High frequency of cholecystitis in dogs with gallbladder mucocoele in Hong Kong.

The aims of this retrospective study were to characterise the epidemiological, clinical, histopathological, and microbiological findings as well as surgical outcomes in dogs admitted to a specialist veterinary hospital in Hong Kong for surgical management of gallbladder mucocoele (GBM). Inclusion criteria were cases with histopathological diagnosis of GBM and accompanying abdominal imaging, serum biochemistry, bile culture, and liver biopsy histology results. Fifty-six cases met the inclusion criteria. The median age at diagnosis was 12 years (range, 5-16 years). Miniature or toy pure-breed dogs were most commonly affected, including Poodles, Pomeranians, Schnauzers, Bichon frises and Chihuahuas. However, no breed was over-represented compared with their expected proportions among annual hospital admissions. Histological evidence of cholecystitis was present in 84% of cases, including acute cholecystitis in 18%, chronic cholecystitis in 37.5%, acute on chronic cholecystitis in 28% and acute with necrosis in 6%. The most common liver lesions were cholestasis in 64%, along with portal fibrosis in 55%, oedema in 50% and bile duct hyperplasia in 50%. Bile culture was positive in 29.6% of cases. Escherichia coli and Enterobacter species were most commonly isolated. Stentrophomonas maltophili was cultured from one case. Of the 16 cases where bacteria were isolated from bile culture, 94% had evidence of chronic cholecystitis and 81% had evidence of cholangiohepatitis. Fifty dogs (89.3%) survived to discharge including 5/5 dogs with ruptured gallbladders. Of 34 dogs with follow-up data, 21/34 (61.8%) were still alive 12 months later. Gallbladder mucocoeles were frequently associated with both acute and chronic inflammation. High survival rates to discharge were achieved.

Selective cytotoxicity of low-density lipoprotein to helper T cells of cutaneous T-cell lymphoma after photoperoxidation with 8-methoxypsoralen.

Lymphocyte-containing plasma subjected to photolysis in the presence of 8-methoxypsoralen (methoxsalen, 8-MOP) has previously been shown to be effective against cutaneous T-cell lymphoma and the AIDS-related complex. The mechanism of this effect was thought to involve photoreaction of 8-MOP with DNA, based on certain in vitro experiments. The results of this study suggest a different mechanism. Low-density lipoprotein (LDL) from fresh human plasma was photosensitized by addition of 8-MOP and exposure to UV light (mp-LDL), and the reactions of the LDL lipids and the chemical actions induced by these reactions were monitored. In a separate procedure, LDL was peroxidized with hydrogen peroxide and peroxidase (p-LDL). mp-LDL and p-LDL were then tested in cytotoxicity assays on HuT-78 helper T cells of cutaneous T-cell lymphoma. These results indicate that (a) LDL in plasma in the presence of very low concentrations of 8-MOP (200 ng/mL) can be peroxidized by UV light; (b) this photoperoxidized LDL is cytotoxic to helper T cells of cutaneous T-cell lymphoma in a dose-dependent manner; but (c) it does not kill normal lymphocytes under similar conditions. The findings also suggest alternative therapeutic strategies for treatment of cutaneous T-cell lymphoma, such as direct utilization of peroxidized LDL.

Cell death induced by peroxidized low-density lipoprotein: endopepsis.

Peroxidized low-density lipoprotein (p-LDL) has been previously demonstrated to be preferentially cytotoxic to certain malignant cells compared to normal cells of the same type. We present evidence that p-LDL is at least partially taken up through the LDL receptor and that it becomes localized in lysosomes. The integrity of lysosomes of p-LDL-treated cells is compromised, and leakage of their contents into the cytosol occurs. This leakage occurs early and precedes mitochondrial dysfunction. Brefeldin A inhibits this leakage, perhaps by interfering with the traffic between endosomes and lysosomes. Electron micrographs taken at various times suggest a mechanism of cell death which resembles certain aspects of the broad definition of apoptosis. However, we suggest that the cell death observed following p-LDL-induced release of lysosomal contents is essentially unique, with released lysosomal enzymes degrading the cell from within. We suggest that this process should be described as endopepsis.

beta-Endorphin. Intravenous infusion causes behavioral change in psychiatric inpatients.

