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.

Caspase-3 deficiency reveals a physiologic role for Smac/DIABLO in regulating programmed cell death.

Inhibitor of apoptosis protein (IAP)-binding proteins such as Grim, Reaper and HID have been shown to exert a critical role in regulating caspase activity in species such as D. Melanogaster. However, a comparable role for the mammalian homologue of second mitochondrial-derived activator of caspase/direct IAP-binding protein with low pI (Smac/DIABLO) has yet to be clearly established in vivo. Despite tremendous interest in recent years in the use of so-called Smac mimetics to enhance chemotherapeutic potency, our understanding of the true physiologic nature of Smac/DIABLO in regulating programmed cell death (PCD) remains elusive. In order to critically evaluate the role of Smac/DIABLO in regulating mammalian PCD, deficiency of caspase-3 was used as a sensitizing mutation in order to reduce aggregate levels of executioner caspase activity. We observe that combinatorial deletion of Diablo and Casp3, but neither alone, results in perinatal lethality in mice. Consistent with this, examination of both intrinsic and extrinsic forms of PCD in lines of murine embryonic fibroblasts demonstrate that loss of Smac/DIABLO alters both caspase-dependent and caspase-independent intrinsic PCD. Comparative small interfering RNA inhibition studies of X-linked inhibitor of apoptosis, cellular inhibitor of apoptosis (cIAP)-1, cIAP-2, caspase-6 and -7 in both wild-type and Casp3/Diablo DKO mouse embryonic fibroblast lineages, supports a model in which Smac/DIABLO acts to enhance the early phase executioner caspase activity through the modulation of inhibitory interactions between specific IAP family members and executioner caspases-3 and -7.

Hypothalamus and amygdala response to acupuncture stimuli in Carpal Tunnel Syndrome.

Brain processing of acupuncture stimuli in chronic neuropathic pain patients may underlie its beneficial effects. We used fMRI to evaluate verum and sham acupuncture stimulation at acupoint LI-4 in Carpal Tunnel Syndrome (CTS) patients and healthy controls (HC). CTS patients were retested after 5 weeks of acupuncture therapy. Thus, we investigated both the short-term brain response to acupuncture stimulation, as well as the influence of longer-term acupuncture therapy effects on this short-term response. CTS patients responded to verum acupuncture with greater activation in the hypothalamus and deactivation in the amygdala as compared to HC, controlling for the non-specific effects of sham acupuncture. A similar difference was found between CTS patients at baseline and after acupuncture therapy. For baseline CTS patients responding to verum acupuncture, functional connectivity was found between the hypothalamus and amygdala--the less deactivation in the amygdala, the greater the activation in the hypothalamus, and vice versa. Furthermore, hypothalamic response correlated positively with the degree of maladaptive cortical plasticity in CTS patients (inter-digit separation distance). This is the first evidence suggesting that chronic pain patients respond to acupuncture differently than HC, through a coordinated limbic network including the hypothalamus and amygdala.

Correlating acupuncture FMRI in the human brainstem with heart rate variability.

Past neuroimaging studies of acupuncture have demonstrated variable results for important brainstem nuclei. We have employed cardiac-gated fMRI with T1-variability correction to study the processing of acupuncture by the human brain. Furthermore, our imaging experiments collected simultaneous ECG data in order to correlate heart rate variability (HRV) with fMRI signal intensity. Subjects experienced one of three stimulations over a 31.5 minute fMRI run: (1) electro-acupuncture at 2Hz/15Hz over the acupoint ST-36 (2) electro-acupuncture at a sham non-acupoint, or (3) sensory control tapping over ST-36. The ECG was analyzed with power spectral methods for low frequency and high frequency components, which reflect the balance in the autonomic nervous system. The HRV data was then correlated with the time-varying fMRI signal intensity. Our data suggests that fMRI activity in the hypothalamus, the dorsal raphe nucleus, the periaqueductal gray, and the rostroventral medulla showed significant correlation with LF/HF ratio calculated from simultaneous HRV data. The correlation of time-varying fMRI response with physiological parameters may provide insight into connections between acupuncture modulation of the autonomic nervous system and neuroprocessing.

Acupuncture modulates the limbic system and subcortical gray structures of the human brain: evidence from fMRI studies in normal subjects.

Acupuncture, an ancient therapeutic technique, is emerging as an important modality of complementary medicine in the United States. The use and efficacy of acupuncture treatment are not yet widely accepted in Western scientific and medical communities. Demonstration of regionally specific, quantifiable acupuncture effects on relevant structures of the human brain would facilitate acceptance and integration of this therapeutic modality into the practice of modern medicine. Research with animal models of acupuncture indicates that many of the beneficial effects may be mediated at the subcortical level in the brain. We used functional magnetic resonance imaging (fMRI) to investigate the effects of acupuncture in normal subjects and to provide a foundation for future studies on mechanisms of acupuncture action in therapeutic interventions. Acupuncture needle manipulation was performed at Large Intestine 4 (LI 4, Hegu) on the hand in 13 subjects [Stux, 1997]. Needle manipulation on either hand produced prominent decreases of fMRI signals in the nucleus accumbens, amygdala, hippocampus, parahippocampus, hypothalamus, ventral tegmental area, anterior cingulate gyrus (BA 24), caudate, putamen, temporal pole, and insula in all 11 subjects who experienced acupuncture sensation. In marked contrast, signal increases were observed primarily in the somatosensory cortex. The two subjects who experienced pain instead of acupuncture sensation exhibited signal increases instead of decreases in the anterior cingulate gyrus (BA 24), caudate, putamen, anterior thalamus, and posterior insula. Superficial tactile stimulation to the same area elicited signal increases in the somatosensory cortex as expected, but no signal decreases in the deep structures. These preliminary results suggest that acupuncture needle manipulation modulates the activity of the limbic system and subcortical structures. We hypothesize that modulation of subcortical structures may be an important mechanism by which acupuncture exerts its complex multisystem effects.

Acupuncture: pain management coupled to immune stimulation.

The phenomenon of acupuncture is both complex and dynamic. Recent information demonstrates that acupuncture may exert its actions on pain and immune processes. The coupling of these two systems occurs via common signaling molecules, i.e., opioid peptides. In this regard, we surmise that opioid activation leads to the processing of opioid peptides from their precursor, proenkephalin, and the simultaneous release of antibacterial peptides contained within the precursor as well. Thus, central nervous system pain circuits may be coupled to immune enhancement. Furthermore, acupuncture needle manipulation elicited signal increases bilaterally in the region of the primary and secondary somatosensory corticies in human brain as determined by magnetic resonance imaging. The maps reveal marked signal decreases bilaterally in multiple limbic and deep gray structures including the nucleus accumbens, amygdala, hypothalamus, hippocampus, and ventral tegmental area. Taken together, we surmise a major central nervous system pathway as well as local pain and immune modulation during acupuncture.

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.

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.

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.

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.

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.

Hostility and differences between clinic, self-determined, and ambulatory blood pressure.

This study examined the role of personality factors in differences between three methods of assessing blood pressure (clinic, self, ambulatory) in 45 patients with mild hypertension. The data were obtained after the patients were withdrawn from antihypertensive medications and had achieved stable clinic diastolic blood pressure levels of 95 to 110 mm Hg, averaged over three visits in 2 to 4 weeks. Significant differences were obtained in systolic blood pressure (SBP) and diastolic blood pressure (DBP) as a function of method of assessment. These differences in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were associated with individual differences in the total score and several subscales of the Buss-Durkee Hostility Inventory (Assault, Resentment, Guilt), but not in anxiety, depression, or other characteristics. High hostile subjects had consistently high blood pressure values in both clinic, self, and ambulatory recordings. Low hostile subjects were significantly lower in self-recorded blood pressure readings taken at home and in ambulatory recordings, compared with clinic values. Implications of these findings for "white coat hypertension" are discussed.

Effects of varying marijuana smoking profile on deposition of tar and absorption of CO and delta-9-THC.

We investigated the effects of previously observed differences in smoking technique for marijuana (M) versus tobacco (T) on the amount of inhaled tar, the percentage retention of inhaled tar in the lung, the pre- to postcigarette boost in blood carboxyhemoglobin (COHb) and in serum delta-9-tetrahydrocannabinol (THC concentrations), and psychophysiologic responses to THC (increased heart rate and subjective "high"). Ten healthy, habitual smokers of M were studied on 6 separate days. On each day, subjects smoked a single M cigarette (approximately 900 mg, 1.24% delta-9-THC) using one of 6 different smoking profiles typical for marijuana [puff volume (PV) approximately 70 ml; breathholding time, (BHT) 14-16 s] or tobacco (PV approximately 45 ml; BHT 4-5 s) or a combination of the two techniques (PV approximately 70 ml and BHT 4-5 s; or PV approximately 45 ml and BHT 14-16 s). Inhaled volume (1.5 liters), interpuff interval (30 s) and number of puffs (6) were all fixed, except that for the approximately 45-ml PV condition, the number of puffs was increased to 10 in 2 additional sessions to standardize the total amount of cigarette consumed to that of the approximately 70-ml PV condition. The longer BHT significantly increased both percent retention of tar in the lung and the pre- to postsmoking rise in blood COHb, serum THC and heart rate, independent of puff volume and number. In contrast, the larger PV had no significant influence on these variables for the same amount of cigarette consumed.(ABSTRACT TRUNCATED AT 250 WORDS)

Tar, CO and delta 9THC delivery from the 1st and 2nd halves of a marijuana cigarette.

Previous in vitro studies suggest that, with successive puffs from a marijuana cigarette, delta-9-THC becomes concentrated in the remaining uncombusted portion of the cigarette. These observations are consistent with the common practice of smoking marijuana cigarettes to a smaller butt length than that to which tobacco cigarettes are smoked. The purpose of the present study was to compare the delivery of delta-9-THC, as well as total insoluble smoke particulates (tar) and carbon monoxide, from the distal ("first") versus the proximal ("second") halves of a standard marijuana cigarette during "natural" smoking of marijuana. On 4 separate days, ten habitual marijuana users smoked nearly all or approximately 1/2 of a standard marijuana cigarette (83 mm length; 800-900 mg; 1.24% THC), as follows: day 1, "whole" cigarette (60 mm smoked, leaving a 23-mm butt); day 2, "first" half (first 30 mm); day 3, "second" half (second 30 mm) after the "first" half was presmoked with a syringe; and day 4, "second" half after the "first" half was excised. A previously described smoking apparatus (20) was used for measurement of puff volume and inhaled tar. Puff volume and number were allowed to vary spontaneously (provided that the specified length of cigarette was consumed), while inhaled volume (1.5 liters), breathholding time (14 s) and interpuff interval (30 s) were held constant. Blood samples were withdrawn prior to smoking and serially after completion of smoking for analysis of blood carboxyhemoglobin (COHb) and serum delta-9-THC. Heart rate was measured before and 5 min after smoking. Subjects rated their level of "high" 20 min after completion of smoking.(ABSTRACT TRUNCATED AT 250 WORDS)

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.