Paradoxical effects of the cannabinoid CB2 receptor agonist GW405833 on rat osteoarthritic knee joint pain.

OBJECTIVE: The present study examined whether local administration of the cannabinoid-2 (CB(2)) receptor agonist GW405833 could modulate joint nociception in control rat knee joints and in an animal model of osteoarthritis (OA). METHOD: OA was induced in male Wistar rats by intra-articular injection of sodium monoiodo-acetate with a recovery period of 14 days. Immunohistochemistry was used to evaluate the expression of CB(2) and transient receptor potential vanilloid channel-1 (TRPV1) receptors in the dorsal root ganglion (DRG) and synovial membrane of sham- and sodium mono-iodoacetate (MIA)-treated animals. Electrophysiological recordings were made from knee joint primary afferents in response to rotation of the joint both before and following close intra-arterial injection of different doses of GW405833. The effect of intra-articular GW405833 on joint pain perception was determined by hindlimb incapacitance. An in vitro neuronal release assay was used to see if GW405833 caused release of an inflammatory neuropeptide (calcitonin gene-related peptide - CGRP). RESULTS: CB(2) and TRPV1 receptors were co-localized in DRG neurons and synoviocytes in both sham- and MIA-treated animals. Local application of the GW405833 significantly reduced joint afferent firing rate by up to 31% in control knees. In OA knee joints, however, GW405833 had a pronounced sensitising effect on joint mechanoreceptors. Co-administration of GW405833 with the CB(2) receptor antagonist AM630 or pre-administration of the TRPV1 ion channel antagonist SB366791 attenuated the sensitising effect of GW405833. In the pain studies, intra-articular injection of GW405833 into OA knees augmented hindlimb incapacitance, but had no effect on pain behaviour in saline-injected control joints. GW405833 evoked increased CGRP release via a TRPV1 channel-dependent mechanism. CONCLUSION: These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.

Sediment management in sustainable urban drainage system ponds.

Since removal and disposal of sustainable urban drainage system (SUDS) sediment can incur high maintenance costs, assessments of sediment volumes, quality and frequency of removal are required. Sediment depth and quality were surveyed annually from 1999-2003 in three ponds and one wetland in Dunfermline, Scotland, UK. Highest sediment accumulation occurred in Halbeath Pond, in the most developed watershed and with no surface water management train. From comparison of measured potentially toxic metal concentrations (Cd, Cr, Cu, Fe, Ni, Pb, Zn) with standards, the average sediment quality should not impair aquatic ecosystems. 72-84% of the metal flux into the SUDS was estimated to be associated with coarse sediment (> 500 microm diameter) suggesting that management of coarse sediment is particularly important at this site. The timing of sediment removal for these SUDS is expected to be determined by loss of storage volume, rather than by accumulation of contaminants. If sediment removal occurs when 25% of the SUDS storage volume has infilled, it would be required after 17 years in Halbeath Pond, but only after 98 years in Linburn Pond (which has upstream detention basins). From the quality measurements, sediment disposal should be acceptable on adjacent land within the boundaries of the SUDS studied.

Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes.

AIMS: To compare blood glucose control using insulin glargine + insulin lispro with that on NPH insulin + unmodified human insulin in adults with Type 1 diabetes managed with a multiple injection regimen. METHODS: In this 32-week, five-centre, two-way cross-over study, people with Type 1 diabetes (n = 56, baseline HbA1c 8.0 +/- 0.8%) were randomized to evening insulin glargine + mealtime insulin lispro or to NPH insulin (once- or twice-daily) + mealtime unmodified human insulin. Each 16-week period concluded with a 24-h inpatient plasma glucose profile. RESULTS: HbA1c was lower with glargine + lispro than with NPH + human insulin [7.5 vs. 8.0%, difference -0.5 (95% CI -0.7, -0.3) %, P < 0.001]. This was confirmed by an 8% lower 24-h plasma glucose area under the curve (AUC) (187 vs. 203 mmol l(-1) h(-1), P = 0.037), a 24% reduction in plasma glucose AUC > 7.0 mmol/l1 (47 vs. 62 mmol l(-1) h(-1), P = 0.017) and a 15% lower post-prandial plasma glucose AUC (75 vs. 88 mmol l(-1) h(-1), P = 0.002). There was no reduction in night-time plasma glucose AUC or increase in plasma glucose area < 3.5 mmol/l. Monthly rate of nocturnal hypoglycaemia was reduced by 44% with glargine + lispro (0.66 vs. 1.18 episodes/month, P < 0.001). CONCLUSIONS: Compared with NPH insulin + unmodified human insulin, the combination of insulin glargine with a rapid-acting insulin analogue as multiple-injection therapy for Type 1 diabetes improves overall glycaemic control as assessed by HbA1c and 24-h plasma glucose monitoring to a clinically significant degree, together with a reduction in nocturnal hypoglycaemia.

The biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistance.

This study was designed to assess the biological variability of total testosterone and SHBG in polycystic ovarian syndrome (PCOS) and to determine the use of SHBG as a surrogate marker of insulin resistance in PCOS. Fasting blood samples were collected at 4-d intervals on 10 consecutive occasions from 12 PCOS patients and 11 age- and weight-matched controls. Duplicate samples were analyzed for SHBG, testosterone, and insulin in a single batch, and insulin resistance was calculated by the homeostasis model assessment method (HOMA-IR). The PCOS group had higher testosterone (mean +/- SD, 3.9 +/- 0.8 vs. 3.2 +/- 1.3 nmol/liter; P = 0.001), lower SHBG (28.6 +/- 17.1 vs. 57.6 +/- 30.2 nmol/liter; P = 0.001), and greater HOMA-IR (5.85 +/- 5.3 vs. 1.67 +/- 0.63 U; P = 0.001) than the controls. In contrast to HOMA-IR (1.09 vs. 0.48 U; P = 0.001), the intraindividual variation in SHBG was lower in the PCOS group (mean, 3.4 vs. 6.3 nmol/liter; P = 0.041). The index of individuality for SHBG and testosterone in PCOS was 0.49 and 0.69, respectively. This study shows that for patients with PCOS, SHBG is an integrated marker of insulin resistance that may be of use to identify insulin-resistant individuals for targeted treatment with insulin-sensitizing agents. However, SHBG and testosterone concentrations measured in isolation are inherently unsuitable for use as tests to detect hyperandrogenemia.

The trail of chromium(III) in vivo from the blood to the urine: the roles of transferrin and chromodulin.

The chromium-binding oligopeptide chromodulin (also known as low-molecular-weight chromium-binding substance) has been shown to activate the tyrosine kinase activity of the insulin receptor in response to insulin and has been proposed to be part of a novel autoamplification mechanism for insulin signaling. The model requires that Cr3+ be moved from the blood to insulin-sensitive tissues in response to insulin and subsequently be lost in the urine as chromodulin; however, the model has not been tested by in vivo studies. In vivo studies with rats have shown that the iron transport protein transferrin serves as the major chromic ion transport agent and that this transport is stimulated by insulin. The ion is transported to a variety of tissues, while liver and kidneys are the major target. In hepatocytes, chromodulin occurs in appreciable levels in the cytosol and in the nucleus. Apochromodulin levels appear to be maintained under homeostatic control, although the only detectable form of urinary chromium is probably chromodulin. Increases in urinary chromium loss in response to insulin are reflected by increases in chromodulin, establishing a direct link between carbohydrate metabolism and the oligopeptide.

17beta-estradiol vaginal tablet versus conjugated equine estrogen vaginal cream to relieve menopausal atrophic vaginitis.

OBJECTIVES: The efficacy and safety of 25-microg 17beta-estradiol vaginal tablets (Vagifem) were assessed and compared with 1.25-mg conjugated equine estrogen vaginal cream (Premarin Vaginal Cream) for the relief of menopausal-derived atrophic vaginitis, resulting from estrogen deficiency. DESIGN: In a multicenter, open-label, randomized, parallel-group study, 159 menopausal women were treated for 24 weeks with either vaginal tablets or vaginal cream. Efficacy was evaluated by relief of vaginal symptoms and concentrations of serum estradiol and follicle-stimulating hormone. Safety was monitored by the incidence of adverse events, evaluation of endometrial biopsies, and clinical laboratory results. Patients also assessed the acceptability of the study medications. RESULTS: Composite scores of vaginal symptoms (dryness, soreness, and irritation) demonstrated that both treatments provided equivalent relief of the symptoms of atrophic vaginitis. At weeks 2, 12, and 24, increases in serum estradiol concentrations and suppression of follicle-stimulating hormone were observed in significantly more patients who were using the vaginal cream than in those who were using the vaginal tablets (p < 0.001). Fewer patients who were using the vaginal tablets experienced endometrial proliferation or hyperplasia compared with patients who were using the vaginal cream. Significantly more patients who were using the vaginal tablets rated their medication favorably than did patients who were using the vaginal cream (p < or = 0.001). Patients who were receiving the vaginal tablets also had a lower incidence of patient withdrawal (10% versus 32%). CONCLUSIONS: Treatment regimens with 25-microg 17beta-estradiol vaginal tablets and with 1.25-mg conjugated equine estrogen vaginal cream were equivalent in relieving symptoms of atrophic vaginitis. The vaginal tablets demonstrated a localized effect without appreciable systemic estradiol increases or estrogenic side effects. Vaginal tablet therapy resulted in greater patient acceptance and lower withdrawal rates compared with vaginal cream therapy.

