Hair Shaft Abnormalities as a Dermoscopic Feature of Mycosis Fungoides: Pilot Results.

INTRODUCTION: Diagnosis of persistent erythematous, scaly patches, or plaques can be complex since psoriasis (Ps), eczematous dermatitis (ED), and mycosis fungoides (MF) can be considered. Dermoscopy, which is a noninvasive diagnostic tool, is commonly used to examine blood vessels, scales, and background color; however, research on hair shaft evaluation in inflammatory dermatoses remains scarce. The aim of the study was dermoscopic evaluation of hair shafts in skin lesions localized on the non-scalp skin areas in patients diagnosed with MF, Ps, and ED. METHODS: This was a retrospective evaluation of 55 patients diagnosed with MF, Ps, and ED. Photographic and dermoscopic documentation of these patients and detailed medical history were evaluated. RESULTS: A total of 21 patients with MF, 21 patients with Ps, and 13 patients with ED were evaluated. The examination revealed the presence of various abnormalities of hair shafts (e.g., numerous pili torti, single pili torti, 8-shaped hairs, pigtail hairs, broken hairs, hair shafts rapidly tapered over long sections, hair shafts irregular in thickness, angulated hairs, branched hairs, the presence of trichorrhexis nodosa, and monilethrix-like hairs), yellow dots, and black dots. The presence of pili torti was found in 80% of patients with MF, compared with 16% of patients with Ps and 8% of patients with ED (p < 0.005), with multiple pili torti found only in MF patients (67%) (p < 0.005). Statistically significant differences also applied to hair shafts rapidly tapering over long sections and 8-shaped hairs, which occurred only in MF patients (p < 0.005 and p = 0.035, respectively). CONCLUSIONS: The presence of hair shaft abnormalities such as numerous pili torti, 8-shaped hairs, and hair shafts rapidly tapering over long sections is an important criterion that should be considered in the dermoscopic differentiation of the patchy/plaque mycosis fungoides and inflammatory dermatoses, such as psoriasis and eczematous dermatitis localized on the non-scalp skin areas.

Dermoscopy as a Noninvasive Diagnostic Tool for Hailey-Hailey Disease and Darier Disease.

INTRODUCTION: Hailey-Hailey disease (HHD) and Darier disease (DD) are rare genetic disorders for which differential diagnosis, especially in less obvious cases, can be difficult. The diagnosis is based on the clinical picture and family history, and is confirmed by histopathologic examination. Dermoscopy is a noninvasive technique that is primarily used at the present time to diagnose skin cancers. However, in the past few years this technique has also been increasingly used as a noninvasive diagnostic tool of inflammatory skin diseases. The aim of the study was to evaluate whether dermoscopy is a useful noninvasive diagnostic tool for HHD and DD. METHODS: We performed an observational retrospective case series study involving 13 patients with HHD (n = 8) and DD (n = 5). The presence or absence of standardized dermoscopic features of inflammatory diseases (according to International Dermoscopy Society [IDS] guidelines) was assessed in these patients. RESULTS: The most distinctive feature of HHD was white clouds separated by pink furrows, visible in all cases (8/8; 100.0%). Another distinctive clue of HHD was the crumbled fabric pattern seen in six patients with HHD (6/8; 75.0%). These dermoscopic findings were not present in patients with DD. The most typical features of DD in the dermoscopic examination was star-like or oval-shaped yellow areas surrounded by whitish halo, visible in all patients (5/5; 100.0%). Another distinctive dermoscopic clue of DD was pinkish homogeneous structureless background, which was present in all patients (5/5, 100.0%). These latter two features were not observed in patients with HHD. CONCLUSION: Dermoscopy reveals distinctive features of HHD and DD, respectively. Therefore, we conclude that dermoscopy can be an excellent complementary noninvasive tool in the diagnostic process of patients with HHD and DD.

Hailey-Hailey disease and Darier disease are rare genetic disorders, which are diagnosed based on the clinical picture and confirmed with skin biopsy. Dermoscopy is noninvasive diagnostic tool, which enables skin visualization at a 10-fold magnification. Currently, dermoscopy is mainly used to diagnose skin cancers. In the recent years, dermoscopy has been also increasingly used as a noninvasive diagnostic tool of inflammatory skin diseases. The aim of the study was to assess whether demoscopy may be a useful tool in diagnosing Hailey-Hailey disease and Darier disease. The study included thirteen patients: eight with Hailey-Hailey disease and five with Darier disease. The most typical dermoscopic feature of Hailey-Hailey disease was white clouds separated by pink furrows, which were visible in all cases. Another distinctive clue was crumbled fabric pattern seen in 75.0% of patients with Hailey-Hailey disease. These dermoscopic findings were not present in patients with Darier disease. In dermoscopic examination the most typical feature of Darier disease was star-like or oval-shaped yellow areas surrounded by whitish halo, visible in all patients. Also, pinkish homogeneous structureless background was present in all patients with Darier disease. These features were not observed in patients with Hailey-Hailey disease. Dermoscopy reveals characteristic features of Hailey-Hailey disease and Darier disease. Therefore, it can be an excellent complementary tool in the diagnostic process of patients with those diseases.

Cutaneous T-cell lymphoma in erythrodermic cases may be suspected on the basis of scalp examination with dermoscopy.

Erythrodermic variants of cutaneous T-cell lymphoma (CTLC) are one of the case of erythroderma. The aim of the study was to assess the value of scalp dermoscopy in differentiation between erythrodermic CTCL, psoriasis, and atopic dermatitis. A total of 76 patients were included into the study (16 patients with erythrodermic CTCL, 20 patients with psoriatic erythroderma, 20 with erythrodermic atopic dermatitis, and 20 healthy volunteers). The most common trichoscopic features of erythrodermic CTCL were: numerous pili torti, numerous broken hairs, white thick interfollicular bands, and patchy hyperpigmentation of the background. They were observed in 81% (13/16), 75% (12/16), 56% (9/16), and 37.5% (6/16) of patients with CTCL, respectively (p < 0.001). Other specific features of erythrodermic CTCL were 8-shaped hairs (19%; 3/16) and visible anagen bulbs (12.5%; 2/16) (p < 0.05 and p = 0.052, respectively). The most common vascular pattern of erythrodermic CTCL was perifollicular arrangement of glomerular (50%; 8/16; p < 0.001) or linear vessels (31%; 5/16; p < 0.05). Follicular spicules-like scaling was pathognomonic for erythrodermic CTCL (12%, 2/16) although its presence did not reach statistical significance (p = 0.052). In conclusion, the characteristic trichoscopic findings of erythrodermic CTCL are numerous pili torti, eight-shaped hairs, thick white interfollicular bands, color heterogeneity of the background and perifollicular arrangement of vessels.

miR-132 Regulates Dendritic Spine Structure by Direct Targeting of Matrix Metalloproteinase 9 mRNA.

Mir-132 is a neuronal activity-regulated microRNA that controls the morphology of dendritic spines and neuronal transmission. Similar activities have recently been attributed to matrix metalloproteinase-9 (MMP-9), an extrasynaptic protease. In the present study, we provide evidence that miR-132 directly regulates MMP-9 mRNA in neurons to modulate synaptic plasticity. With the use of luciferase reporter system, we show that miR-132 binds to the 3'UTR of MMP-9 mRNA to regulate its expression in neurons. The overexpression of miR-132 in neurons reduces the level of endogenous MMP-9 protein secretion. In synaptoneurosomes, metabotropic glutamate receptor (mGluR)-induced signaling stimulates the dissociation of miR-132 from polyribosomal fractions and shifts it towards the messenger ribonucleoprotein (mRNP)-containing fraction. Furthermore, we demonstrate that the overexpression of miR-132 in the cultured hippocampal neurons from Fmr1 KO mice that have increased synaptic MMP-9 level provokes enlargement of the dendritic spine heads, a process previously implicated in enhanced synaptic plasticity. We propose that activity-dependent miR-132 regulates structural plasticity of dendritic spines through matrix metalloproteinase 9.

