The Standardization of Outpatient Procedure (STOP) Narcotics after anorectal surgery: a prospective non-inferiority study to reduce opioid use.

BACKGROUND: Prescription of opioid medication after ambulatory anorectal surgery may be excessive and lead to opioid misuse. The purpose of this study was to evaluate the efficacy of a multi-modality opioid-sparing approach to control postoperative pain and reduce opioid prescriptions after outpatient anorectal surgery. METHODS: A prospective non-inferiority pre- and post-intervention study was completed at three academic hospitals. Patients included were 18-75 years of age who had outpatient anorectal surgeries. The Standardization of Outpatient Procedure (STOP) Narcotics intervention was implemented, which is a multi-pronged analgesia bundle integrating patient education, health care provider education, and intra-/postoperative analgesia focused on multi-modal pain control strategies and opioid-reduced prescriptions. The primary outcome was patient-reported average pain in the first 7 postoperative days. Secondary outcomes included patient-reported quality of pain management, medication utilization, prescription refills and medication disposal. RESULTS: Ninety-three patients had outpatient anorectal surgery (42 pre-intervention and 51 post-intervention). No difference was seen in average postoperative pain in the pre- vs. post-intervention groups (2.8 vs. 2.6 on an 11-point scale, p = 0.33) or patient-reported quality of pain control (good/very good in 57% vs. 63%, p = 0.58). The median oral morphine equivalents (OME) prescribed was significantly less [112.5 (IQR 50-150) pre-intervention vs. 50 (IQR 50-50) post-intervention, p < 0.001]. In the post-intervention group, only 45% of patients filled their opioid prescription and median opioid use was 12.5 OME (2.5 pills). CONCLUSIONS: While pain control after anorectal surgery must consider the individual patient's needs, a standardized pain care bundle significantly decreased opioid prescribing without an increase in patient-reported postoperative pain.

Hydroxylation of demethoxy-Q6 constitutes a control point in yeast coenzyme Q6 biosynthesis.

Coenzyme Q is a lipid molecule required for respiration and antioxidant protection. Q biosynthesis in Saccharomyces cerevisiae requires nine proteins (Coq1p-Coq9p). We demonstrate in this study that Q levels are modulated during growth by its conversion from demethoxy-Q (DMQ), a late intermediate. Similar conversion was produced when cells were subjected to oxidative stress conditions. Changes in Q(6)/DMQ(6) ratio were accompanied by changes in COQ7 gene mRNA levels encoding the protein responsible for the DMQ hydroxylation, the penultimate step in Q biosynthesis pathway. Yeast coq null mutant failed to accumulate any Q late biosynthetic intermediate. However, in coq7 mutants the addition of exogenous Q produces the DMQ synthesis. Similar effect was produced by over-expressing ABC1/COQ8. These results support the existence of a biosynthetic complex that allows the DMQ(6) accumulation and suggest that Coq7p is a control point for the Q biosynthesis regulation in yeast.

Testis-specific transcription initiation sites of rat farnesyl pyrophosphate synthetase mRNA.

A variety of rat tissues were screened at low stringency with a rat farnesyl pyrophosphate (FPP) synthetase cDNA. In testis, an FPP synthetase-related RNA was detected that was larger than the liver FPP synthetase mRNA and was present at very high levels comparable with liver FPP synthetase RNA levels obtained from rats fed diets supplemented with cholestyramine and mevinolin. Sequence analysis of testis cDNA clones, together with primer extension and S1 nuclease experiments, indicated that testis FPP synthetase transcripts contain an extended 5' untranslated region. The 5' extension contained one or two out-of-frame upstream ATGs, depending on the site of transcription initiation. Protein in vitro translation studies indicated that the extended 5' untranslated region may play a role in regulating the translation of the FPP synthetase polypeptide in rat testis. Southern blot analysis with a probe containing both testis and liver 5' untranslated sequences provided evidence that both liver and testis transcripts derive from the same gene. The data suggest that an upstream testis-specific promoter results in the abundant production of FPP synthetase transcripts that are translated at low efficiency; another promoter functions in liver and other somatic tissues and directs the regulated synthesis of shorter discrete transcripts.

Molecular cloning and sequence of a cholesterol-repressible enzyme related to prenyltransferase in the isoprene biosynthetic pathway.