Ten depressed and eight schizophrenic patients received synthetic human beta-endorphin infusions in a double-blind, placebo-controlled, crossover design. Physicians' and nurses' ratings and patients' self-ratings were used to measure behavioral change. Depressed patients improved significantly two to four hours after beta-endorphin treatment when compared with placebo treatment. There was no significant change in the schizophrenic patients as a group, although six of eight worsened after beta-endorphin treatment. No significant behavioral effects were observed during the infusions themselves or on postinfusion days.

Outcome of hypertension management in Asian Americans.

BACKGROUND: Ethnic and/or racial differences in drug response to antihypertensive agents have been recognized, yet the prescribing practices and the information on efficacy of various agents rely mainly on the response of whites to drugs. OBJECTIVES: To assess the management of hypertension in Asian Americans and to compare it with an age- and sex-matched group of white patients with hypertension. METHODS: The patients' medical records were used as the primary source of information for the data collection. The observational period was a 12-month window and included 200 patients of Asian origin with hypertension and 196 white patients with hypertension whose medical records were randomly selected. RESULTS: The study describes the pattern of use of antihypertensive agents and the differences in response to antihypertensive agents between Asian Americans and whites. The preferred antihypertensive agents in both Asian and white patients included monotherapy with either calcium channel blockers or angiotensin-converting enzyme inhibitors. However, medication changes, dose reduction, and the experience of side effects were all significantly more frequently recorded in Asian patients than in white patients (P < .001, P < .008, and P < .002, respectively). CONCLUSIONS: These findings are supportive of some previous reports on ethnic differences in drug response to antihypertensive agents. The findings also point to the need for further prospective studies on the outcome of hypertension management in Asian American patients.

Intravenous infusion of beta-endorphin increases serum prolactin, but not growth hormone or cortisol, in depressed subjects and withdrawing methadone addicts.

In a randomized, double blind, cross-over study, human beta-endorphin or saline was infused iv over 30 min into six depressed psychiatric patients and four methadone addicts. All depressed subjects showed prompt, 2- to 4-fold increases in serum PRL levels, which lasted at least 2 h. The addicts, who were undergoing acute methadone withdrawal, showed similar PRL increases, which were dose dependent. beta-Endorphin did not increase serum levels of cortisol or GH in either group of subjects. These results suggest that iv beta-endorphin has potent but selective neuroendocrine effects in depressed patients and subjects withdrawing from methadone.

Lymphocyte beta-adrenergic receptors are not altered in hyperthyroidism.

Binding of (-)3H]-dihydroalprenolol (3H-DHA) to lymphocytes from five thyrotoxic patients and five age- and sex-matched contents were examined to ascertain whether beta-adrenergic receptor number or binding affinity were altered in thyrotoxicosis. Whereas an increase in beta-adrenoceptor density has been reported in triiodothyronine-induced hyperthyroidism, we did not find changes in beta-adrenergic receptor density or binding affinity. In one patient studied sequentially, we did not find alteration in 3H-DHA bindings before or after the subject was rendered euthyroid. We conclude that lymphocyte beta-adrenergic receptor density and affinity are not altered in spontaneous hyperthyroidism.

Reversal of human lymphocyte beta-adrenoceptor desensitization by glucocorticoids.

To investigate the effect of glucocorticoids on beta-agonist-induced desensitization, we studied the effect of a single intravenous dose of methylprednisolone (2 mg/kg) on beta-receptor density and affinity in lymphocytes from four normal and four mildly asthmatic subjects at the end of 3 to 5 wk of terbutaline therapy and from four normal subjects taking no other drug. Terbutaline decreased (-)[3H]-dihydroalprenolol binding sites by 53% in normal and by 42% in asthmatic subjects. Methylprednisolone restored the number of binding sites to levels statistically indistinguishable from the preterbutaline values in both groups of subjects. In subjects not exposed to terbutaline beforehand there was no significant alteration in receptor density after methylprednisolone, nor in normal lymphocytes incubated in vitro for 90 min with hydrocortisone (10(-5)M). No significant change in the dissociation constant was observed in any situation. A single intravenous dose of methylprednisolone reverses terbutaline-induced down-regulation of beta-adrenoceptors. This may provide a mechanism for the beneficial effect of steroids in restoring catecholamine responsiveness in asthmatic subjects.

Pharmacokinetics of fosinopril in patients with various degrees of renal function.

Single-dose kinetics of fosinopril, a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid, fosinoprilat, were investigated in patients with mild, moderate, or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg), total body clearance of fosinoprilat was significantly greater (p less than 0.05) in patients with normal renal function than in renally impaired patients but was not related to the degree of renal impairment in patients with creatinine clearance values of 11 to 72 ml/min/1.73 m2. Decreases in renal clearance were compensated for by increases in hepatic clearance, so that total clearance was maintained. After oral 14C-fosinopril (10 mg), plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin-converting enzyme inhibitors.

