Presence of gout is associated with increased prevalence and severity of knee osteoarthritis among older men: results of a pilot study.

BACKGROUND: Gout and osteoarthritis (OA) are the most prevalent arthritides, but their relationship is neither well established nor well understood. OBJECTIVES: We assessed whether a diagnosis of gout or asymptomatic hyperuricemia (AH) is associated with increased prevalence/severity of knee OA. METHODS: One hundred nineteen male patients aged 55 to 85 years were sequentially enrolled from the primary care clinics of an urban Veterans Affairs hospital, assessed and categorized into 3 groups: gout (American College of Rheumatology Classification Criteria), AH (serum urate ≥6.8 mg/dL, no gout), and control (serum urate <6.8 mg/dL, no gout). Twenty-five patients from each group subsequently underwent formal assessment of knee OA presence and severity (American College of Rheumatology Clinical/Radiographic Criteria, Kellgren-Lawrence grade). Musculoskeletal ultrasound was used to detect monosodium urate deposition at the knees and first metatarsophalangeal joints. RESULTS: The study showed 68.0% of gout, 52.0% of AH, and 28.0% of age-matched control subjects had knee OA (gout vs control, P = 0.017). Odds ratio for knee OA in gout versus control subjects was 5.46 prior to and 3.80 after adjusting for body mass index. Gout subjects also had higher Kellgren-Lawrence grades than did the control subjects (P = 0.001). Subjects with sonographically detected monosodium urate crystal deposition on cartilage were more likely to have OA than those without (60.0 vs 27.5%, P = 0.037), with crystal deposition at the first metatarsophalangeal joints correlating most closely with OA knee involvement. CONCLUSIONS: Knee OA was more prevalent in gout patients versus control subjects and intermediate in AH. Knee OA was more severe in gout patients versus control subjects.

Effects of combined insulin-sulfonylurea therapy in type II patients.

We conducted a double-blind crossover study to determine which patient characteristics best predict a beneficial response to combined insulin-glyburide therapy. Glyburide (15 mg/day) or placebo was added to the treatment regimen of 31 insulin-treated type II (non-insulin-dependent) diabetic subjects. During glyburide therapy, there was a significant improvement in glycemic control with a reduction in glycosylated hemoglobin from 9.9 +/- 1.3 to 9.1 +/- 1.3% (P less than .001). Patients who responded had higher fasting C-peptide levels (P less than .001) and shorter durations of insulin therapy (P less than .01) than those who did not respond. Glyburide withdrawal was associated with a greater than expected deterioration in glycemic control. Patients on insulin therapy for greater than 8 yr are unlikely to benefit significantly from the addition of glyburide to their treatment regimen.

Selective suppression of FSH by testicular extracts.

Studies were undertaken to determine the effects of intravenous infusions of bovine testicular extracts on plasma levels of FSH and LH in castrate male sheep. Decapsulated bovine testes were homogenized with phosphate buffer, the homogenates centrifuged at 30,000 X g for 30 min, and the supernatants extracted with diethyl ether. The aqueous extracts were filtered using Diaflo XM-100 membranes and the ultra-filtrates lyophilized. The extracts were infused over 24 hours, and plasma FSH and LH were measured prior to, during, and after the infusion. Control studies using infusions of saline and liver extracts demonstrated no decrease in FSH levels in 6 out of 7 controls, while LH levels tended to rise. Following infusions with the testicular extracts, the levels of FSH were selectively decreased to between 42% and 85% of baseline levels, and they subsequently remained suppressed for at least 24 hours. These results suggest that the testis is the site of production of a water-soluble, non-steroidal substance which exerts an inhibitory effect on the production and/or release of FSH.

Acid-ethanol-extractable nonsuppressible insulin-like activity (NSILA-S) during pregnancy and the puererium, and in cord serum at term.

