Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological and immunohistochemical parameters.

BACKGROUND: Phosphorylase kinase (PhK), also known as adenosine triphosphate (ATP)-phosphorylase b phosphotransferase, integrates multiple calcium/calmodulin-dependent signalling pathways, including those involved in cell migration and cell proliferation, while coupling these pathways to glycogenolysis and ATP-dependent phosphorylation, thus ensuring continuing energy supply for these activities. OBJECTIVES: Our laboratory recently reported correlation of elevated PhK activity with psoriatic activity. This study further evaluates the significance of drug-induced suppression of PhK activity on psoriatic activity. PATIENTS AND METHODS: PhK activity was assayed in four groups, each with 10 patients: (i) active untreated psoriasis; (ii) resolving psoriasis treated by calcipotriol (Dovonex(R), Bristol Myers Squibb, Princeton, NJ, U.S.A. ), a vitamin D3 analogue and an indirect inhibitor of PhK; (iii) curcumin (diferuloylmethane), a selective PhK inhibitor; and (iv) 10 normal non-psoriatic subjects. RESULTS: PhK activity in units mg-1 protein was highest in active untreated psoriasis (1204 +/- 804.3; mean +/- SD), lower in the calcipotriol-treated group (550.7 +/- 192. 9), lower in curcumin-treated group (207.2 +/- 97.6), and lowest in normal skin (105.4 +/- 44.6). One-way analysis of variance performed on log-transformed PhK activity measure showed significant differences among the four groups, F3,36 = 48.79, P < 0.0001. Decreased PhK activity in curcumin-and calcipotriol-treated psoriasis was associated with corresponding decreases in keratinocyte transferrin receptor (TRR) expression, severity of parakeratosis and density of epidermal CD8+ T cells. CONCLUSIONS: Our results demonstrate that drug-induced suppression of PhK activity is associated with resolution of psoriatic activity as assessed by clinical, histological and immunohistochemical criteria, and support the hypothesis that effective antipsoriatic activity may be achieved through modulation of PhK activity.

Involvement of luminal bacteria, heat shock protein 60, macrophages and gammadelta T cells in dextran sulfate sodium-induced colitis in rats.

The in vivo immunological events in dextran sulfate sodium (DSS) -induced colitis were evaluated. Rats were fed water (control) or 5% DSS. Colonic sections were assessed by light microscopy, Gram stain, immunohistochemistry, and electron microscopy. A progressive decline in number and increase in fragmentation of bacteria in the colonic lumen was observed over time. Luminal bacteria were the first to show heat shock protein 60 (HSP60) staining (day 3). Macrophages in close proximity to these bacteria were next to show such staining (day 6), and finally the damaged epithelial cells when colitis became severe (day 15). Ultrastructural assessment showed cell-cell contact interactions between macrophages and dendritic gammadelta T cells. An increase in the number of gammadelta T cells and ED1-positive macrophages in the affected colonic tissue over time was documented. These results suggest colonic bacteria, host macrophages, and gammadelta T cells play specific roles in the immunological reactions in DSS-induced colitis, possibly via an HSP60-mediated mechanism.

Epidemiology of Warthin's tumour of the parotid gland in an Asian population.

BACKGROUND: Recent studies have documented a number of changing demographic features in the occurrence of Warthin's tumour (adenolymphoma) of the parotid gland. In order to analyse its epidemiology in an Asian population, a retrospective study was performed on all parotid neoplasms (n = 289) operated on between 1988 and 1998. PATIENTS AND METHODS: A total of 209 consecutive patients were selected for study, 136 with pleomorphic adenomas (one bilateral) and 73 with Warthin's tumours (seven bilateral). Patients were analysed with regard to tumour incidence, age, sex and race. Smoking as an aetiological factor in the development of Warthin's tumour was also studied. RESULTS: Warthin's tumour formed 25 per cent of parotid tumours and its ratio to pleomorphic adenomas was 1 : 1.9. Multicentricity was found in 14 patients (19 per cent). The male : female ratio for Warthin's tumours was 4.6 : 1. The proportion of Warthin's tumours did not show any increasing trend relative to pleomorphic adenomas. The racial distribution of Warthin's tumours showed an increased incidence among Chinese and a reduced incidence among Malays and Indians. The adjusted odds ratio for sex and age favouring an association between smoking and Warthin's tumour was 39.5 (95 per cent confidence interval 10.5-149. 0; P < 0.0001). CONCLUSION: The incidence of Warthin's tumour is considerable among Asians although there is still male predominance. There is no rising incidence of Warthin's tumour; the trend parallels the declining smoking rate in the population. The lower incidence among ethnic groups with dark skin seems to suggest concomitant genetic factors other than environmental factors alone in histogenesis. Smokers have a 40-fold greater risk than non-smokers of developing a Warthin's tumour.

Murine typhus: a forgotten cause of febrile illness in Singapore.

We report 6 cases of marine typhus presented to us within a period of 3 months. The diagnoses were made based on the Weil-Felix reaction in the context of supportive clinical and epidemiological features, and response to appropriate antimicrobial therapy. This review serves to remind us that murine typhus is still an important cause of acute febrile illness in Singapore, especially among the migrant Indian workers.

Metabolic alterations of zinc and prostaglandins in both human and animal colonic tumor cells.

OBJECTIVE: To understand the relationship between zinc and prostaglandin (PG) metabolisms in inducing colon cancer incidence in human and animals. METHODS: Human colonic tumor and normal cells were obtained from Departments of Surgery and Pathology at the Kaiser Permanente Medical Center, Los Angeles, CA and US VA Medical Center, North Hills, CA. Rat colonic tumor and normal cells were isolated from the rats that received two injections of 50 mg/kg of Azoxymethan (AOM) in 2 weeks and then kept 30 weeks in the animal facility. Then, the effects of zinc on the PGE2 synthesis and PGE2 on zinc metabolism in tumor and normal cells were determined. RESULTS: PGE2 concentrations in both human and AOM-induced rat colonic tumor cells increased compared to those in adjacent normal colonocytes, whereas PGF2 alpha concentrations did not change. Gene expression of inducible form of prostaglandin synthase (PGS-2) is stimulated in rat colonocytes by epidermal growth factor and by tetradecanoyl 13-phorbol acetate (a tumor promoter and mitogen) only in the presence of zinc. PGE2 binding activity of rat enterocytes was maximum at 15 microM of zinc (normal plasma zinc concentration), but PGE2 synthesis activity increased for the first 15 minutes when extracellular zinc concentrations were either higher or lower than the normal extracellular zinc concentration. However, variations in extracellular zinc concentrations did not change the rate of PGF2 alpha synthesis in the normal rat enterocytes. PGE2 significantly increased zinc uptake rates of colonic tumor cells but PGF2 alpha showed only moderate effect. CONCLUSIONS: These results suggest that zinc is required for PGS-2 gene expression, that maintaining an optimal zinc nutriture is important for normal PG synthesis of intestinal cells, and that only PGE2 synthesis mechanisms rather than PGS-2 gene expression are altered in colonic tumor cells resulting in the abnormal zinc nutriture of these cells.

Heat-shock protein 65 and activated gamma/delta T cells in injured arteries.

Because immune mechanisms are implicated in atherogenesis, we investigated the T-lymphocyte subset and factors related to its activation after acute arterial ligation (22 ligated and 13 non-ligated specimens). Ligated arteries produced heat-shock protein 65 (hsp65) and were infiltrated with activated T cells (mostly dendritic, CD3+, CD4-, CD8-, and gamma/delta T-cell-receptor bearing). The protein was found with dendritic T cells, with immunogold-labelled hsp65 beside the dendritic processes. Thus, the immune reaction after acute arterial injury may be associated with binding and recognition of in-situ hsp65 by dendritic gamma/delta T-cells.

Elevated phosphorylase kinase activity in psoriatic epidermis: correlation with increased phosphorylation and psoriatic activity.

To determine whether abnormal activity of a calmodulin-containing enzyme which catalyses phosphorylation reactions may play a pathogenetic role in psoriasis, the presence and activity of phosphorylase kinase (PK) in human epidermis were determined in patients with untreated/active psoriasis (n = 10), treated/resolving psoriasis (n = 10), and non-psoriatic controls (n = 10). Biopsies were taken from involved and uninvolved skin for PK, organic phosphorus, and inorganic phosphate estimation, and light and electron microscopy. The enzyme was present in involved and uninvolved skin of every patient in the study. PK activity (units/mg protein) was significantly higher in active psoriasis than in resolving psoriasis and controls. PK activity correlated directly with organic phosphorus levels, and inversely with the extent of cellular glycogenolysis measured by the depletion of glycogen granules within the keratinocytes. The study demonstrates that PK is present in both psoriatic and normal epidermis, with significantly higher levels in active psoriasis. Furthermore, higher levels of PK activity, glycogenolysis and phosphorylation are associated with increased clinical psoriatic activity. We conclude that PK, a calmodulin-containing enzyme, is involved in regulating calcium-dependent phosphorylation events in human epidermis, and disturbance of its activity may play a key role in the clinical manifestations of psoriasis.

Reciprocity between tissue calmodulin and cAMP levels: modulation by excess zinc.

Signal transduction of many intracellular events is initiated by a minute influx of calcium ions into the cells, resulting in the formation of calcium-calmodulin complex and cAMP. Because zinc appears to have an inhibitory effect on a number of tissue reactions, it is postulated that this occurs through modulation of intracellular calcium influx. To test the hypothesis that the inhibitory effects of zinc are mediated through the calcium-calmodulin-cAMP pathway, zinc was administered by various routes to five groups of nude mice (control, intragastric, intraperitoneal, intradermal and oral groups), and calmodulin and cAMP concentrations were measured in the cytosol of epidermal cells. Calmodulin levels decreased significantly in the groups given intraperitoneal zinc (P < 0.025) and intradermal zinc (P < 0.001) injections. Significant elevations of cAMP levels were noted with intradermal zinc (P < 0.025). Overall, the relationship between calmodulin and cAMP appeared to be inversely logarithmic, with the lowest calmodulin levels associated with the highest cAMP concentrations. In addition, there was a significant trend towards a smaller calmodulin/cAMP ratio in all zinc-treated groups, except the mice fed dietary zinc. These results appear to correlate with tissue zinc levels obtained with these various forms of zinc administration. Our results therefore indicate that there is a reciprocity between epidermal calmodulin and cAMP levels, which may be modulated by external factors such as zinc.

Changes in cardiovascular function during inversion.

Although inversion therapy is used increasingly as a therapy for musculoskeletal back disorders, its effects on cardiovascular function have not been systematically determined. Heart rate, blood pressure and echocardiographic measurements were performed in 20 normal male volunteers before, during and after bent-knee inversion. Compared to control measurements in the supine position, inversion significantly increased heart rate, systolic and diastolic blood pressure, rate-pressure product, systemic vascular resistance and left ventricular (LV) wall stress. Inversion also resulted in a significant decrease in LV diastolic volume, cardiac output and ejection fraction. Thus inversion produces an increase in LV afterload and myocardial oxygen demand concomitantly with a decrease in LV preload and global systolic function, and may be contraindicated in patients with cardiovascular disease.

Expression of the L-fucose moiety on infrainfundibular follicular keratinocytes of terminal follicles, its decreased expression on vellus and indeterminate follicles of androgenetic alopecia, and re-expression in drug-induced hair regrowth.

The distribution of various glycoprotein molecules on the surface of follicular keratinocytes was studied with a panel of lectins with specificity for various sugar moieties on biopsy specimens from both bald/balding scalp and normal occipital scalp, of 23 patients with androgenetic alopecia as well as on biopsies of normal forearm skin of four patients. The most significant differences between bald and normal scalp biopsy were noted with Ulex europaeus agglutinin I (UEA I). We noted an increased (91.8% +/- 3.1; mean +/- SE) expression of UEA I binding sites on the infra-infundibular follicular keratinocytes in anagen terminal scalp hairs, compared to 28.5% +/- 5.2 in the indeterminate (anagen) hairs of balding scalps, and 23.2% +/- 6.3 in the anagen follicles of vellus fore-arm hairs. By contrast, the telogen hairs demonstrated minimal UEA I staining: 4.0% +/- 0.8, mean +/- SE in telogen scalp hairs, 1.8% +/- 0.5 in telogen hairs of balding scalps (0% in completely bald scalps, in which all the hairs were in the telogen phase), and 1.9% +/- 0.2 in telogen forearm hairs. The percentage of UEA I staining correlated with the length of the infra-infundibular follicles in all cases studied. In three cases of hair regrowth after hair growth promotors, the UEA I staining increased to 80.6% +/- 6.1 in anagen hairs and correlated with increased length of infra-infundibular follicles. Our data indicate that there are 1) marked differences between anagen and telogen follicles in UEA I binding to infra-infundibular follicular keratinocytes; 2) the percentage of UEA I staining reflects the size (length) of the infra-infundibular hair follicle; and 3) the anagen follicles of balding scalps (indeterminate hairs) show UEA I staining resembling that exhibited by anagen follicles of vellus hairs.