Survey of diabetic retinopathy screening services in England and Wales.

A postal survey of diabetologists was conducted regarding the provision of diabetic retinopathy screening services in England and Wales. About 2.5 million people had no existing or planned screening service. For the rest, the perceived percentage of patients with diabetes screened varied from less than 25% to more than 90%. Multiple modes of screening were used in most units. Lack of funding was identified as the major reason for non-provision of an adequate screening service. About 18% of the units had to use research or charitable funds for screening. Only 50% of the units using optometrists for screening had standard protocols for referral. The average wait before an ophthalmologist's opinion on sight threatening retinopathy detected by screening was unacceptably high in some units. We would suggest that establishment of identical screening protocols and provision of adequate funding on a national basis ought to be the priority if incidence of blindness from diabetic retinopathy is to be reduced according to the St Vincent Declaration.

Zyme, a novel and potentially amyloidogenic enzyme cDNA isolated from Alzheimer's disease brain.

The deposition of the beta amyloid peptide in neuritic plaques and cerebral blood vessels is a hallmark of Alzheimer's disease (AD) pathology. The major component of the amyloid deposit is a 4.2-kDa polypeptide termed amyloid beta-protein of 39-43 residues, which is derived from processing of a larger amyloid precursor protein (APP). It is hypothesized that a chymotrypsin-like enzyme is involved in the processing of APP. We have discovered a new serine protease from the AD brain by polymerase chain reaction amplification of DNA sequences representing active site homologous regions of chymotrypsin-like enzymes. A cDNA clone was identified as one out of one million that encodes Zyme, a serine protease. Messenger RNA encoding Zyme can be detected in some mammalian species but not in mice, rats, or hamster. Zyme is expressed predominantly in brain, kidney, and salivary gland. Zyme mRNA cannot be detected in fetal brain but is seen in adult brain. The Zyme gene maps to chromosome 19q13.3, a region which shows genetic linkage with late onset familial Alzheimer's disease. When Zyme cDNA is co-expressed with the APP cDNA in 293 (human embryonic kidney) cells, amyloidogenic fragments are detected using C-terminal antibody to APP. These co-transfected cells release an abundance of truncated amyloid beta-protein peptide and shows a reduction of residues 17-42 of Abeta (P3) peptide. Zyme is immunolocalized to perivascular cells in monkey cortex and the AD brain. In addition, Zyme is localized to microglial cells in our AD brain sample. The amyloidogenic potential and localization in brain may indicate a role for this protease in amyloid precursor processing and AD.

The effects of acute hypoglycemia on relative cerebral blood flow distribution in patients with type I (insulin-dependent) diabetes and impaired hypoglycemia awareness.

To examine the hypothesis that in diabetic patients with impaired hypoglycemia awareness the relative regional distribution of cerebral blood flow (rCBF) would be abnormal in a specific area, namely the frontal lobes, rCBF was examined in 20 type I diabetic patients, of whom 10 had a normal awareness of hypoglycemia and 10 had a history of impaired hypoglycemia awareness. rCBF was determined sequentially using single photon emission computed tomography (SPECT) during (1) normoglycemia (arterialized blood glucose 4.5 mmol. L-1) and (2) hypoglycemia (blood glucose 2.5 mmol.L-1) induced by a hyperinsulinemic glucose clamp technique. Distribution of the isotope, 99mTc-Exametazime, was detected using a single-slice multi-detector head scanner. A split-dose technique was used, with 250 MBq being injected during steady-state normoglycemia and 250 MBq during subsequent hypoglycemia. rCBF was estimated in 30 regions of interest, derived from a standard neuroanatomical atlas on two parallel slices at 40 and 60 mm above the orbitomeatal line (OML). No between-group differences in the pattern of overall rCBF or changes in regional tracer uptake were demonstrated. In comparison to the rCBF during normoglycemia, both patient groups exhibited significant changes in the pattern of rCBF during hypoglycemia, with increments of rCBF to both superior frontal cortices and the right thalamus and reduced rCBF to the right posterior cingulate cortex and the right putamen. This pattern of relative redistribution of rCBF during hypoglycemia was preserved in patients who had impaired hypoglycemia awareness.