Differential hybridization and molecular cloning have been used to isolate CR39, a cDNA which hybridizes to a 1.2-kilobase (kb) mRNA in rat liver. The level of CR39 mRNA was increased seven- to ninefold over normal levels by dietary cholestyramine and mevinolin and decreased about fourfold compared with normal levels by cholesterol feeding or administration of mevalonate. Similar changes in the mRNA levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and HMG-CoA synthase were observed under the various conditions. In vitro translation of either CR39 hybrid selected RNA or 1.2-kb CR39 RNA generated by an SP6 in vitro transcription system produced a polypeptide of 39,000 daltons. As deduced from the nucleotide sequence of a full-length CR39 cDNA, the rat CR39 polypeptide contained 344 amino acids and had a molecular weight of 39,615. The predicted amino acid composition and submit molecular weight of the rat CR39 were very similar to those of prenyltransferases isolated from chicken, pig, and human. The sequence of amino acid residues 173 through 203 in the rat CR39 polypeptide showed that 17 out of 30 matched an active-site peptide of avian liver prenyltransferase. Thus, alterations in the rate of cholesterogenesis resulted in the coordinate regulation of three mRNAs encoding HMG-CoA reductase, HMG-CoA synthase, and CR39, the latter being tentatively identified as prenyltransferase.

Purification of complexes of nuclear oncogene p53 with rat and Escherichia coli heat shock proteins: in vitro dissociation of hsc70 and dnaK from murine p53 by ATP.

Oligomeric protein complexes containing the nuclear oncogene p53 and the simian virus 40 large tumor antigen (D. I. H. Linzer and A. J. Levine, Cell 17:43-51, 1979), the adenovirus E1B 55-kilodalton (kDa) tumor antigen, and the heat shock protein hsc70 (P. Hinds, C. Finlay, A. Frey, and A. J. Levine, Mol. Cell. Biol. 7:2863-2869, 1987) have all been previously described. To begin isolating, purifying, and testing these complexes for functional activities, we have developed a rapid immunoaffinity column purification. p53-protein complexes are eluted from the immunoaffinity column by using a molar excess of a peptide comprising the epitope recognized by the p53 monoclonal antibody. This mild and specific elution condition allows p53-protein interactions to be maintained. The hsc70-p53 complex from rat cells is heterogeneous in size, with some forms of this complex associated with a 110-kDa protein. The maximum apparent molecular mass of such complexes is 660,000 daltons. Incubation with micromolar levels of ATP dissociates this complex in vitro into p53 and hsc70 110-kDa components. Nonhydrolyzable substrates of ATP fail to promote this dissociation of the complex. Murine p53 synthesized in Escherichia coli has been purified 660-fold on the same antibody affinity column and was found to be associated with an E. coli protein of 70 kDa. Immunoblot analysis with specific antisera demonstrated that this E. coli protein was the heat shock protein dnaK, which has extensive sequence homology with the rat hsc70 protein. Incubation of the immunopurified p53-dnaK complex with ATP resulted in the dissociation of the p53-dnaK complex as it did with the p53-hsc70 complex. This remarkable conservation of p53-heat shock protein interactions and the specificity of dissociation reactions suggest a functionally important role for heat shock proteins in their interactions with oncogene proteins.

Genetic evidence for a multi-subunit complex in the O-methyltransferase steps of coenzyme Q biosynthesis.

Coq3 O-methyltransferase carries out both O-methylation steps in coenzyme Q (ubiquinone) biosynthesis. The degree to which Coq3 O-methyltransferase activity and expression are dependent on the other seven COQ gene products has been investigated. A panel of yeast mutant strains harboring null mutations in each of the genes required for coenzyme Q biosynthesis (COQ1-COQ8) have been prepared. Mitochondria have been isolated from each member of the yeast coq mutant collection, from the wild-type parental strains and from respiratory deficient mutants harboring deletions in ATP2 or COR1 genes. These latter strains constitute Q-replete, respiratory deficient controls. Each of these mitochondrial preparations has been analyzed for COQ3-encoded O-methyltransferase activity and steady state levels of Coq3 polypeptide. The findings indicate that the presence of the other COQ gene products is required to observe normal levels of O-methyltransferase activity and the Coq3 polypeptide. However, COQ3 steady state RNA levels are not decreased in any of the coq mutants, relative to either wild-type or respiratory deficient control strains, suggesting either a decreased rate of translation or a decreased stability of the Coq3 polypeptide. These data are consistent with the involvement of the Coq polypeptides (or the Q-intermediates formed by the Coq polypeptides) in a multi-subunit complex. It is our hypothesis that a deficiency in any one of the COQ gene products results in a defective complex in which the Coq3 polypeptide is rendered unstable.