Focal endothelial cell degeneration and proliferative endarteritis in trauma-induced early lesions of necrobiosis lipoidica diabeticorum.

Microangiopathy is an essential component in diabetic vascular pathology. We report ultrastructural observations of ballooning degeneration involving isolated endothelial cells of cutaneous capillaries, while leaving adjacent endothelial cells relatively intact in six diabetic patients with early lesions of necrobiosis lipoidica induced by trauma. Focal proliferation of endothelial cells encroaching upon the vascular lumina (obliterative endarteritis) was also observed. Lectin studies on biopsy specimens of older lesions of necrobiosis lipoidica revealed paucity of dermal blood vessels. These observations enable us to gain further insight into the pathophysiological mechanisms that underlie diabetic microvascular disease.

Beta, partial agonists to treat heart failure: effects of xamoterol upon cardiac function and clinical status.

The presence of systolic dysfunction, diastolic dysfunction, or both is an important consideration in selecting the optimal pharmacologic approach to the treatment of congestive heart failure in an individual patient. Cardiac glycosides and arterial vasodilators act only on systolic function, whereas beta 1-adrenoceptor-stimulating agents, such as beta 1 full and partial agonists, have both inotropic and lusitropic activity. Acute and chronic administration of xamoterol, a new beta 1 partial agonist, to patients with congestive heart failure has been shown to improve myocardial contractility, as indicated by increases in the peak rate of rise in left ventricular pressure, left ventricular ejection fraction, and cardiac output. Improvement in ventricular relaxation and filling, reflected by increases in the peak rate of decline in left ventricular pressure, reductions in the time constant of the decrease in isovolumic pressure, improved left ventricular compliance, and increases in the atrial contribution to diastolic filling, are other beneficial effects of xamoterol on diastolic function. Exercise capacity increases in response to xamoterol therapy, while heart rate at maximum exercise declines. Relief of the signs and symptoms of congestive heart failure and improvement in functional status have also been demonstrated in xamoterol-treated patients. The undesirable effects of beta 1 full agonists, such as tachycardia, arrhythmias, increased myocardial oxygen consumption, and effects on the peripheral vasculature, are not seen with xamoterol. The beta 1 partial agonist also causes no beta-adrenoreceptor down-regulation, a finding that may account for its sustained effectiveness with long-term therapy.

The value of Holter monitoring in evaluating the elderly patient who falls.

Ambulatory cardiac (Holter) monitoring is often recommended in the routine evaluation of patients who fall; however, the prevalence of arrhythmias in old people is high, and the usefulness of such monitoring is unproven. As part of a large study of institutionalized elderly fallers, we compared Holter findings of fallers (N = 51) with a group of nonfallers (N = 27) having similar medical and demographic characteristics. Prevalence of ventricular arrhythmias was 82% in each group, and all patients had supraventricular arrhythmias. The mean number of ventricular and supraventricular couplets and runs did not differ between groups. There was no difference in severity of arrhythmias between fallers and nonfallers; in fact, fallers had slightly fewer Lown 4B arrhythmias than nonfallers (10% vs 18%, NS). Prevalence of heart disease was 78% in both groups and was associated with increased ventricular ectopy in the form of runs and couplets (P less than .05). No symptoms were reported during the Holter monitoring. We conclude that Holter monitoring should not be a routine part of the work-up of the patient who falls.

Healing of necrobiotic ulcers with antiplatelet therapy. Correlation with plasma thromboxane levels.

Necrobiosis lipoidica in diabetics has been considered to be a cutaneous manifestation of diabetic microangiopathy. Seven diabetic patients with necrobiotic ulcers of recent onset that healed after administration of acetylsalicylic acid and dipyridamole had elevated thromboxane levels. Healing was associated with depression of the elevated thromboxane levels in all seven patients.