Bronchodilator effects of caffeine in coffee. A dose-response study of asthmatic subjects.

Although caffeine is a universal drug and has multiple pharmacologic and physiologic actions in man, there are surprisingly few objective data about its effect on pulmonary function. We conducted a short-term, double-blind, randomized crossover study in nine asthmatic adults who ingested decaffeinated coffee containing varying amounts of added caffeine (mean of 0.2,2.5,5.6, and 7.2 mg/kg of body weight) on different days. The subjects also ingested decaffeinated coffee and aminophylline (200 mg) on a separate day of study. Baseline and post-drug determinations of serum levels of caffeine and theophylline, forced expired volume and flow, specific airway conductance (Gaw/VL), vital signs, and reported symptoms were obtained. Peak increases in serum caffeine concentrations (mean, 12.4 micrograms/ml +/- 1.5 micrograms/ml) occurred 45 minutes following the highest dose of caffeine (7.2 mg/kg), whereas the peak theophylline level (mean 3.8 micrograms/ml +/- 0.4 micrograms/ml) occurred 90 minutes following oral administration of aminophylline (mean theophylline, 2.6 mg/kg). Comparable peak increases in the forced expiratory volume in one second (FEV1), the forced expiratory flow during the middle half of the forced vital capacity (FEF25-75%), and Gaw/VL occurred at 120 minutes following aminophylline and the highest dose of caffeine, indicating that caffeine is an effective bronchodilator but is only 40 percent as active as an equivalent molar dose of theophylline. Regression analysis revealed statistically significant dose-response relationships between peak increases in serum caffeine concentrations and increases in FEV1, FEF25-75%, and Gaw/VL from baseline values. These findings have diagnostic and therapeutic implications regarding the use of caffeine prior to tests of pulmonary function and as a dietary agent, alone or in combination with theophylline.

Hostility and the response to diuretic in mild-to-moderate hypertension.

Forty-two patients with mild-to-moderate hypertension between the ages of 35 and 65 (23 men, 19 women) were studied to determine whether psychological characteristics can help differentiate between responders and nonresponders to diuretic (hydrochlorothiazide 25 mg and triamterene 50 mg). To qualify for inclusion in the study, the subjects were required to have a mean unmedicated clinic diastolic blood pressure (DBP) between 95 and 110 mm Hg. Positive response to diuretic was defined as a reduction in clinic DBP < or = 90 mm Hg. Of the 42 subjects, 22 were responders to diuretic, achieving a BP level of 129/86 mm Hg, a reduction of 16/11 mm Hg from their unmedicated level. Nonresponders achieved a reduction of 8/4 mm Hg. Compared with nonresponders, responders were characterized by slightly lower initial BP levels and significantly lower scores on the Buss-Durkee Hostility Inventory and several subscales of this test. The pattern of results indicated higher levels of suppressed hostility in the nonresponders. Ambulatory BP data paralleled the clinic BP changes.

Blood pressure morning surge and hostility.

This study examined the effects of hostility on blood pressure (BP) during the early morning hours before awakening and several hours afterward. Our objective was to determine whether the pattern of BP change and the slope of the morning BP surge were related to hostility. The subjects were 32 patients with a history of Stage 1 hypertension. The morning surge in BP was derived from ambulatory BP monitoring of sleeping and waking hours, which were averaged per subject and centered around the wake-up hour. The periods used were 3 h before and 3 h after awakening. Only systolic blood pressure (SBP) is being reported on in this paper as this is the primary measure found relevant to the morning surge phenomenon. Hostility was assessed by the Buss-Durkee Hostility Inventory (total score). The results revealed significant differences between low and high hostility subjects for overall levels of sleep SBP: 120 +/- 11.4 mm Hg for low hostility and 131.3 +/- 14.9 mm Hg for high hostility subjects (P = .02). Low hostility subjects showed a steep rise in SBP from sleeping to waking while high hostility subjects had almost reached their post-sleep level of SBP in the hours immediately before waking up (P = .03). These data indicate that individual differences in hostility are related to different patterns of BP during sleep and the early morning hours, a period of the day that has been associated with an increased risk of cardiovascular incidents. The data also suggest the need for further study of the significance of hostility and other personality traits and the relationship of these traits to the mechanisms of the morning surge and the risk of cardiovascular events.