A longitudinal study of serum NSILA-S during normal human pregnancy and the puerperium has demonstrated that levels rose progressively during pregnancy and returned to nonpregnant values about 48 h after delivery. Low concentrations were defined within the feto-placental circulation at term. Cord arterial and venous levels were equivalent, but there was no significant correlation between these and matched maternal values.

Changes in NSILA-S in response to somatotropin administration and hypophysectomy.

The effects on the serum levels of NSILA-S of the administration of human GH (hGH) or of hypophysectomy have been studied. hGH given im (5 mg daily for 3 days) raised the NSILA-S levels of three GH-deficient subjects into the normal range. Significant elevations of NSILA-S were also seen in three normal subjects given im GH. In the same groups of three normal and three GH-deficient subjects, 5 mg hGH administered iv induced an elevation of NSILA-S within 15-60 min. Hypophysectomy in three acromegalics and one subject with a chromophobe adenoma was followed by significant falls of serum NSILA-S. These studies provide further evidence of the dependence of NSILA-S levels on GH.

A bioassay for NSILA-S in individual serum samples and its relationship to somatotropin.

A practical bioassay for the acid-ethanol soluble non-suppressible insulin-like activity (NSILA-S) of individual serum samples has been developed utilizing the incorporation of 14C-glucose into the lipid faction of isolated adipocytes. NSILA-S activity was correlated with somatotropin status. Thus, the mean potencies (+/-SD) relative to an extract of pooled normal human serum were: normal samples 1.11 +/- 0.14, acromegalic 2.91 +/- 0.72, and somatotropin deficient 0.13 +/- 0.06. This variation in NSILA-S was not due to variability in extraction recoveries. The within assay precision was 9% (coefficient of variation) and the between assay 23%. This method allows the simultaneous extraction and processing of relatively large numbers of samples, and compares favorably with other more complex methods. Because of the evidence that NSILA-S may be related to the somatomedins, the present method should provide a simpler and more reliable alternative to the cartilage bioassays used to measure somatomedin activity.

Serum levels of the acid-ethanol soluble component of non-suppressible insulin-like activity in untreated and treated streptozotocin-diabetic rats.

Streptozotocin-diabetic rats suffered growth failure and had reduced serum levels of the acid--ethanol soluble component of non-suppressible insulin-like activity (NSILA-S) compared with normal rats. Chronic insulin substitution (6 weeks) resulted in a normalization of serum levels of NSILA-S; this was accompanied by a normal increase in weight. Insulin therapy for 3 days resulted in a partial recovery of serum levels of NSILA-S and a slight but significant accompanying gain in weight. Short-term administration of GH also resulted in a partial recovery of the serum level of NSILA-S, in spite of continued uncontrolled diabetes. These results demonstrate that, in the rat, insulin as well as GH contributes to the regulation of serum levels of NSILA-S.

Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery.

Potassium channels are amongst the most heterogeneous class of ion channels known and are responsible for mediating a diverse range of biological functions. The most recently described family of K+ channels, the 'two pore-domain family', contain four membrane spanning domains and two pore-forming domains, suggesting that two channel subunits associate to form a functional K+ pore. Several sub-families of the two pore domain potassium channel family have been described, including the weakly inward rectifying K+ channel (TWIK), the acid-sensitive K+ channel (TASK), the TWIK-related K+ channel (TREK) and the TWIK-related arachidonic acid stimulated K+ channel (TRAAK). However, comparison of the mRNA expression of these channels has been difficult due to the differences in methods used and the species studied. In the present study, we used a single technique, TaqMan semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), to investigate the mRNA distribution of all currently known two pore potassium channels in human central nervous system (CNS) and peripheral tissues. TWIK-1 and the TWIK-1-like channel KCNK7 were predominantly expressed in the CNS, in contrast to TWIK-2 which was preferentially expressed in peripheral tissues such as pancreas, stomach, spleen and uterus. TASK-1 was expressed in the CNS and some peripheral tissues, whereas TASK-2 was exclusively expressed in the periphery except for mRNA expression observed in dorsal root ganglion and spinal cord. In addition, mRNA expression of the recently identified TASK-3, was almost completely exclusive to cerebellum with little or no mRNA detected in any other tissues. TREK-1 and TRAAK mRNA expression was predominantly CNS specific in contrast to the closely related TREK-2, which was expressed in both CNS and peripheral tissues. Studying the mRNA expression profiles of known two pore domain K+ channels will aid in the understanding of the biological roles of these channels. Furthermore, identification of common areas of expression may help identify which channels, if any, associate to form heteromeric K+ channel complexes.

Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel.

We have isolated, by degenerate PCR, a complementary DNA encoding a novel two pore domain potassium channel. This is the 7th functional member of the human tandem pore domain potassium channel family to be reported. It has an open reading frame of 1.125 kb and encodes a 374 amino acid protein which shows 62% identity to the human TASK-1 gene: identity to other human members of the family is 31-35% at the amino acid level. We believe this gene to be human TASK-3, the ortholog of the recently reported rat TASK-3 gene: amino acid identity between the two is 74%. 'Taqman' mRNA analysis demonstrated a very specific tissue distribution pattern, showing human TASK-3 mRNA to be localised largely in the cerebellum, in contrast rat TASK-3 was reported to be widely distributed. We have shown by radiation hybrid mapping that human TASK-3 can be assigned to chromosome 8q24.3. Human TASK-3 was demonstrated to endow Xenopus oocytes with a negative resting membrane potential through the presence of a large K(+) selective conductance. TASK-3 is inhibited by extracellular acidosis with a mid-point of inhibition around pH 6. 5, supporting the predictions from the sequence data that this is a third human TASK (TWIK-related acid sensitive K(+) channel) gene.

A comparison of the efficacy of captopril and enalapril given once daily for the treatment of hypertension: a study using 24-hour ambulatory blood pressure monitoring.

Sixteen patients who had essential hypertension were stabilized on either captopril or enalapril monotherapy and had 24-hour blood pressure profiles monitored by using one of two automatic, non-invasive ambulatory systems: Spacelabs 5300 (Squibb, Princeton, NJ) or PAR Physioport II (Kardiotec, Mannheim). In four subjects (group 1), ambulatory pressures were repeated 4 to 6 weeks later using the same equipment and the same drug. In four subjects (group 2), the drug was changed (dose ratio: captopril:enalapril, 5:1) after the first measurement, but the monitoring equipment was not changed. In four subjects (group 3), the drug was constant, but the equipment was changed for the second measurement of ambulatory pressure. In four subjects (group 4), both drug and equipment were reversed after the first measurement. The results showed that both drugs (given once daily) controlled blood pressure during the 24-hour period, with no clinically significant difference between them.

The neuroprotective agent sipatrigine (BW619C89) potently inhibits the human tandem pore-domain K(+) channels TREK-1 and TRAAK.

We have cloned and functionally expressed the human orthologue of the mouse TRAAK gene. When cDNA for hTRAAK is expressed in either Xenopus oocytes or HEK293 cells it forms a K(+)-selective conductance and hyperpolarises the resting membrane potential. Quantitative mRNA expression analysis using Taqman revealed that hTRAAK mRNA is predominantly present in the central nervous system where it exhibits a regionally diverse pattern of expression. Like the related channel TREK-1, the activity of TRAAK was potentiated by arachidonic acid. The neuroprotective agent sipatrigine (10 microM) inhibited both hTREK-1 (73.3+/-4.4%) and hTRAAK (45.1+/-11.2%) in a reversible, voltage-independent manner. Inhibition of both channels was dose-dependent and for TREK-1 occurred with an IC(50) of 4 microM. The related compound lamotrigine, which is a better anticonvulsant but weaker neuroprotective agent than sipatrigine, was a far less effective antagonist of both channels, producing <10% inhibition at a concentration of 10 microM.

Factors influencing pregnancy rates following in vitro fertilization and embryo transfer.