Concomitant administration of simvastatin with ivabradine in contrast to metoprolol intensifies slowing of heart rate in normo- and hypercholesterolemic rats.

INTRODUCTION: ß-Blockers play a significant role in therapeutic heart rate (HR) management and angina control. In patients who are unable to tolerate ß-blockers ivabradine could be particularly useful. The aim of the study was to establish whether concomitant administration of simvastatin with ivabradine or metoprolol had any effect on rat HR and blood pressure (BP). MATERIAL AND METHODS: The experiments were performed in hyper- and normocholesterolemic outbred Wistar rats. Animals were divided into 2 groups: receiving during 4 weeks normal diet (normocholesterolemic rats) or diet with 5% cholesterol and 2.5% cholic acid (hypercholesterolemic rats). Then rats received placebo (0.1% methylcellulose), 2) metoprolol 30 mg/kg bw; 3) ivabradine 10 mg/kg bw; 4) simvastatin 10 mg/kg bw; 5) simvastatin 10 mg/kg bw + metoprolol 30 mg/kg bw; 6) simvastatin 10 mg/kg bw + ivabradine 10 mg/kg bw. Drugs were given during a 4-week period. HR and BP measure were provided by an Isotec pressure transducer connected to a direct current bridge amplifier. For the further lipid profile examination, 0.25 ml of blood samples were taken. RESULTS: After administration of ivabradine with simvastatin to normocholesterolemic and hypercholesterolemic rats the mean HR was significantly reduced as compared to rats receiving simvastatin (312.0 ±30.2 min(-1) vs. 430.7 ±27.8 min(-1), p<0.05); (329.8 ±24.2 min(-1) vs. 420.5 ±9.2 min(-1), p<0.05) or ivabradine alone (312.0 ±30.2 min(-1) vs. 350.2 ±16.0 min(-1), p<0.05); (329.8 ±24.2 min(-1) vs. 363.0 ±21.7 min(-1), p<0.05). CONCLUSIONS: Concomitant administration of simvastatin with ivabradine intensified slowing of HR, although it did not influence BP in normo-and hypercholesterolemic rats. Statin-induced intensification of HR deceleration after metoprolol administration was not observed.

Effects of 4-week administration of simvastatin in different doses on heart rate and blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.

INTRODUCTION: Statins and ß1-adrenergic antagonists are well established in cardiovascular events therapy and prevention. The previous study showed that statins might impact on ß-adrenergic signalling and blood pressure in a dose-dependent manner. The aim of the study was to evaluate the impact of 4-week administration of simvastatin given at different doses on the heart rate and blood pressure after injection of metoprolol in rats. MATERIAL AND METHODS: The experiments were performed in normocholesterolaemic and normotensive Wistar rats. Rats received simvastatin in doses of 1, 10 and 20 mg/kg body weight (bw) for 4 weeks. The control group received 0.2% methylcellulose. For the further estimation of the heart rate and blood pressure, metoprolol at 5 mg/kg bw or 0.9% NaCl was injected intraperitoneally. RESULTS: Simvastatin at doses of 1, 10 and 20 mg/kg bw did not influence the heart rate or blood pressure as compared to the control group. Metoprolol injection statistically significantly decreased the heart rate (439.29±14.03 min(-1) vs. 374.41±13.32 min(-1); p<0.05). In rats receiving simvastatin during the 4-week period after metoprolol injection, heart rate and blood pressure (mean, systolic, diastolic) were similar as compared to the group receiving metoprolol alone. CONCLUSIONS: Simvastatin administration during a 4-week period in different doses did not influence the heart rate or blood pressure after metoprolol injection in normocholesterolaemic and normotensive rats.

The influence of high-dose simvastatin and diltiazem on myocardium in rabbits: a haemodynamic study.

INTRODUCTION: Simvastatin and diltiazem are often prescribed together for the treatment of hypercholesterolaemia in patients with hypertension and/or angina pectoris. However, diltiazem, a CYP3A inhibitor, is a well-recognized risk factor of skeletal muscle myopathy. It is not known whether such interaction also affects myocardial efficiency causing haemodynamic changes. The aim of the experiment was to establish the impact of simvastatin co-administered with diltiazem on the haemodynamic parameters after continuous infusion of dopamine. MATERIAL AND METHODS: The experiments were performed on 28 New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC - methylcellulose (control group); diltiazem; simvastatin; simvastatin + diltiazem, for 14 days (po). The following haemodynamic parameters were estimated: cardiac output index (CI), heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP) and total peripheral resistance index (TPRI). The registration of haemodynamic parameters was performed by the Doppler method and during the experiments the animals were anaesthetized with α-chloralose (75 mg/kg bw) and urethane (500 mg/kg bw). RESULTS: Dopamine did not cause a statistically significant increase in CI in rabbits receiving simvastatin alone. Diltiazem significantly increased CI if given simultaneously with simvastatin, which might suggest the improvement of cardiac efficiency resulting from such interaction. CONCLUSIONS: The possibility of another mechanism of drug-drug interaction than the one based on CYP3A inhibition, and its impact on cardiac or skeletal muscle, might be considered.

Stability studies of expired tablets of metoprolol tartrate and propranolol hydrochloride. Part 1. Content determination.

In recent years the growing interest in drug stability problem has been observed. The stability of pharmaceutical products seems to play an important role from the economical point of view. However, there are not many studies that reported about the stability of drugs past their expiration dates. The objective of the current study was to determine tablet content of expired tablets and tablets with expiry date has not been exceeded. The analyzed tablets contained metoprolol tartrate (50 mg) and propranolol hydrochloride (10 mg), respectively. Content determination was performed using HPLC method with UV detection. The proposed method was validated with regard to linearity, sensitivity, intermediate accuracy and precision. No discrepancies between the results of determination and the declared values range for all the analyzed tablets were observed. The results of performed study might suggest that storage of analyzed batches of tablets over time period exceeding the expiry date given by the manufacturer did not influence their contents.

Stability studies of expired tablets of metoprolol tartrate and propranolol hydrochloride. Part 2. Dissolution study.

The objective of the current study was to determine tablet content and perform dissolution test of expired tablets and tablets which expiry date has not exceeded. The analyzed tablets contained metoprolol tartrate (50 mg) and propranolol hydrochloride (10 mg), respectively. Content determination was performed using spectrophotometric method with UV detection; the percent of dissolved substance from tablets during dissolution test was performed using spectrophotometric method, as well. The proposed methods were validated with regard to linearity, sensitivity, and intermediate accuracy and precision. No discrepancies between the results of determination and the declared values range for all the analyzed tablets were observed. The results of performed study might suggest that the storage of analyzed batches of tablets over time period exceeding the expiry date given by the manufacturer did not influence their contents.

Dose-dependent influence of two-week administration of simvastatin and metoprolol injection on the blood pressure in normocholesterolemic rats.

UNLABELLED: Beta-blockers are widely used in clinical practice. It is connected with their multiple cardiac effects: slowing heart rate, decrease of myocardial contractility and lowering of systemic blood pressure. Early use of beta-blocker in acute myocardial infarction reduces the risks of reinfarction and ventricular fibrillation. However, the above effects may be associated with the risk of cardiogenic shock. Many patients with cardiovascular diseases receiving beta-blockers are recommended to statin therapy, as well. There are several reports indicating that statins have beneficial cardiovascular effects through their broad spectrum of cholesterol-independent action. It has been revealed that statins could decrease blood pressure, as well. The aim of the study was to evaluate the influence of simvastatin in different doses and metoprolol injection on the blood pressure in normocholesterolemic rats. The experiments were performed on Wistar rats, outbred males. Simvastatin at 1, 10 and 20 mg/kg or vehicle (0.2% methylcellulose) were given intragastrically during two-week period. After two week simvastatin administration, rats were injected intraperitoneally with metoprolol at 5 mg/kg b. w. The arterial blood pressure signals were provided by Isotec pressure transducer connected to a direct current bridge amplifier and catheter was implanted into the right carotid artery. CONCLUSION: Two week administration of simvastatin in different doses to normocholesterolaemic rats does not modify metoprolol impact on the blood pressure.

Interaction between different doses of simvastatin after two-week administration and metoprolol injection on the heart rate in normocholesterolemic rats.

UNLABELLED: Heart rate slowing is the beneficial effect after beta-blocker administration in cardiac heart failure and ischemic heart disease. However, bradycardia and another cardiac disturbances after beta-blockers therapy are the most dangerous side effects. Many patients with cardiovascular diseases receiving beta-blockers are recommended to statin therapy, as well. Previous study showed that statins may desensitize beta-adrenergic signaling, in cardiac myocytes via reduction of isoprenylation of G-protein gamma-subunits. The aim of the study was to evaluate the influence of simvastatin at different doses and metoprolol injection on the heart rate in normocholesterolemic rats. The experiments were performed in Wistar rats, outbred males. Simvastatin at 1, 10 or 20 mg/kg or vehicle (0.2% methylcellulose) were given intragastrically during two-week period. After two week administration of simvastatin, rats were injected intraperitoneally with metoprolol at 5 mg/kg b.w. The heart rate signals were provided by Isotec pressure transducer connected to a direct current bridge amplifier and catheter was implanted into the right carotid artery. No changes in the baseline heart rate among all groups of the animals were observed. Metoprolol administration caused statistically significant decrease in heart rate in all groups of rats. In the control group, after metoprolol administration heart rate slowed down to 83.11 +/- 1.11% (p < 0.05) of the baseline values, in group receiving simvastatin at 1 mg/kg b.w. 82.72 +/- 5.49% (p < 0.05), in group receiving simvastatin at 10 mg/kg b.w. 85.13 +/- 4.75 (p <0.05) and in group receiving simvastatin at 20 mg/kg b.w. 85.13 +/- 4,75% (p < 0.05) of the baseline values. No significant decrease in heart rate in the control group as compared to groups receiving simvastatin in different doses was observed. No significant changes among animals receiving simvastatin in different doses were observed, as well. CONCLUSION: Two week administration of simvastatin in different doses to normocholesterolaemic rats does not modify metoprolol-induced depressing influence on the heart rate.

Statins: a new insight into their mechanisms of action and consequent pleiotropic effects.

In the recent years, 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitors have emerged as the most important class of lipid-lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis resulting in up-regulation of low density lipoproteins (LDL) receptors on the cell membrane and reduction of atherogenic LDL consequences. The wide spectrum of non-lipid-mediated pleiotropic effects of statins includes: improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant effects, anti-inflammatory and immunomodulatory properties, stabilization of atherosclerotic plaques and inhibition of cardiac hypertrophy. Several clinical trials have demonstrated and confirmed these beneficial effects of statins in cardiovascular disorders, in primary and secondary prevention settings. Recent studies have reported that the physiological background of the widespread therapeutic efficacy of HMG-CoAreductase inhibitors involved various mechanisms, partially associated with statin impact on posttranslational modifications (e.g. prenylation process). In this review, we have focused on some of them, especially including the statin impact on the endothelial dysfunction and inflammation, peroxisome poliferator-activated receptor (PPAR), beta-adrenergic signaling, renin-angiotensin system and their possible mutual mechanistic linkage.

Influence of simvastatin at high dose and nifedipine on hemodynamic parameters in rabbits.