A reappraisal of topical steroid potency.

Topical corticosteroids have been one of the cornerstones of dermatologic treatment for nearly 40 years. At present the most widely used topical steroid ranking system is the vasoconstrictor assay. To determine whether this is a satisfactory measure of the agents' potency in clinical settings, we examined rankings from the published literature achieved by four different methods: vasoconstriction, clinical outcome, therapeutic index (a ratio of efficacy to systemic safety), and cost, safety, and efficacy. Overall clinical outcome (efficacy) rankings in this study corresponded in only 11 (62%) of 17 topical steroid preparations with the expected vasoconstrictor rankings. The therapeutic index rankings did not correspond with the clinical outcome (33%) or the vasoconstrictor assay (33%) rankings. It was difficult to compare studies because of lack of standardization of clinical trials. We urge that topical steroid rankings not be based solely on vasoconstrictor assays, and that a standard method be developed for clinical trials of the drugs to allow for comparison among preparations.

Comparison of growth of masking functions and speech discrimination abilities in younger and older adults.

This study examined the possibility that age-related differences in speech discrimination abilities may reflect individual differences in the amount of masking and in the rate of growth of on- and off-frequency masking. Young (mean age = 26 years) and older (mean age = 60 years) adult listeners were selected, all of whom had hearing thresholds equal to or better than 30 dB HL at audiometric frequencies < or = 2000 Hz and equal or better than 40 dB HL at audiometric frequencies from 3000 to 6000 Hz. Listeners were tested on a consonant identification task in which nonsense words were presented in quiet, high-pass-filtered, low-pass-filtered and in wide-band noise. Despite their good hearing thresholds, the older listeners made significantly more errors in all four test conditions. Masked thresholds and growth of masking functions were obtained for all listeners at signal frequencies of 750, 1000, and 1500 Hz, in the presence of a one-third-octave band of noise centred at 1000 Hz, with four noise levels from 50 to 80 dB SPL. The older listeners had higher masked thresholds overall, when compared to younger listeners, even though their audiometric thresholds at these frequencies were within normal limits. However, the slope of the growth of masking functions at and above the masker frequency did not differ with age. These results show that older listeners show reduced speech discrimination abilities both in difficult listening conditions and in quiet, even when their pure-tone thresholds are within normal limits. Moreover, these effects cannot be attributed to differences in masked thresholds or in the rate of growth of masking.

Cutaneous manifestations of renal transplantation in a New Zealand population.

AIM: To document the skin manifestations of renal transplant recipients. METHODS: The findings in 52 patients (27 males; mean age 43.5 yr; range 22-74 yr; SD 12.0) with a stable renal transplant for a mean of 115.6 mth (range 3-258; SD 70.6). Thirty seven patients were on prednisone and azathioprine and 18 on prednisone, azathioprine and cyclosporin. RESULTS: Including prior observations, 48 cutaneous malignancies were identified in nine patients, with the ratio of squamous cell to basal cell carcinoma being 1.2:1. No metastases were detected. Actinic keratoses were present in 20 patients and tended to be multiple and present on sun exposed skin. A wide range of nonneoplastic lesions was documented, including warts in 75%. Human papillomavirus was isolated from 43% of warts. CONCLUSIONS: Renal transplant recipients require regular skin examination. Patients with high recreational or work related sun exposure prior to, or after transplantation, and those who have had a previous skin malignancy, should be identified as high risk patients for skin cancer and have regular dermatological follow up.

Structural equation modeling of symptoms, awareness and fear of hypoglycemia, and personality in patients with insulin-treated diabetes.

