. The concentration of Pb in blood and critical organs and Pb diuresis were measured. The effect of Pb on heme synthesis was determined by assaying the urinary delta-aminolevulinic acid (delta-ALA), and blood zinc protoporphyrin (ZPP). DMSA reversed the hematological effects of Pb, decreased the blood, brain, bone, kidney, and liver Pb concentration, and produced a marked Pb diuresis, even when challenged with ongoing Pb exposure. In conclusion, even though DMSA treatment without exposure to Pb is optimal, oral DMSA could be beneficial even when challenged with ongoing Pb exposure.

Doctors and the law.

Many doctors are concerned about the law and the way it relates to their professional life, as was evident from the number of delegates attending the conference on legal aspects of medicine held at the Royal College of Physicians in November 1993. Those taking part came from a diversity of professional backgrounds--junior and career grade hospital staff working in various specialties, general medical and dental practitioners, prison medical officers and police surgeons, specialists in forensic medicine, lawyers and coroners. The result was a stimulating exploration of the interface between medicine and the law, considering first the doctor's responsibilities in law and the circumstances which may lead to an appearance in court, and then the doctor as carer of the victims or perpetrators of crime.

Restriction endonuclease analysis of adenovirus type 3 isolated in Norway from 1970 to 1991.

Forty-three strains of adenovirus type 3 isolated from patients in Norway between 1970 and 1991 were analyzed with four restriction endonucleases. Bg1 II was the most discriminative enzyme. Five genotypes were identified and one of these has not been described before (Ad3a12). During both the epidemics in this period, new genotypes were introduced into the population. The same genotypes were identified in Norway as have previously been found in the northern parts of Europe, America and the Soviet Union.

Negative regulation of the glycoprotein hormone alpha gene promoter by thyroid hormone: mutagenesis of a proximal receptor binding site preserves transcriptional repression.

Transcription of the glycoprotein hormone alpha gene is repressed by the thyroid hormone receptor (TR) in a hormone dependent manner. Previous studies identified a TR binding site immediately downstream of the TATA box. Site directed mutagenesis and transient gene expression studies were used to evaluate the role of this TR binding site as a negative thyroid response element (nTRE). Mutagenesis of the putative negative thyroid response element (nTRE) site eliminated TR binding but failed to eliminate negative regulation by T3. A mutation which converted the putative nTRE to a higher affinity palindromic element did not enhance repression, but rather eliminated thyroid hormone dependent negative regulation. Proximal alpha promoter sequences between -100 and +44 were replaced with a heterologous thymidine kinase promoter resulting in a construct that was not repressed by T3 treatment. This finding confirmed that repression required proximal alpha promoter sequences and also indicated that repression did not occur by interference with the function of upstream the alpha gene enhancers. These studies indicate that TR binding adjacent to the TATA box is not required for T3 mediated repression of the alpha promoter and suggest that negative regulation may involve protein-protein interactions with promoter-specific transcription factors.

Regulation of alpha and thyrotrophin-beta subunit mRNA levels by androgens in the female rat.

Thyroid and steroid hormones act by similar mechanisms to influence gene expression in the anterior pituitary gland. The genes encoding the common alpha and TSH-beta glycoprotein subunits are known to be regulated by thyroid hormones; we report here the effects of androgen administration on levels of alpha and TSH-beta mRNA in pituitary cytoplasm in the euthyroid and hypothyroid female rat. Dihydrotestosterone (DHT) suppressed both alpha and TSH-beta mRNAs to levels lower than those found in untreated animals; a similar reduction was seen in hypothyroid animals treated with DHT. A biphasic response of TSH-beta mRNA was seen following administration of tri-iodothyronine (T3) to hypothyroid rats, with early stimulation followed by later inhibition; these changes were also evident after administration of T3 to androgen-treated animals, although mRNA levels were again suppressed. The effects of testosterone were similar to those of DHT. In contrast to the changes in mRNA levels, androgen administration did not lead to significant alterations in serum TSH concentrations or pituitary TSH content. These results indicate that, like thyroid hormones, androgens suppress both alpha and TSH-beta subunit mRNA levels in the female rat. Androgens, however, exert differential effects on TSH synthesis and release which contrast with those of thyroid hormones.

DNA hybridization evidence of hominoid phylogeny: a reanalysis of the data.