Recent findings in vitro have shown that statins could reduce cardiomyocyte viability. The correlation between statin cardiotoxicity, assessed in vitro, and cardiac efficiency, investigated in vivo has not been estimated so far. The aim of the present experiment was to establish the impact of high-dose simvastatin on the hemodynamic parameters, especially on myocardium efficiency, after continuous infusion of dopamine. Moreover, hemodynamic interaction between simvastatin and nifedipine, metabolized by the same izoenzyme CYP3A4 was examined. The experiments were performed on twenty seven New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% methylcellulose (MC) (control group), nifedipine, simvastatin or simvastatin + nifedipine, for 14 days (p.o.). The following hemodynamic parameters were estimated: cardiac output index (COI), heart rate (HR), systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP) and total peripheral resistance index (TPRI). The registration of hemodynamic parameters was performed by Doppler method (Hugo Sachs Electronic Haemodyn). Dopamine did not cause a statistically significant increase in COI in rabbits receiving simvastatin alone or concomitantly with nifedipine. Nifedipine significantly lowered COI, BP and HR in rabbits if given simultaneously with simvastatin. In conclusion, administration of nifedipine may elicit detrimental impact on statin therapy, resulting in the worsening of cardiac performance. This may suggest another mechanism of drug-drug interaction than the one based on CYP3A4 inhibition.

The influence of simvastatin at high dose and diltiazem on myocardium in rabbits, the biochemical study.

3-Hydroxy-3-methyl-glytaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") have been proved to be extremely useful in the management of hypercholesterolemia, as well as in prevention of primary and secondary coronary heart disease. However, they may produce rare but severe muscle-related symptoms such as myopathy and rhabdomyolysis. Recent findings in vitro have shown that statins can reduce cardiomyocyte viability. The exact mechanism of statin myotoxicity still remains unclear. Diltiazem as CYP3A4 inhibitor, is a well recognized risk factor of skeletal muscles myopathy, if co-administered with simvastatin. It is not known whether such interaction affects myocardial efficiency causing biochemical changes. The experiments were performed on thirty six New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC (control group): diltiazem (5 mg/kg); simvastatin (50 mg/kg) or diltiazem + simvastatin, daily for 14 days (po). The following biochemical parameters were estimated: creatine kinase (CK), serum transaminases (ALT and AST), as well as myocardial injury markers: troponin I (Tnl) and creatine kinase MB (CK-MB). Simultaneous administration of simvastatin and diltiazem caused 23-fold increase (p < 0.01), in rabbit serum CK levels and 20-fold increase (p = 0.056) in TnI levels, as compared to the initial values. Also in these rabbits significant increase in CK (12411,60 vs 839.87 IU/L) and TnI (0,26 vs 0,014 ng/mL), as compared to control group were observed. Significant increase in CK (12411,60 vs 1100,92 IU/L) and TnI (0,26 vs 0,012 ng/mL), as compared to diltiazem alone were noted, too. This may suggest another mechanism of drug-drug interaction than the one based on CYP3A4 inhibition if the impact on cardiac or skeletal muscle is considered.

Drug-induced myopathies. An overview of the possible mechanisms.

Myopathy is usually a non-fatal muscle disease involving skeletal muscle weakness, tenderness and pain with the possibility of the plasma creatinine kinase elevation. There are many different types of myopathies, some of which are genetic, inflammatory, or related to endocrine dysfunction. Also, numerous drugs have been reported to possess myotoxic effect. Myopathy is included among the potential side-effects and toxicities associated with the lipid lowering agents, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. However, the precise mechanism of statin-induced muscle toxicity remains unclear. The muscle-related side-effects reported with lipid-lowering drugs are significant but quite rare (0.1%), when used in monotherapy; while the incidence of steroid-induced myopathy has varied from 7 to 60%% and chronic alcoholic myopathy seems to be common complication of alcoholism affecting approximately 50% of patients, respectively. This review focuses on the differential pathophysiological grounds of these muscular injuries induced by statins, fibrates, as well as some other agents: corticosteroids or alcohol. A wide spectrum of possible mechanisms and hypotheses including muscle enzyme defects, changes in mitochondrial function and intracellular metabolism, the influence on the cell membrane stability and drug interactions involving P-glycoprotein or cytochrome P 450 system have been presented.