Ambulatory blood pressure, microalbuminuria, and autonomic neuropathy in adolescents with type 1 diabetes.

OBJECTIVE: To examine the relationship between 24-h blood pressure (BP) measurements, urinary albumin excretion rates, and autonomic neuropathy (AN) in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 31 patients with microalbuminuria (MA), 20 patients with intermittent MA (I-MA) and 11 patients with persistent MA (P-MA) were identified from the diabetes clinics at two major Australian tertiary care pediatric hospitals. Two control groups were used; one consisted of 19 age-, sex-, and diabetes duration-matched adolescents with normoalbuminuria (NA), and the other consisted of 46 age- and sex-matched nondiabetic control subjects. A medical history and physical examination were followed by a series of noninvasive tests of cardiovascular and pupillary autonomic function and then by 24-h ambulatory blood pressure monitoring (ABPM). RESULTS: ABPM showed an incremental increase in all BP parameters from nondiabetic control subjects through subjects with NA. A parallel incremental increase in diurnal and nocturnal ambulatory heart rates was also evident. Subjects with MA had significantly reduced pupillary adaptation to darkness compared with nondiabetic subjects and subjects with NA. The above results paralleled an incremental increase in HbAlc levels in adolescents with type 1 diabetes from subjects with NA to subjects with P-MA. CONCLUSIONS: Higher 24-h BP values and evidence of subclinical signs of AN are present before P-MA develops and may have important implications for timing the introduction of treatments designed to prevent or retard the microvascular complications of type 1 diabetes in adolescents.

Cloning of a rat cDNA encoding dihydroxypolyprenylbenzoate methyltransferase by functional complementation of a Saccharomyces cerevisiae mutant deficient in ubiquinone biosynthesis.

3,4-Dihydroxy-5-hexaprenylbenzoate methyltransferase (DHHB-MTase) is the product of the COQ3 gene in Saccharomyces cerevisiae and catalyses the fourth step in the biosynthesis of ubiquinone (coenzyme Q) from p-hydroxybenzoic acid. A full-length cDNA encoding a mammalian homologue of DHHB-MTase was isolated from a newly constructed rat testis cDNA library by functional complementation of a coq3 deletion mutant of S. cerevisiae. The complementing clone contained a 1.1-kb poly(A)(+)-tailed insert with a 858-bp open reading frame and presumably encodes 3,4-dihydroxy-5-polyprenylbenzoate-MTase. The deduced rat amino acid (aa) sequence has a 39% identity over 138 aa with the yeast DHHB-MTase and a 37% identity over this same region with an Escherichia coli protein encoded by the ubiG gene, a MTase that catalyses the terminal step of ubiquinone biosynthesis. The rescue of the yeast coq3 mutant by the rat homologue suggests that yeast and rat synthesize ubiquinone via the same early steps in this pathway.

Sensitivity to treatment with polyunsaturated fatty acids is a general characteristic of the ubiquinone-deficient yeast coq mutants.

The biosynthesis of ubiquinone (Q) and the functional consequences of Q-deficiency was studied in the yeast Saccharomyces cerevisiae. Lipid extracts were prepared from various respiratory deficient mutants grown in the presence of p-[U-14C]hydroxybenzoic acid. Q mutant strains harboring mutations in the coq3, coq4, coq5, coq6, coq7, or coq8 genes were unable to produce Q and accumulated an early intermediated that corresponded to 3-hexaprenyl-4-hydroxybenzoic acid. Several respiratory deficient yeast including both nuclear and mitochondrial petite mutant strains, retain the ability to produce Q. Thus, the inability to produce Q is a specific phenotype manifested in the class of mutants termed 'coq'. Previous studies described the enhanced sensitivity of the Q-deficient yeast strain containing a deletion in the COQ3 gene to the products of autoxidized polyunsaturated fatty acids (Do et al., 1996, Proceeding of the National Academy of Science USA, 93, 7534-7539). The results presented here show this to be a general phenotype resulting from Q-deficiency, as all of the coq mutant yeast strains tested exhibit hypersensitivity to polyunsaturated fatty acid treatment.

Characterization of Saccharomyces cerevisiae ubiquinone-deficient mutants.

Ubiquinol (QH2) is a lipid-soluble molecule that participates in cellular redox reactions. Previous studies have shown that yeast mutants lacking QH2 are hypersensitive to treatment with polyunsaturated fatty acids (PUFAs) indicating that QH2 can function as an antioxidant in vivo. In this study the effect of 1 mM linolenic acid on levels of Q6 and Q6H2 is assessed in both wild-type and respiration-deficient (atp2 delta) strains. The response of Q-deficient mutants to other forms of oxidative stress is further characterized to define those conditions where QH2 acts as an antioxidant. Endogenous antioxidant defense systems were also assessed in wild-type, Q-deficient, and atp2 delta strains. Superoxide dismutase (SOD) activity decreased and catalase activity increased in both Q-deficient and atp2 delta mutants compared to wild-type cells, suggesting that such changes result from the loss of respiration rather than the lack of Q.

Deliberate self poisoning in adolescents.

A retrospective study of 90 adolescents admitted to a district general hospital after deliberate drug overdoses was carried out. Underlying risk factors, the inpatient assessment, and the initial management offered to each patient were recorded. The longer term outcomes were assessed, with particular emphasis on psychiatric and related disorders. Many had underlying family problems; the parents of nearly half the patients were separated or divorced, and over half the families had already been seen by the social services or at the child guidance clinic. Three quarters of the patients had psychiatric assessments during admission, and of these 59 (66%) were referred for further psychiatric treatment. Of these over half withdrew from treatment. Eleven (12%) of the children took a further drug overdose. This study emphasises the need for psychiatric assessment and treatment in these children, but the results suggest that the success of management is limited by poor patient compliance.

The COQ7 gene encodes a protein in saccharomyces cerevisiae necessary for ubiquinone biosynthesis.

Ubiquinone (coenzyme Q) is a lipid that transports electrons in the respiratory chains of both prokaryotes and eukaryotes. Mutants of Saccharomyces cerevisiae deficient in ubiquinone biosynthesis fail to grow on nonfermentable carbon sources and have been classified into eight complementation groups (coq1 coq8; Tzagoloff, A., and Dieckmann, C. L.(1990) Microbiol. Rev. 54, 211-225). In this study we show that although yeast coq7 mutants lack detectable ubiquinone, the coq7 1 mutant does synthesize demethoxyubiquinone (2-hexaprenyl-3-methyl-6-methoxy-1,4-benzoquinone), a ubiquinone biosynthetic intermediate. The corresponding wild-type COQ7 gene was isolated, sequenced, and found to restore growth on nonfermentable carbon sources and the synthesis of ubiquinone. The sequence predicts a polypeptide of 272 amino acids which is 40% identical to a previously reported Caenorhabditis elegans open reading frame. Deletion of the chromosomal COQ7 gene generates respiration defective yeast mutants deficient in ubiquinone. Analysis of several coq7 deletion strains indicates that, unlike the coq7 1 mutant, demethoxyubiquinone is not produced. Both coq7 1 and coq7 deletion mutants, like other coq mutants, accumulate an early intermediate in the ubiquinone biosynthetic pathway, 3-hexaprenyl-4-hydroxybenzoate. The data suggest that the yeast COQ7 gene may encode a protein involved in one or more monoxygenase or hydroxylase steps of ubiquinone biosynthesis.

Angel trumpet lily poisoning in five adolescents: clinical findings and management.

OBJECTIVE: To describe clinical features and management of Angel trumpet lily poisoning in adolescents. METHODOLOGY: Case notes of five adolescent males who presented to the emergency department of a teaching hospital were reviewed. RESULTS: All five boys ingested a mixture of coca-cola and a brew prepared by boiling the leaves and flowers of the plant. They presented to the emergency department with various degrees of agitation and confusion and specific clinical signs. All were treated with charcoal and cathartics and discharged after 36 h. CONCLUSIONS: Due to its hallucinogenic effects, abuse of Angel trumpet lily is not uncommon and should be suspected in adolescents presenting with altered mental state and hallucinations in conjunction with other anticholinergic symptoms and signs.

Isolation and functional expression of human COQ3, a gene encoding a methyltransferase required for ubiquinone biosynthesis.

The COQ3 gene in Saccharomyces cerevisiae encodes an O-methyltransferase required for two steps in the biosynthetic pathway of ubiquinone (coenzyme Q, or Q). This enzyme methylates an early Q intermediate, 3,4-dihydroxy-5-polyprenylbenzoic acid, as well as the final intermediate in the pathway, converting demethyl-Q to Q. This enzyme is also capable of methylating the distinct prokaryotic early intermediate 2-hydroxy-6-polyprenyl phenol. A full-length cDNA encoding the human homologue of COQ3 was isolated from a human heart cDNA library by sequence homology to rat Coq3. The clone contained a 933-base pair open reading frame that encoded a polypeptide with a great deal of sequence identity to a variety of eukaryotic and prokaryotic Coq3 homologues. In the region between amino acids 89 and 255 in the human sequence, the rat and human homologues are 87% identical, whereas human and yeast are 35% identical. When expressed in multicopy, the human construct rescued the growth of a yeast coq3 null mutant on a nonfermentable carbon source and restored coenzyme Q biosynthesis, although at lower levels than that of wild type yeast. In vitro methyltransferase assays using farnesylated analogues of intermediates in the coenzyme Q biosynthetic pathway as substrates showed that the human enzyme is active with all three substrates tested.

Ubiquinone biosynthesis in Saccharomyces cerevisiae. Isolation and sequence of COQ3, the 3,4-dihydroxy-5-hexaprenylbenzoate methyltransferase gene.

Ubiquinone (or coenzyme Q) is a lipid component of the respiratory chain in the inner mitochondrial membrane, in which it functions in electron transport. Recent reports show that ubiquinone and ubiquinone biosynthetic enzymes are present in both mitochondrial and nonmitochondrial membranes of cells (Kalen, A., Appelkvist, E.-L., Chojnacki, T., and Dallner, G. (1990) J. Biol. Chem. 265, 1158-1164) although the functions that ubiquinone may play outside of the mitochondrion are not understood. To study coenzyme Q synthesis and function we cloned the 3,4-dihydroxy-5-hexaprenylbenzoate (DHHB) methyltransferase gene by functional complementation of a yeast coenzyme Q mutant strain, defective in the COQ3 gene (Tzagoloff, A., and Dieckmann, C. L. (1990) Microbiol. Rev. 54, 211-225). This gene restores both coenzyme Q synthesis in the mutant strain and the ability to grow on media containing glycerol, a nonfermentable substrate. A one-step in situ gene replacement with the cloned DHHB methyltransferase DNA directs integration to the yeast COQ3 locus on chromosome XV of Saccharomyces cerevisiae, establishing that the COQ3 locus encodes the DHHB methyltransferase structural gene. The predicted amino acid sequence of the yeast DHHB methyltransferase contains a methyltransferase consensus sequence and shows a 40% identity with an open reading frame of Escherichia coli, the gyrA5' hypothetical protein. This open reading frame is adjacent to the gyrA gene and close to the mapped location of the ubiG gene at 48 min on the E. coli chromosome. These results suggest that the E. coli gyrA5' open reading frame encodes a methyltransferase and may correspond to the ubiG gene, which is required for ubiquinone biosynthesis.

Enhanced sensitivity of ubiquinone-deficient mutants of Saccharomyces cerevisiae to products of autoxidized polyunsaturated fatty acids.

Coenzyme Q (ubiquinone or Q) plays a well known electron transport function in the respiratory chain, and recent evidence suggests that the reduced form of ubiquinone (QH2) may play a second role as a potent lipid-soluble antioxidant. To probe the function of QH2 as an antioxidant in vivo, we have made use of a Q-deficient strain of Saccharomyces cerevisiae harboring a deletion in the COQ3 gene [Clarke, C. F., Williams, W. & Teruya, J. H. (1991) J. Biol. Chem. 266, 16636-16644]. Q-deficient yeast and the wild-type parental strain were subjected to treatment with polyunsaturated fatty acids, which are prone to autoxidation and breakdown into toxic products. In this study we find that Q-deficient yeast are hypersensitive to the autoxidation products of linolenic acid and other polyunsaturated fatty acids. In contrast, the monounsaturated oleic acid, which is resistant to autoxidative breakdown, has no effect. The hypersensitivity of the coq3delta strains can be prevented by the presence of the COQ3 gene on a single copy plasmid, indicating that the sensitive phenotype results solely from the inability to produce Q. As a result of polyunsaturated fatty acid treatment, there is a marked elevation of lipid hydroperoxides in the coq3 mutant as compared with either wild-type or respiratory-deficient control strains. The hypersensitivity of the Q-deficient mutant can be rescued by the addition of butylated hydroxytoluene, alpha-tocopherol, or trolox, an aqueous soluble vitamin E analog. The results indicate that autoxidation products of polyunsaturated fatty acids mediate the cell killing and that QH2 plays an important role in vivo in protecting eukaryotic cells from these products.