Reduction in drug requirements for hypertension by means of a cognitive-behavioral intervention.

The purpose of the present study was to test the effectiveness of a cognitive-behavioral intervention as an adjunctive treatment of hypertension. To qualify for the study, subjects had to have an unmedicated clinic diastolic blood pressure > or = 95 mm Hg. After qualification, minimal drug requirements were established using a diuretic and a beta-blocker to control blood pressure at < or = 90 mm Hg. Subjects were then randomized into a 6-week cognitive-behavioral intervention or a measurements-only control group. After the treatment phase, medication levels were reduced in all subjects by means of a systematic stepdown procedure. Subjects were followed for 1 year after the stepdown was completed. Addition of the cognitive-behavioral intervention was twice as effective as the control procedure in reducing drug requirements. At 12-months follow-up, 73% of the treatment group were at lower levels of medication than at the time of randomization, compared to 35% in the control group. Moreover, 55% of the treatment group remained completely free of medication, compared to 30% of the control group, at the 12-month follow-up. The reductions in medication were associated with maintained controlled levels of clinic, ambulatory, and home blood pressure. The addition of a standardized and inexpensive group-administered cognitive-behavioral intervention to the drug treatment of hypertension is beneficial as an adjunctive treatment in reducing drug requirements for patients with hypertension, thereby reducing the costs and potential side effects of antihypertensive medications.

Invasive pharmacodynamics of fosinopril in patients with congestive heart failure.

Five patients with NYHA Class III CHF received 5 mg of fosinopril on each of 4 days. Hemodynamics were measured with a Swan-Ganz catheter after dosing on day 1. Measurements of plasma fosinoprilat, ACE activity, renin, and aldosterone were obtained. An Emax model was used to fit the effect-site concentration and mean arterial pressure change. A linear model was used to fit the effect-site concentration and the pulmonary artery wedge pressure (PAWP) change. At steady state on day 4, AUC0-24 was 1668 +/- 476 ng.hr/mL and Cmax was 143.5 +/- 33.6 ng/mL. The mean elimination half-life of fosinoprilat was 11.3 +/- 0.7 hours, and median Tmax occurred at 3 hours, corresponding to maximum plasma ACE inhibition. Plasma renin activity was unchanged, and mean plasma aldosterone level declined. Emax modeling using fosinoprilat concentrations and mean arterial pressure showed good prediction of the pharmacodynamic effects from the effect-site concentration. A linear relationship was observed between the effect-site concentrations of fosinoprilat and PAWP. When expressed in an Emax model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its pharmacokinetics.

Invasive verrucous carcinoma of urinary bladder treated by irradiation.

A case of inoperable, invasive verrucous carcinoma of the urinary bladder treated by irradiation is presented. The incidence of anaplastic transformation of verrucous carcinoma after irradiation is lower and the coincidence of verrucous carcinoma and well-differentiated squamous carcinoma higher than is generally recognized. Radiation should be considered in inoperable cases. The pertinent literature is reviewed.

Protein kinase A and/or C inhibitors potentiate isoproterenol-induced cyclic AMP accumulation in intact human lymphocytes.

The objective of the present study was to investigate the roles of protein kinase A and/or C in agonist-induced beta adrenoceptor activation in intact human lymphocytes. LYmphocytes from healthy subjects were incubated with isoproterenol and phosphodiesterase inhibitor (IBMX, 1.0 mM) after 20 minutes of preincubation with (or without) various compounds possessing protein kinase A and/or C inhibitory activities. These compounds included the relatively selective protein kinase C (PK-C) inhibitors (W-7, calmidazolium, polymyxin B, neomycin, tamoxifen and clomiphene), purified protein inhibitors of protein kinase A (PK-A) (obtained synthetically, or purified from bovine hearts and porcine hearts) and the two compounds (H-7, H-9), which have been found to inhibit both PK-A and PK-C. The results showed that all PK-C inhibitors alone decreased cellular basal cAMP levels while inhibitors of PK-A as well as both H-7 and H-9 increased basal cAMP levels in a dose dependent manner at certain concentrations. All inhibitors studied potentiated isoproterenol-induced cAMP accumulation. The protein kinase A and C inhibitor, H-7, also potentiated PGE1 (but not forskolin)-induced cAMP accumulation. In contrast, the protein kinase C activator, PMA, inhibited isoproterenol- and PGE1- (but not forskolin) induced cAMP accumulation. These data suggest that the potentiating effects of PK-A and/or C inhibitors may be related to the inhibition of PK-A and/or PK-C, both of which have been shown to be involved in beta 2 adrenoceptor desensitization and phosphorylation.

The effects of calcium channel blockers on isoproterenol induced cyclic adenosine 3',5'-monophosphate generation in intact human lymphocytes.

We have investigated the effects of clinically available calcium channel blockers (nifedipine, verapamil and diltiazem) on isoproterenol stimulated cyclic adenosine 3',5'-monophosphate (cyclic AMP) generation in intact human lymphocytes. After preincubation of various calcium antagonists with intact lymphocytes at 37 degrees C for 15 minutes, 10 microM nifedipine or verapamil partially inhibited isoproterenol induced cyclic AMP generation in the presence of cyclic AMP phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) while they alone had no effect on cyclic AMP level at a concentration of up to 100 microM. In contrast, 10 nM-1.0 microM nifedipine, verapamil or diltiazem potentiated cyclic AMP generation induced by isoproterenol in a dose dependent manner. Similar results were observed in the time course studies of cyclic AMP generation. These effects are somewhat similar to the effect of phenothiazine, a calmodulin inhibitor, which, at 10 microM (close to IC50), also potentiated the effects of isoproterenol. In contrast, lanthanum chloride (LaCl3), an extracellular inorganic calcium antagonist, at 1.0 mM, inhibited isoproterenol induced cyclic AMP generation. The biochemical mechanisms underlying these potentiating effects are unknown. It may be partly related to the effect of calcium channel blockers (at least for nifedipine) on preventing beta 2 adrenergic receptor desensitization. This may provide a potential mechanism for the synergistic effect between calcium channel blockers and beta 2 adrenoceptor agonists on bronchial dilatation.

Ketotifen increases cyclic adenosine 3',5'-monophosphate in intact human lymphocyte and potentiates other adenylate cyclase activating agents.

We have investigated the effects of ketotifen on the cyclic adenosine 3',5'-monophosphate (cyclic AMP) response of intact human lymphocyte and its interaction with adenylate cyclase activating agents. In the presence of cyclic AMP phosphodiesterase inhibitor (3-isobutyl-1-methyl-xanthine), ketotifen (10(-8)-10(-4) M) caused an 80% increase in cyclic AMP content of human lymphocyte, a magnitude similar to that observed with hydrocortisone. The cyclic AMP level peaked at about 15 minutes and remained elevated for at least 45 minutes. In addition, ketotifen (10(-6)-10(-4) M) markedly potentiated the effect of several adenylate cyclase stimulating agents, including L-isoproterenol, prostaglandin E1 and forskolin. The biochemical mechanisms underlying these effects are unknown. It may be at least partly related to the ability of ketotifen to reverse and prevent beta 2 adrenoceptor desensitization and to promote the formation of hormone - nucleotide - high affinity receptor complex. These effects may contribute to its prophylactic effect in the treatment of bronchial asthma.

Interaction of berberine with human platelet alpha 2 adrenoceptors.

Berberine, an alkaloid, has been found to have a myriad of pharmacological effects including hypotensive, antisecretory, sedative, and antimicrobial effects, some of which are similar to those of clonidine, an alpha 2 adrenoceptor partial agonist. The interaction of berberine with human platelet alpha 2 adrenoceptor was investigated in this study. Berberine was found to inhibit competitively the specific binding of [3H]-yohimbine. The displacement curve was parallel to those of clonidine, epinephrine, norepinephrine, with the rank order of potency (IC50) being clonidine (0.4 microM) greater than epinephrine (7.5 microM) greater than norepinephrine (14.5 microM) = berberine (16.6 microM). Increasing concentrations of berberine from 0.1 microM to 10 microM inhibited [3H]-yohimbine binding, shifting the saturation binding curve to the right without decreasing the maximum binding capacity. In platelet cyclic AMP accumulation experiments, berberine at concentrations of 0.1 microM to 0.1 mM inhibited the cAMP accumulation induced by 10 microM prostaglandin E1 in a dose dependent manner, acting as an alpha 2 adrenoceptor agonist. In the presence of L-epinephrine, berberine blocked the inhibitory effect of L-epinephrine behaving as an alpha 2 adrenoceptor antagonist. These properties are similar to those of clonidine on human platelets, suggesting that berberine is a partial agonist of platelet alpha 2 adrenoceptors. These findings may provide potential mechanisms for the hypotensive, antisecretory, and sedative effects of berberine.