OBJECTIVE: To assess the possible influence of personality on self-reported awareness, symptoms, and fear of hypoglycemia and also to identify the relationship among these self-reported measures using formal structural equation modeling. RESEARCH DESIGN AND METHODS: A structured questionnaire, which included questions about sociodemographic details, awareness of the onset of hypoglycemia, and a list of symptoms of hypoglycemia, was completed by 305 consecutive insulin-treated diabetic patients attending the diabetic clinic at the Royal Infirmary of Edinburgh. They also completed the Hypoglycemia Fear Survey (HFS), and personality was assessed using the short form of the shortened Eysenck Personality Questionnaire-Revised (EPQ-R). Formal structural equation modeling was performed using the following variables: awareness, autonomic symptoms, neuroglycopenic symptoms, severe hypoglycemic episodes in the last year, worry and behavior (from the HFS), and extroversion and neuroticism (from the short EPQ-R). This allowed a model to be constructed that expressed the putative causal associations among the variables that could be tested statistically. RESULTS: Of the 302 patients who had experienced hypoglycemia, 111 (37%) reported reduced awareness, and these patients scored higher on the worry subscale of the HFS (reduced awareness: 41 +/- 12 vs. normal awareness: 34 +/- 12, P < 0.001). The patients with reduced awareness scored higher for neuroticism than did the patients with normal awareness (reduced awareness: 6.1 +/- 3.4 vs. normal awareness: 4.9 +/- 3.3, P < 0.01) and scored lower for extroversion (reduced awareness: 5.8 +/- 3.7 vs. normal awareness: 7.1 +/- 3.7, P < 0.01). In the structural equation modeling exercise, neuroticism was a significant putative determinant of many of the other variables. CONCLUSIONS: Personality was the major determinant of the variance that could be accounted for in this study and influenced self-reported symptoms, awareness, and fear of hypoglycemia. Personality factors may, therefore, influence self-reports from patients, particularly when soft measures, such as symptoms, are assessed and even when using validated clinical questionnaires. This finding stresses the importance of using additional evidence, such as reports from relatives, to substantiate reports from patients of loss of hypoglycemia awareness.

PASAT performance and the pattern of uptake of 99mTc-exametazime in brain estimated with single photon emission tomography.

The effect of the paced auditory serial addition test (PASAT) on the regional uptake of 99mTc-exametazime was determined by single photon emission computed tomography. Twenty insulin-treated diabetic outpatients were scanned at rest and during the performance of the PASAT task using split-dose injection of tracer. When resting and activation scans were compared there were significant decreases in tracer uptake in the right anterior cingulate and left posterior cingulate areas during PASAT activation. The findings are compared with previous studies which had implicated the anterior cingulate area in the mechanisms of attention in humans and other animals. The potentially confounding role of anxiety during attentional tasks is discussed.

Psychological and demographic correlates of glycaemic control in adult patients with type 1 diabetes.

The relationship between an objective measure of glycaemic control (glycated haemoglobin (HbA1)) and personality variables was examined in two separate groups of adult Type 1 (insulin-dependent) diabetic patients. Study 1 included 121 patients, all of whom also had subjective self-reporting of treatment compliance assessed, while the first 57 patients had individual differences in intelligence, major dimensions of personality and forgetfulness documented. Study 2 examined 303 patients, all of whom had their major dimensions of personality assessed using a shortened and updated version of the original personality questionnaire. Demographic indices (age, onset-age, duration of diabetes) were assessed in both groups. No significant correlation was found between HbA1 and self-report compliance suggesting that self-reporting may be invalid as a measure of glycaemic control. In study 1 personality and intelligence variables did not correlate significantly with HbA1 values. Older patients with shorter duration of diabetes had significantly better glycaemic control (p < 0.05). A significant correlation was observed between HbA1 concentration and onset-age of diabetes (p < 0.001); the patients who had developed diabetes later in life were achieving better control of their blood glucose. In the larger number of subjects in study 2 no significant correlations were evident between HbA1 and personality variables. It is concluded that the predictors of glycaemic control indexed by HbA1 may be distinct from predictors of self-report compliance and that the latter have limited or no value in providing an assessment of quality of glycaemic control. There is no evidence of an effect of personality on glycaemic control as measured by HbA1.

Regional cerebral blood flow in IDDM patients: effects of diabetes and of recurrent severe hypoglycaemia.

Chronic hyperglycaemia and recurrent severe hypoglycaemia have both been implicated as causing cerebral damage in patients with diabetes. Although cognitive dysfunction and intellectual impairment have been demonstrated in patients with recurrent severe hypoglycaemia, structural correlates have not been described, and it is not known whether specific functional changes occur in the brains of affected patients. Regional cerebral blood flow was estimated by SPECT with 99mTechnetium Exametazime in 20 patients with IDDM. Ten patients had never experienced severe hypoglycaemia and 10 had a history of recurrent severe hypoglycaemia. Patient results were compared with 20 age- and sex-matched healthy volunteers. We observed differences between the two patient groups and the control group. Tracer uptake was greater in diabetic patients in the superior pre-frontal cortex. This effect was particularly pronounced in the group who had a history of previous severe hypoglycaemia. Patients with a history of recurrent hypoglycaemia also had a relative reduction in tracer uptake to the calcarine cortex. This suggests an alteration in the pattern of baseline regional cerebral blood flow in diabetic patients with frontal excess and relative posterior reduction in cerebral blood flow.