Sibley and Ahlquist (1984, 1987) presented the results of a study of 514 DNA-DNA hybrids among the hominoids and Old World monkeys (Cercopithecidae). They concluded that the branching order of the living hominoid lineages, from oldest to most recent, was gibbons, orangutan, gorilla, chimpanzees, and human. Thus, a chimpanzee-human clade was indicated, rather than the chimpanzee-gorilla clade usually suggested from morphological evidence. The positions of the gibbon and orangutan branches in the phylogeny are supported by substantial evidence, but whether the chimpanzee lineage branched most recently from the human lineage or from the gorilla lineage remains controversial. The conclusions of Sibley and Ahlquist (1984, 1987) have been supported by several independent studies cited by Sibley and Ahlquist (1987), plus the DNA sequence data of Hayasaka et al. (1988), Miyamoto et al. (1988), Goodman et al. (1989, 1990), and the DNA-DNA hybridization data of Caccone and Powell (1989). The laboratory and data analysis methods have been criticized by Marks et al. (1988) and Sarich et al. (1989). In response to these critics, and for our own interests, we present a reanalysis of the Sibley and Ahlquist data, including a description of the corrections applied to the "raw counts." The validity of the laboratory methods is supported by the congruence of tree topology and delta values with those of Caccone and Powell (1989), although their tetraethylammonium chloride technique differs from the hydroxyapatite method in several respects. The utility of the T50H distance measure is indicated by its congruence with percent sequence divergence at least to delta T50H 30, as noted by Goodman et al. (1990). The Sibley and Ahlquist uncorrected data indicate that Pan is genetically closer to Homo than to Gorilla, but that Gorilla may be genetically closer to Pan than to Homo. Melting curves are presented for the pertinent experiments, plus one that includes representatives of most of the groups of living primates.

Relationships of the chromosomal species in the Eurasian mole rats of the Spalax ehrenbergi group as determined by DNA-DNA hybridization, and an estimate of the spalacid-murid divergence time.

DNA-DNA hybridization was used to measure the average genomic divergence among the four chromosomal species of the Eurasian mole rats belonging to the Spalax ehrenbergi complex (Rodentia: Spalacidae). The percent nucleotide substitutions in the single-copy nuclear DNA among the species ranged from 0 to 5%, suggesting that speciation has occurred with minor genomic changes in these animals. The youngest chromosomal species appear to differ by 0.2-0.6% base pair mismatch, which is only between one and three base differences in a 500-bp fragment. The interspecific values of percent nucleotide differences permit the recognition of two well-separated speciation events in the S. ehrenbergi complex, the older (of Lower Pleistocene age) having isolated the chromosomal species 2n = 54 before the divergence of the three other species. DNA-DNA hybridization was also used to compare the Spalacinae (Eurasian mole rats), Murinae (Old World rats and mice), and Arvicolinae (voles and lemmings). These data enabled us to estimate the time of divergence of the spalacids at ca. 19 million years ago. The dates of divergence among the other rodent lineages, as predicted by DNA hybridization results, agree well with paleontological data. These dates of divergence are obtained by the relation between geological time and single-copy nuclear DNA change, a relation that was calibrated by Catzeflis et al. (1987) through the use of fossil Arvicolinae and Murinae data.

Effect of hypothyroidism and thyroid hormone treatment of the rat on hepatic Spot 14 and thyroxine binding prealbumin mRNAs.

We have examined the influence of hypothyroidism and thyroid hormone replacement on hepatic levels of Spot 14 and thyroxine binding prealbumin mRNAs determined by dot hybridization and by Northern blot hybridization to specific complementary DNA probes. A marked reduction in Spot 14 mRNA was demonstrated in hypothyroidism, compared with the euthyroid state. T3 replacement of hypothyroid rats, using a wide dose range of T3 (1-20 micrograms) and 6 and 72 h time points, demonstrated no sustained effect at 6 h, but a dose-dependent stimulation of Spot 14 mRNA at 72 h after daily treatment with T3 was commenced. In contrast, no effect of hypothyroidism or T3 replacement on hepatic levels of thyroxine binding prealbumin mRNA was demonstrated, indicating the specificity of thyroid hormone action. T3 treatment of euthyroid rats was also associated with a dose-related stimulation of Spot 14 mRNA levels. The effect of hypothyroidism and T3 treatment of the rat on hepatic Spot 14 mRNA contrasts with divergent regulatory influences of thyroid status in the anterior pituitary and ventricular myocardium demonstrated using identical animal models, indicating the tissue specific influences of thyroid status.

Thyroid hormone response elements in pituitary genes.

Thyroid hormones regulate the transcription of a number of genes in the anterior pituitary gland. A thyroid hormone response element in the regulatory region of the rat growth hormone gene has previously been shown to mediate the effects of thyroid hormones on growth hormone gene transcription. The 5' flanking regions of the thyrotrophin alpha and beta subunit and prolactin genes have now been examined for the presence of sequences similar to this response element. Southern blotting reveals that no such sequences are present in the regions of the thyrotrophin subunit and prolactin genes examined, suggesting that the thyroid response elements of these genes differ from that of the rat growth hormone gene.