Beta-adrenoceptor antagonist-induced psoriasiform eruption. Clinical and pathogenetic aspects.

A number of beta-adrenoceptor blocking drugs have been reported to induce a papulosquamous eruption which resembles psoriasis. We report distinctive clinical, histopathologic, immunocytochemical, and electron microscopic features in beta-blocker-induced psoriasiform eruptions that differentiate this syndrome from psoriasis. Preliminary data suggest that biopsy specimens from eruptions caused by beta 1-selective adrenoceptor blocking agents (metoprolol and atenolol) were characterized by excessive degranulation of the neutrophils in the dermis, while the nonselective beta blockers (propranolol, nadolol, and sotalol) were marked by excessive release of proteolytic enzymes from macrophages, which are thought to possess beta 2-adrenergic receptors. Surprisingly, excessive release of enzymes by lymphocytes were noted in both the beta 1-selective and in the nonselective induced syndromes. It is believed that excessive lysosomal enzyme release by neutrophils, lymphocytes, and macrophages is responsible for the presence of basal keratinocyte herniations, which have previously been shown to correlate with hyperproliferation and psoriasiform changes, as well as with the presence of excessive proteolytic enzymes in the skin. It is postulated that the beta-blocker-induced syndrome may result from enhanced proliferation, motility, and activity of lymphocytes, neutrophils, and cells of the macrophage-Langerhans cell series, stemming from depressed intracellular cyclic adenosine monophosphate levels caused by the beta blockade.

Changes in left ventricular wall stress during isometric and isotonic exercise in healthy men.

Changes in left ventricular (LV) meridional and circumferential end-systolic wall stress during isometric and isotonic exercises were determined noninvasively in 12 healthy subjects using echocardiography and cuff blood pressure measurements. Isometric exercise was performed at 20 and 40% of maximal voluntary contraction using a handgrip dynamometer, and isotonic exercise was done on a cycle ergometer at 150 kpm/min increments every 3 minutes to a maximum of 600 kpm/min. Although the increase in systolic blood pressure was similar in both forms of exercise, LV systolic stress in the circumferential and meridional planes increased markedly during isometric exercise but decreased slightly during higher intensity isotonic exercise. Isometric exercise also produced a significant decrease in fractional shortening, whereas isotonic exercise significantly increased fractional shortening. Wall stress and fractional shortening were linearly and inversely related, but isometric and isotonic exercise produced divergent and significantly different linear regressions. In normal subjects isometric exercise produces a significant increase in LV afterload that leads to a decrease in LV global function. In contrast, isotonic exercise causes an increase in LV global function, most likely from an unchanged or slight decrease in afterload associated with increased LV contractility from greater catecholamine release.

Significance of T wave normalization in the electrocardiogram during exercise stress test.

Although normalization of previously inverted T waves in the ECG is not uncommon during exercise treadmill testing, the clinical significance of this finding is still unclear. This was investigated in 45 patients during thallium-201 exercise testing. Patients with secondary T wave abnormalities on the resting ECG and ischemic exercise ST segment depression were excluded. On the thallium-201 scans, the left ventricle was divided into anterior-septal and inferior-posterior segments; these were considered equivalent to T wave changes in leads V1 and V5, and aVF, respectively. A positive thallium-201 scan was found in 43 of 45 (95%) patients and in 49 of 52 (94%) cardiac segments that showed T wave normalization. When thallium scans and T wave changes were matched to sites of involvement, 76% of T wave normalization in lead aV, was associated with positive thallium scans in the inferior-posterior segments, and 77% of T wave normalization in V1 and V5 was associated with positive thallium scans in the anterior-septal segments. These site correlations were similar for reversible and fixed thallium defects, and for patients not on digoxin therapy. Similar correlations were noted for the sites of T wave changes and coronary artery lesions in 12 patients who had angiography. In patients with a high prevalence for coronary artery disease, exercise T wave normalization is highly specific for the presence of the disease. In addition, it represents predominantly either previous injury or exercise-induced ischemic changes over the site of ECG involvement, rather than reciprocal changes of the opposite ventricular wall.