Retinoids in the treatment of photoageing: A histological study of topical retinoid efficacy in black skin.

BACKGROUND: Photoageing describes complex cutaneous changes that occur due to chronic exposure to solar ultraviolet radiation (UVR). The 'gold standard' for the treatment of photoaged white skin is all-trans retinoic acid (ATRA); however, cosmetic retinol (ROL) has also proven efficacious. Recent work has identified that black skin is susceptible to photoageing, characterized by disintegration of fibrillin-rich microfibrils (FRMs) at the dermal-epidermal junction (DEJ). However, the impact of topical retinoids for repair of black skin has not been well investigated. OBJECTIVES: To determine the potential of retinoids to repair photoaged black skin. METHODS: An exploratory intervention study was performed using an in vivo, short-term patch test protocol. Healthy but photoaged black volunteers (>45 years) were recruited to the study, and participant extensor forearms were occluded with either 0.025% ATRA (n = 6; 4-day application due to irritancy) or ROL (12-day treatment protocol for a cosmetic) at concentrations of 0.3% (n = 6) or 1% (n = 6). Punch biopsies from occluded but untreated control sites and retinoid-treated sites were processed for histological analyses of epidermal characteristics, melanin distribution and dermal remodelling. RESULTS: Treatment with ATRA and ROL induced significant acanthosis (all p < 0.001) accompanied by a significant increase in keratinocyte proliferation (Ki67; all p < 0.01), dispersal of epidermal melanin and restoration of the FRMs at the DEJ (all p < 0.01), compared to untreated control. CONCLUSIONS: This study confirms that topical ATRA has utility for the repair of photoaged black skin and that ROL induces comparable effects on epidermal and dermal remodelling, albeit over a longer timeframe. The effects of topical retinoids on black photoaged skin are similar to those reported for white photoaged skin and suggest conserved biology in relation to repair of UVR-induced damage. Further investigation of topical retinoid efficacy in daily use is warranted for black skin.

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors.

Background: Based on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor. Patients and methods: We used a previously published next generation sequencing dataset of 21 matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also carried out the myChoice HRD analysis on an independent cohort of 17 breast cancer patients with matched primary/brain metastasis pairs. Results: All of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort, the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria. Conclusions: The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.

Comparison of immunophenotypes of primary breast carcinomas and multiple corresponding distant metastases: an autopsy study of 25 patients.

Phenotypical change in metastatic breast carcinoma has widely been accepted as an inherent biological feature rather than technical fault. We analyzed the immunohistochemical phenotype and histopathological features of 25 primary breast carcinomas and 90 corresponding distant metastases in 23 organs retrospectively. Histological slides were reviewed for prognostic and predictive factors. Overall, metastases were more similar to each other and often differed from the primary tumor. We created a 3-step grouping system based on the localization of metastases. Regions: tumors metastasizing to the abdominal region were likely to lose ER (p = 0.002); we detected loss of PR in metastases to the thorax (p = 0.039) and abdomen (p < 0.001). Organ systems: loss of ER and PR was observed in metastases to the gastrointestinal system (p = 0.026 and p = 0.001, respectively), in the respiratory system only the loss of PR was significant (p = 0.05). Individual organs: the primaries were likely to lose the hormone receptors in liver metastases (ER p = 0.026; PR p = 0.004). In lung metastases only loss of PR was apparent (p = 0.049). We did not observe significant change in HER2 status, regarding Ki67 change occurred only in bone metastases compared to the primary (p = 0.048). 7/25 patients' distant metastases had heterogeneous immunoprofiles. The later the metastasis was discovered the more likely it had a differing IHC profile compared to the primary tumor, patients who had longer OS had a higher chance to develop a discordant metastasis. Immunoprofile of metastases may differ from primary breast cancer and from each other, probably resulting in different response to therapy.

Shortening the second phase duration of biphasic shocks: effects of class III antiarrhythmic drugs on defibrillation efficacy in humans.