In 831 patients having 1533 in vitro fertilization treatments, pregnancy rates were examined in relation to clinical and laboratory factors. Pregnancy rates were significantly affected by the month and year of treatment, the age of the patient, the type of ovarian stimulation, the use of human chorionic gonadotropin, the number of eggs collected, the number of eggs fertilized, the number of embryos developed, and the number of embryos transferred. The most important factors determining pregnancy rates were the number of oocytes collected and the number of embryos transferred. The low pregnancy rate when only one egg was collected raises the problem of how to predict and manage such a patient in a current or future treatment cycle.

The relationship of basal cell carcinomas and squamous cell carcinomas to solar keratoses.

Six thousand four hundred sixteen people aged 40 years and over from three different locations in Victoria (Australia) were examined on the hands, forearms, head, and neck for the presence of solar keratoses and basal (BCCs) and squamous cell carcinomas (SCCs). Analysis of the relationship between these tumors revealed that the factors which predicted the likelihood of developing a solar keratosis were essentially the same as those that predicted the likelihood of developing a BCC and/or an SCC. These were age, sex, years of residence in Australia, indoor or outdoor occupation, tanning ability, propensity to sunburn, and location of residence. The presence of a coexisting solar keratosis was necessary for the development of an SCC in contrast to the development of a BCC. The findings suggest that unlike BCCs, the majority of SCCs in light-exposed areas may arise from preexisting solar keratoses. Whereas the prevalence of BCCs and SCCs was relatively constant in the three locations, the prevalence of solar keratoses differed markedly in direct relation to the degree of isolation. This suggests that solar keratoses are a more sensitive indicator of sunlight exposure than invasive carcinoma.

Skin irritation potential of mixed surfactant systems.

Virtually all current detergent formulations contain mixtures of surfactants. Our experience and test data on these formulations, which is in agreement with that of many others, has shown that in use the formulations exhibit lower acute irritation potential than predicted by simple summation of the irritation potential of the individual actives. Using the criteria of the Dangerous Preparations Directive (EC Directive 88/379/EEC), many of these formulations classify as irritant in the neat state, with consequent labelling requirements. Such classification is based on addition of irritant components giving a total concentration which exceeds a nominal threshold. In this study, mixtures of surfactants were tested by application to a panel of 31 human volunteers for up to 4 hr, using the technique established for the assessment of acute skin irritation potential. The positive control, sodium dodecyl sulfate (SDS) at 20% concentration, gave an 84% positive response. Dimethyl dodecyl amido betaine (DDAB) at the same concentration gave a 94% response. However, a combination of 20% of each of these surfactants in the same panellists gave a response of only 44%--a significant reduction in the irritation potential. A further test conducted with a mixture of 10% SDS and 10% DDAB in a second panel gave a 31% positive response compared with a 94% positive response to the 20% SDS control in that panel. These results clearly demonstrate that the acute irritation potential of mixed surfactants cannot be predicted by simple summation of the irritation potential of the component substances. Initial results of the mechanistic investigation indicate that the reduced irritation induced by the mixed surfactant systems correlates with a reduced critical micelle concentration (CMC). However, the reduced CMC itself seems not to be responsible for the lowered irritation, since these experiments were conducted at concentrations well above the CMC. It is proposed that the critical event leading to skin irritation is binding to skin protein and that in mixed surfactant systems, the individual surfactants exhibit less affinity for this protein.

Reproducibility of musculoskeletal ultrasound for determining monosodium urate deposition: concordance between readers.

OBJECTIVE: Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. METHODS: Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] ≥6.9 mg/dl), and controls (no gout, serum UA ≤6.8 mg/dl), and reader concordance within these 3 groups was assessed. RESULTS: We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, κ = 1.000), 2) total joints (n = 200, 99% agreement, κ = 0.942), 3) FAC (n = 100, 99% agreement, κ = 0.942), and 4) first MTP joints (n = 100, 99% agreement, κ = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. CONCLUSION: Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia.