Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes.

AIMS: To test the hypothesis that treatment with a sodium-glucose co-transporter-2 inhibitor would reverse ventricular repolarization heterogeneity, a predictor of cardiovascular mortality, in people with Type 2 diabetes. METHODS: We retrospectively analysed changes in indices of ventricular repolarization before and after treatment with a sodium-glucose co-transporter-2 inhibitor in 46 people with Type 2 diabetes. RESULTS: Sodium-glucose co-transporter-2 inhibitor treatment reduced HbA1c concentration [62±13 mmol/mol (7.7±1.2%) vs 59±16 mmol/mol (7.5±1.4%)], body weight (77.8±13.9 vs 74.7±12.5 kg) and systolic blood pressure (133±18 vs 126±12 mmHg) in the study participants. Heart rate and QTc interval were not changed by sodium-glucose co-transporter-2 inhibitor treatment, but QTc dispersion was significantly reduced (median, 48.8 vs 44.2 ms). Sodium-glucose co-transporter-2 inhibitor treatment reversed QTc dispersion more in participants who had larger QTc dispersion before the treatment. Changes in systolic blood pressure (Spearman's ρ= 0.319; P=0.031), but not in HbA1c concentration, were correlated with changes in QTc dispersion after sodium-glucose co-transporter-2 inhibitor treatment. CONCLUSIONS: The findings suggest that sodium-glucose co-transporter-2 inhibitor treatment reverses ventricular repolarization heterogeneity in people with Type 2 diabetes, independently of its effect on glycaemic control. The favourable effect on ventricular repolarization heterogeneity could be the mechanism by which empaglifozin reduced cardiovascular events in a recent study.

Effects of mirthful laughter on growth hormone, IGF-1 and substance P in patients with rheumatoid arthritis.

OBJECTIVE: Growth hormone (GH) plays an ancillary role in the regulation of immune function. GH has been shown to be associated with joint symptoms such as pain and swelling. On the other hand, mirthful laughter has favorable effects on the neuroendocrine-immune system. We evaluated the levels of serum GH, insulin-like growth factor-1 (IGF-1) in RA patients and evaluated the effect of mirthful laughter on GH and IGF-1. METHODS: We compared with the levels of serum GH, IGF-1 and substance P (SP) in patients with RA and healthy subjects (control group) before and after exposure to "Rakugo", a traditional Japanese comical story that induces mirthful laughter. RESULTS: The basal level of serum GH in the RA group was significantly higher than in the control group. After experiencing mirthful laughter, the level of serum GH in the RA group significantly decreased, approaching that in the control group. The serum IGF-1 level was lower in the RA group than in the control group. There was no significant difference in the level of serum SP between the RA group and the control group. CONCLUSION: The basal level of serum GH in the RA group was significantly higher than in the control group, and the level of serum GH significantly decreased after experiencing mirthful laughter These results suggest that the homeostasis of GH in patients with RA is disturbed, and the increased serum GH levels in RA patients may be associated with their stress condition.

Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension.

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.

Effect of atrial natriuretic factor on angiotensin II-induced hypertension in rats.

To assess the physiological role of atrial natriuretic factors in blood pressure regulation, we studied the effect of chronic infusion of a synthetic atrial natriuretic factor of 25 amino acid residues (Arg 102-Tyr 126) in rats with angiotensin II-induced hypertension. Rats were studied while on a normal sodium diet or during sodium loading with 1% NaCl solution used as drinking water. Systolic blood pressure decreased slightly during combined infusion of synthetic atrial natriuretic factor, 150 micrograms/kg/day, and angiotensin II, 900 micrograms/kg/day. This effect was sustained for 3 days in rats receiving a regular sodium intake (p less than 0.01) and during sodium loading (p less than 0.01). Administration of synthetic atrial natriuretic factor to rats made hypertensive by a 3-day infusion of angiotensin II reduced blood pressure slightly, but not to control levels, and this effect was sustained for the remaining 3 days of the experiment in both dietary groups. These results indicate that a nonhypotensive dose of synthetic atrial natriuretic factor can modulate the vasopressor effect of angiotensin II. Thus, the attenuating effect may be involved in blood pressure regulation independently of sodium metabolism, although its actual physiological importance remains undetermined.

Atrial natriuretic factor and cyclic guanosine 3',5'-monophosphate in vascular smooth muscle.

To elucidate the molecular mechanism of the vascular action of atrial natriuretic factor (ANF), we investigated the effects of synthetic ANF and sodium nitroprusside on the levels of intracellular cyclic nucleotides and prostacyclin (measured as its stable metabolite 6-keto-prostaglandin F1 alpha) in cultured vascular smooth muscle cells from rat mesenteric artery and, in some experiments, from rat renal artery. Both ANF and sodium nitroprusside increased intracellular cyclic guanosine 3',5'-monophosphate (cGMP) levels in a dose-dependent manner but did not affect cyclic adenosine 3',5'-monophosphate levels or 6-keto-prostaglandin F1 alpha synthesis. The stimulatory effect of ANF and sodium nitroprusside on cGMP levels were additive. Neither the deprivation of extracellular Ca2+ nor calcium entry blockers affected ANF-stimulated cGMP levels. Preincubation of ANF or sodium nitroprusside with kallikrein attenuated only the effect of ANF on cGMP levels. The effect of kallikrein was abolished by serine protease inhibitors. In contrast, the oxidant methylene blue inhibited the effect of sodium nitroprusside on cGMP levels, but not that of ANF. The stimulatory effect of ANF on cGMP levels was greater in cells from renal artery than in those from mesenteric artery. These results in cultured vascular smooth muscle cells further support the hypothesis that cGMP mediates the vasorelaxant action of ANF.

Antihypertensive effect of MK-421 in rats. Role of the renal kallikrein-kinin system.

To study the hypotensive mechanism of the new oral converting-enzyme inhibitor, MK-421, we evaluated the antihypertensive effect of MK-421 in rats with hypertension induced by chronic administration of norepinephrine (NE) or vasopressin and measured urinary kallikrein and kinin excretions as indices of the renal kallikrein-kinin system. When 6 mg/kg/day of MK-421 was administered simultaneously with 1.8 mg/kg/day of NE, the systolic blood pressure of conscious rats rose on Day 1 to only 122.6 +/- 3.4 mm Hg compared with the rise to 146.3 +/- 1.6 mm Hg when NE alone was infused (p less than 0.001). Similarly, when the same dose of MK-421 was administered simultaneously with 7.2 U/kg/day of vasopressin, the systolic blood pressure of conscious rats rose on Day 1 to only 117.4 +/- 3.8 mm Hg compared with the rise to 141.6 +/- 3.4 mm Hg when vasopressin alone was infused (p less than 0.01). The antihypertensive effect of MK-421 was sustained for 6 days in rats infused with NE or vasopressin. Infusion of NE alone resulted in a small but significant increase in urinary kallikrein excretion and no change in urinary kinin excretion. The combined administration of NE with MK-421 induced additional increases in urinary kallikrein and kinin excretions. Vasopressin alone resulted in marked decreases in urinary kallikrein and kinin excretions. The combined administration of vasopressin with MK-421 induced no additional changes in urinary kallikrein and kinin excretion. These results indicate that the hypotensive effect of MK-421 may depend on a reduced sensitivity of the peripheral arteries to vasoconstrictor substances.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related changes in proliferating cell nuclear antigen levels.

To clarify the effect of aging on rat liver regeneration, we compared proliferating cell nuclear antigen (PCNA) levels in control and regenerating livers from young and aged rats 48 h after partial hepatectomy. The nucleoplasm and cytoplasm from regenerating livers of 2-month and 24 month-old rats were fractionated by phosphocellulose column chromatography, aliquots of fractions were transferred to nitrocellulose filters and the amounts of PCNA in each fraction were measured by an immunostaining method. Two forms of PCNA, L type (eluted at low concentrations of KC1) and H type (eluted at high KC1 concentrations) were observed in the nucleoplasm from both control and regenerating young rat liver. On the other hand, the cytoplasm contained P type (eluted in the pass-through fraction), L type and H type PCNA. In control liver from aged rats, three types of PCNA in the cytoplasm and two types in the nucleoplasm were present at decreased levels. In regenerating liver from young rats, the increases in L type in the cytoplasm and H type in the nucleoplasm were remarkable. However, none of the three PCNA types increased significantly during liver regeneration in aged rats. Treatment with DNase resulted in the disappearance of the H type with a concomitant increase in the P and L types. These results suggest that the H type is a complex form consisting of the P and L types of PCNA and DNA. These results suggest that the increase in the L type in the cytoplasm reflects newly synthesized PCNA production for cellular proliferation and that the increase in the H type in the nucleoplasm is a reflection of binding to DNA and the fundamental role of PCNA itself in liver regeneration in young rats. On the other hand, there was little increase in any of the three types in regenerating liver from 24-month-old rats. Thus, PCNA content may be closely related to the decrease in the rate of cellular proliferation in aged animals.

Uniaxial cyclic stretch induces osteogenic differentiation and synthesis of bone morphogenetic proteins of spinal ligament cells derived from patients with ossification of the posterior longitudinal ligaments.

Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by ectopic bone formation in the spinal ligaments. Mechanical stress, which acts on the posterior ligaments, is thought to be an important factor in the progression of OPLL. To elucidate this mechanism, we investigated the effects of in vitro sinusoidal cyclic stretch (120% peak to peak, at 1 Hz) on cultured spinal ligament cells derived from OPLL and non-OPLL patients. The mRNA expressions of alkaline phosphatase (ALP), osteopontin, bone morphogenetic protein (BMP)-2, BMP-4, and BMP receptors as well as ALP activity in cell layers and production of BMPs into the conditioned medium were significantly increased by cyclic stretch in OPLL cells, whereas no change was observed in non-OPLL cells. A stretch-activated Ca(2+) channel blocker, Gd(3+), the voltage-dependent L-type Ca(2+) channel blockers diltiazem and nifedipine, and Ca(2+)-free medium suppressed stretch-induced ALP activity, which suggests a role of Ca(2+) influx in the signal transduction of mechanical stress to the osteogenic response of OPLL cells. Our study provides first evidences that mechanical stress plays a key role in the progression of OPLL through the induction of osteogenic differentiation in spinal ligament cells and the promotion of the autocrine/paracrine mechanism of BMPs in this lesion.

Comparative study of bone mineral density estimated by various methods of single- and dual-energy quantitative computed tomography: the capability of the four-equation four-unknown method.

A dual-energy (DE) quantitative computed tomography (QCT) method, the four-equation four-unknown method (DEQCT 4E-4U), was assessed and compared to single-energy (SE) QCT and standard DEQCT (two-line method). The results of this study indicate that bone mineral density (BMD) was more accurately estimated by the present method than by the SEQCT or standard DEQCT techniques on the basis of a phantom study when a large fat content was present. The results of both the phantom study and a human study also showed that the present method corrected for fat in estimating BMD in the presence of high-fat content. These findings suggest that use of this method for estimating BMD can provide useful information in studies assessing the metabolic state of bone. We propose that CT numbers estimated from excised vertebral bone marrow can serve as a soft-tissue correction for the present method.

Effects of ouabain on blood pressure regulation in rats.

In order to test the hypothesis that a circulating inhibitor of the sodium-potassium ATPase pump may cause a concomitant rise in blood pressure and increased sodium excretion, we studied chronic effects of continuous infusion of ouabain, an inhibitor of sodium-potassium ATPase, for up to 6 days on systolic blood pressure and urinary sodium excretion in conscious rats. We also evaluated the effect of this substance in rats with hypertension induced by chronic infusion of norepinephrine. Continuous infusion of ouabain (1.2 mg/kg per day) into the jugular vein by an osmotic minipump did not induce any changes in systolic blood pressure and urinary sodium excretion in intact rats on regular diets. Furthermore it did not cause a change in systolic blood pressure in rats drinking 1% NaCl, and in unilaterally nephrectomized rats drinking 1% NaCl, when compared with vehicle-infused animals. When the same dose of ouabain was administered simultaneously with 1.8 mg/kg per day norepinephrine infused intraperitoneally by another osmotic minipump in conscious rats, systolic blood pressure rose on day 1 to only 129.3 +/- 2.8 mmHg compared with the rist to 145.0 +/- 2.0 mmHg when norepinephrine alone was infused (P less than 0.01). The antihypertensive effect of ouabain was sustained for the entire experimental period lasting for 6 days and was not associated with any changes in urinary sodium excretion. The administration of ouabain to rats made hypertensive by a 3-day infusion of norepinephrine, returned the blood pressure to control levels, and the antihypertensive effect was sustained throughout the experimental period lasting a further 3 days and was not associated with any changes in urinary sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sodium and angiotensin II on urinary active and inactive kallikrein in rats.

To assess possible relationships between sodium balance, angiotensin II (ANG II), and renal active and inactive kallikrein, we studied the effects of sodium loading with 1% NaCl and chronic ANG II infusion (900 micrograms/kg per day) on the urinary excretion of total and active kallikrein for 6 days in conscious rats. We determined urinary total, active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). Sodium loading produced a sustained increase in urinary total, active and inactive kallikrein excretion. Chronic infusion of ANG II induced a sustained increase in urinary total, active and inactive kallikrein excretion in rats on a regular diet. In rats loaded with sodium, however, ANG II did not induce any further changes in urinary kallikrein excretion. Thus, the present study suggests that both sodium loading and ANG II infusion might stimulate the synthesis of renal kallikrein. In addition, it is suggested that ANG II infusion might stimulate the synthesis of kallikrein, at least partly, via the same mechanism as sodium loading does.

Renal kallikrein activity in spontaneously hypertensive rats.

To assess possible roles of the renal kallikrein-kinin system in the development of spontaneous hypertension, we determined daily excretion of urinary total and active kallikrein in 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats for up to 2 weeks. We also evaluated the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension in the 6-week-old SHR on ordinary intakes of sodium or on sodium loading with 1% NaCl for up to 2 weeks. Active kallikrein was determined by its kininogenase activity, and the generated kinins were radio-immunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in 7-week-old SHR (1.5 +/- 0.2 microgram/day compared to 2.8 +/- 0.3 micrograms/day in WKY, P less than 0.05) and in 8-week-old SHR (1.6 +/- 0.2 microgram/day compared to 3.2 +/- 0.4 micrograms/day in WKY, P less than 0.01). Urinary total kallikrein excretion was also reduced in the 7- and 8-week-old SHR whereas the ratio of active to total kallikrein did not change. In addition, renal contents of total and active kallikrein were significantly lower in the 8-week-old SHR than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal prostaglandin E in the hypotensive mechanism of MK-421 in conscious rats.

To assess the role of renal prostaglandin E in the hypotensive mechanism of MK-421, we evaluated the effects of chronic infusion of MK-421 (6 mg/kg/day i.p.) on systolic blood pressure and urinary prostaglandin E excretion in conscious rats in states of sodium repletion or depletion and also during chronic infusion of norepinephrine (1.8 mg/kg/day i.p.) or vasopressin (7.2 U/kg/day i.p.). The hypotensive effect of MK-421 was greater in sodium depleted than in sodium repleted rats. The hypertensive effect of norepinephrine or vasopressin was inhibited by the simultaneous administration of MK-421. MK-421 induced an increase in the excretion of urinary prostaglandin E, in both sodium repleted and depleted rats. However, simultaneous administration of MK-421 had no influence on the increase in urinary prostaglandin E excretion induced by norepinephrine or vasopressin. In addition, the combined administration of MK-421 with indomethacin (10 mg/kg/day s.c.) still abolished the hypertensive effect of norepinephrine or vasopressin. The disparate effect of MK-421 on urinary prostaglandin E excretion suggests that the renal prostaglandin system is not essential for the mechanism of the hypotensive effect of MK-421.

A non-radioisotopic reverse transcriptase assay using biotin-11-deoxyuridinetriphosphate on primer-immobilized microtiter plates.

We developed a non-radioisotopic (non-RI) reverse transcriptase assay (RTA). The reverse transcriptase (RT) incorporates biotin-11-deoxyuridine-triphosphate (bio-dUTP) using a poly(rA) template hybridized with oligo(dT) primer that is immobilized on the surface of a 96-well microtiter plate. This assay is thus semi-automated by adapting it to an ELISA testing format. The incorporation of bio-dUTP was enhanced by adding cold dTTP to the reaction mixture, optimally in a molar ratio 4:1 (dTTP:bio-dUTP). This non-RI RTA is more sensitive than the conventional RI assay for the detection of purified Rous-associated virus 2 (RAV-2) and of human immunodeficiency virus type 1 (HIV-1) lysate. Because of its simple procedure, higher sensitivity and non-use of RI materials, the assay can be utilized not only for virological studies but also for routine safety screening of biological products for retroviral contamination.

Ganglioside variations in human liver cirrhosis and hepatocellular carcinoma as shown by two-dimensional thin-layer chromatography.

Gangliosides isolated from 5 cases of normal liver tissues, 11 cases of liver cirrhosis and 5 cases of hepatocellular carcinoma were compared in their concentrations and compositions. Quantitative analysis revealed no significant change of ganglioside levels between normal and cirrhotic liver tissues or hepatocellular carcinoma. There was also no significant difference (p greater than 0.05) between cirrhotic liver tissues and hepatocellular carcinoma. Two dimensional thin-layer chromatography of the total ganglioside preparations of liver tissues from both liver cirrhosis and hepatocellular carcinoma showed proliferation of GM2, GD3, GD1 and at least two unidentified components, named provisionally spots Nos. 1 and 2 in the present report, and loss of GM3. Sialidase treatment and thin-layer chromatography showed the components of these spots to be sialidase-labile monosialogangliosides and distinctly different from GD3 which was described elsewhere.

A monoclonal antibody to scopolamine and its use for competitive enzyme-linked immunosorbent assay.

A hybridoma clone producing a monoclonal antibody (SC78.H81) against scopolamine was established. The monoclonal antibody was an IgG1 (k) antibody with high affinity (1.6 x 10(9) M-1 for methylscopolamine). The monoclonal antibody was cross-reactive with methylscopolamine and butylscopolamine, and showed weak cross-reactivity with 6 beta- and 7 beta-hydroxyhyoscyamine. The cross-reaction with L-hyoscyamine, atropine, scopine and DL-tropic acid was very weak. A competitive enzyme-linked immunosorbent assay using SC78.H81 was established to quantify scopolamine. The sensitivity of the assay allowed detection of 20 pg assay-1 (0.2 ng ml-1) of scopolamine. The assay was applied to the estimation of scopolamine content in hairy root cultures of a Duboisia hybrid.

Contribution of both the sarcolemmal K(ATP) and mitochondrial K(ATP) channels to infarct size limitation by K(ATP) channel openers: differences from preconditioning in the role of sarcolemmal K(ATP) channels.

The roles of sarcolemmal ATP-sensitive K+ (sarcK(ATP)) and mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels in the cardioprotection induced by K(ATP) channel openers remain unclear, though the mitoK(ATP) channel has been proposed to be involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning (PC). In the present study, selective inhibitors of the sarcK(ATP) and mitoK(ATP) channels were used to examine the role of each channel subtype in infarct size limitation by KATP channel openers. Isolated rabbit hearts were perfused in the Langendorff mode with monitoring of the activation recovery interval (ARI) and subjected to 30-min global ischemia/2-h reperfusion to induce infarction. Before ischemia, hearts received 10 microM pinacidil, 100 microM diazoxide, or PC with or without preceding infusion of a sarcK(ATP) channel-selective blocker (5 microM HMR1098) or a mitoK(ATP) channel-selective blocker (100 microM 5-hydroxydecanoate, 5-HD). ARI, an index of action potential duration, was shortened from 118+/-3 ms to 77+/-5 ms after 10 min of ischemia in untreated control hearts. Pinacidil shortened ARI before ischemia from 113+/-2 ms to 78+/-5 ms and enhanced the ARI shortening during ischemia. Diazoxide did not affect ARI before ischemia but accelerated ischemia-induced shortening of ARI. Infarct size as a percentage of the left ventricle (%IS/LV) was reduced by pinacidil and diazoxide from the control value of 47.2+/-4.0% to 4.5+/-1.5% and 5.2+/-1.2%, respectively. HMR1098 significantly inhibited the shortening of ARI by ischemia, pinacidil and diazoxide and partially blocked infarct size limitation by these K(ATP) channel openers (%IS/LV=32.6+/-4.2% and 23.4+/-5.3%, respectively). Infusion of 5-HD did not modify the change in ARI caused by the K(ATP) channel openers but completely abolished cardioprotection (%IS/LV=46.0+/-6.2% with pinacidil and 57.2+/-7.0% with diazoxide). PC with two episodes of 5-min ischemia limited %IS/LV to 21.6+/-4.0%, and this protection was not inhibited by HMR1098. Neither HMR1098 nor 5-HD alone modified infarct size. In conclusion, both sarcK(ATP) and mitoK(ATP) channels may contribute to the anti-infarct tolerance afforded by pinacidil and diazoxide.

Does being easily moved to tears as a response to psychological stress reflect response to treatment and the general prognosis in patients with rheumatoid arthritis?

OBJECTIVE: Psychological stress affects the condition of patients with rheumatoid arthritis (RA). We evaluated the neuroendocrine and immune responses (NEIRs) in the peripheral blood to psychological stress induced by deep emotion with tears in patients with RA. METHODS: We compared the levels of plasma cortisol and interleukin-6 (IL-6), the CD4/CD8 ratio, and natural killer (NK) cell activity in peripheral blood between the patients with easily controlled RA (CRP < 1.0 mg/dl) and those with difficult-to-control RA (CRP > or = 1.0 mg/dl) before and after the stress session. RESULTS: Psychological stress induced by deep emotion with tears had a greater influence on NEIRs in patients with difficult-to-control RA (CRP > or = 1.0 mg/dl) than in those with easily controlled RA (CRP < 1.0 mg/dl). The levels of plasma cortisol, IL-6, and the CD4/CD8 ratio were lower, while NK cell activity in the peripheral blood was higher in those who were not moved to tears than in those who were moved to tears. Patients who were moved to tears were apt to obtain good control of RA (CRP < 1.0 mg/dl) within one year. CONCLUSION: The patients with better RA control are easily moved to tears as an emotional expression; shedding tears is considered to suppress the influence of stress on the NEIRs, thus preventing the buildup of stress. Patients who were moved to tears had a more easily controlled RA compared with those who were emotionally affected but not moved to tears.

Effect of general anesthesia on the abnormal immune response in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the influence of mental stress on the neuroendocrine-immune system in patients with rheumatoid arthritis (RA). METHODS: Twenty-four patients with RA and 10 patients with osteoarthritis (OA) who underwent total knee or hip arthroplasty under general anesthesia were enrolled in this study. The blood levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1Ra), tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (TNF-Rs) and other substances related to stress were measured just before administering anesthesia on the day of the operation when the patients lay on the operating table and roughly 30 min later when the patients were under general anesthesia without mental stress. These values were compared with those at the same time on the day before the operation, which were considered as controls. RESULTS: In patients with RA under general anesthesia, the levels of IL-6, TNF-alpha, and TNF-R1 and TNF-R2 in the peripheral blood were significantly decreased compared with the levels before anesthesia (p < 0.01). Before anesthesia the levels of IL-1Ra in the peripheral blood were significantly higher, and the level of IL-1Ra was enhanced after the administration of general anesthesia, when compared with the level on the day before the operation (p < 0.01). Such changes were not apparent in patients with OA. CONCLUSION: In patients with RA, excessive mental stress should be eliminated to modify the interaction between the stress-immune system and stress-endocrine system as a method to better control disease activity.

Role of the monocarboxylic acid transport system in the intestinal absorption of an orally active beta-lactam prodrug: carindacillin as a model.

Transport of carbenicillin (CBPC) and its orally active prodrug (carindacillin, CIPC) was studied with rat intestinal brush border membrane vesicles (BBMV). CIPC was transported uphill into BBMV in the presence of a H(+) gradient, indicating that CIPC absorption is carrier-mediated. Indeed, CIPC was predominantly transported by the monocarboxylic acid transport system, although it might be possible that CIPC possesses some affinity to the oligopeptide transporter. In contrast, CBPC exhibited no affinity to either the oligopeptide or the monocarboxylic acid transport system. Apparent uptake clearance of CIPC was approximately 70-fold greater than that of CBPC. It was clarified that the modification of the chemical structure of CBPC (a dicarboxylic acid) to CIPC (a monocarboxylic acid) by ester formation may have resulted in the increased affinity to the monocarboxylic acid transport system, which, in turn, led to improved absorption of the prodrug.