A dietary source of coenzyme Q is essential for growth of long-lived Caenorhabditis elegans clk-1 mutants.

Mutations in the clk-1 gene of the nematode Caenorhabditis elegans result in slowed development, sluggish adult behaviors, and an increased lifespan. CLK-1 is a mitochondrial polypeptide with sequence and functional conservation from human to yeast. Coq7p, the Saccharomyces cerevisiae homologue, is essential for ubiquinone (coenzyme Q or Q) synthesis and therefore respiration. However, based on assays of respiratory function, it has been reported that the primary defect in the C. elegans clk-1 mutants is not in Q biosynthesis. How do the clk-1 mutant worms have essentially normal rates of respiration, when biochemical studies in yeast suggest a Q deficiency? Nematodes are routinely fed Escherichia coli strains containing a rich supply of Q. To study the Q synthesized by C. elegans, we cultured worms on an E. coli mutant that lacks Q and found that clk-1 mutants display early developmental arrest from eggs, or sterility emerging from dauer stage. Provision of Q-replete E. coli rescues these defects. Lipid analysis showed that clk-1 worms lack the nematode Q(9) isoform and instead contain a large amount of a metabolite that is slightly more polar than Q(9). The clk-1 mutants also have increased levels of Q(8), the E. coli isoform, and rhodoquinone-9. These results show that the clk-1 mutations result in Q auxotrophy evident only when Q is removed from the diet, and that the aging and developmental phenotypes previously described are consistent with altered Q levels and distribution.

Transcriptional regulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver.

This study addresses whether transcriptional control of the 3-hydroxy-3-methylglutaryl coenzyme A reductase gene in rat liver plays a role in determining the level of reductase mRNA. Isolated rat liver nuclei were allowed to elongate nascent RNA transcripts in the presence of [alpha-32P]CTP, and radiolabeled nuclear reductase RNA was quantitated by filter hybridization. Rats fed a diet supplemented with the drugs cholestyramine and mevinolin and having 20-60-fold induced levels of reductase mRNA exhibited levels of reductase transcription which were 20-fold higher than in rats fed an unsupplemented diet. Over 90% of the transcription of the reductase gene was inhibited by concentrations of alpha-amanitin which selectively inhibit RNA polymerase II. Administration of mevalonolactone (the end product of the reaction catalyzed by reductase) to rats fed cholestyramine and mevinolin caused an 80% decrease in the rate of reductase transcription by approximately 1 h. We conclude that under these conditions changes in reductase transcription are primarily responsible for the regulation of reductase mRNA levels.

Pupillary size in children and adolescents with type 1 diabetes.

Pupillary adaptation to darkness was studied in 63 children and adolescents with Type 1 diabetes using a simple portable pupillometer. Results were compared with those in a group of age-related non-diabetic children and expressed as the ratio of the pupil diameter to the iris diameter (pupil diameter %). In the diabetic patients the pupil diameter % was 61.1 +/- 5.8 (44.4-71.9) % compared with 64.2 +/- 4.1 (53.2-72.6) % in the control subjects (p less than 0.001). Abnormal pupillary adaptation to darkness was found more commonly than abnormal heart rate variation in response to a variety of stimuli in the diabetic patients. Pupillary adaptation to darkness may be useful as an indicator of subclinical autonomic neuropathy in diabetic children.

Limited joint mobility in children and adolescents with insulin dependent diabetes mellitus.

Joint mobility was studied in 70 children with insulin dependent diabetes mellitus aged 8-17 years, and the prevalence of limited joint mobility (LJM) was found to be 31% (22/70). This figure fell to only 7% (5/70) when an alternative method of assessment was used. A high number of non-diabetic, non-sibling controls (6/51 (12%] were found to have LJM. There was a trend towards an increasing prevalence of LJM with increasing age and duration of diabetes, but it was also found in patients with recent onset diabetes. A large proportion of prepubertal patients were noted to have LJM. No correlation was found between LJM and either short stature or diabetic control. There is a need for standardisation of the methods used to define and stage LJM in diabetic patients, and the significance of this clinical finding remains unclear.