INTRODUCTION: The specific waveform providing optimal defibrillation threshold (DFT) is unknown. We compared the defibrillation efficacy of biphasic pulses with second phases (P2) of 2 and 5 msec in a randomized prospective clinical study. METHODS AND RESULTS: Intraoperative DFTs of 62 patients (age 54 +/- 13 years; ejection fraction 43% +/- 17%; amiodarone 47%, d,l-sotalol 13%) were determined in random order using a binary search protocol. Anodal shocks of 60% tilt first phases (P1) and P2 of 2 msec/5 msec were delivered from two 100-microF capacitors between the right ventricular electrode and the test housing of a Phylax 06/XM device. Mean DFT was significantly lower using the shorter P2 (9.5 +/- 4.5 J vs 11.3 +/- 5.2 J; P < 0.0001). According to subgroup analysis, the effect of changing P2 duration was only influenced by antiarrhythmic treatment. DFT decreased markedly using the shorter P2 in patients treated with amiodarone (10.7 +/- 4.9 J vs 13.4 +/- 5.6 J; P < 0.00001) or d,l-sotalol (6.1 +/- 3.3 J vs 9.1 +/- 4.6 J; P < 0.05). The difference in patients not treated with Class III drugs was found to be insignificant. Chronic amiodarone treatment increased DFT only when the longer P2 was used. CONCLUSION: Biphasic shocks with shorter P2 should be used in patients undergoing Class III antiarrhythmic treatment.

Fundamental electrophysiological differences between low-dose intracoronary endothelin-1 infusion and myocardial ischemia revealed by multiple monophasic action potential recording.

The supposed direct arrhythmogenic property of endothelin-1 (ET-1) has not yet been clearly proven. Our study aimed to characterize the electrophysiological changes during left anterior descending artery (LAD) occlusion and intracoronary (i.c.) ET-1 infusion, and to differentiate between the supposed direct and ischemic arrhythmogenic actions of ET-1 in a canine model. Changes of monophasic action potential duration (MAPD90) and upstroke velocity (UV) are capable of detecting local ischemic changes. Left and right ventricular endo- (LVEND, RVEND) and epicardial (LVEP, RVEP) monophasic action potentials were recorded. MAPD90, monophasic action potential dispersion (MAPDISP) and UV were determined. In group A (n = 8) 30 min LAD occlusion was followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into the LAD at rates of 30 (n = 8) and 60 pmol/min (n = 10), respectively. In group A after the LAD occlusion both MAPD90 and UV decreased significantly in the LAD region (LVEP and LVEND 18 +/- 3% and 10 +/- 1%, p < 0.05, and 65 +/- 4% and 52 +/- 8%, respectively, p < 0.05; control and 30 min values in all groups), whereas the increase in MAPDISP remained unchanged. No severe arrhythmias were noticed in this group. In group B, both MAPD90 and MAPDISP increased significantly (LVEP and LVEND 11 +/- 4% and 18 +/- 3%, p < 0.05; MAPDISP 200 +/- 40%, p < 0.05), whereas UV remained unchanged at the end of the infusion. Early afterdepolarizations (EADs) were present in three instances. In group C both MAPD90 and MAPDISP increased significantly (LVEP and LVEND 12 +/- 5% and 26 +/- 8%, respectively, p < 0.05; MAPDISP 215 +/- 30%, p < 0.05) and UV decreased slightly in the LAD region. EADs were observed in five instances. Severe arrhythmias were observed in both groups B and C. We concluded that MAP prolongation, increased MAP dispersion and development of EADs all contribute to the arrhythmogenic action of ET-1. The lack of the almost prompt decrease of UV and MAPD90 which was observed in group A in groups B and C strongly supports the probability of a direct arrhythmogenic effect of ET-1.

The selective endothelin-A-receptor antagonist LU 135.252 inhibits the direct arrhythmogenic action of endothelin-1.

Besides being a strong vasoconstrictor, endothelin-1 (ET-1) also causes severe ventricular arrhythmias. The aim of our study was to differentiate between the vasoconstrictor and arrhythmogenic actions of ET-1 by using the selective endothelin-A-(ETA) receptor antagonist LU 135.252 (LU). A bolus injection of 5 mg/kg LU was administered to 10 anesthetized mongrel dogs in group A. The 30 min intracoronary ET-1 infusion was started 20 min after the LU bolus at a rate of 60 pmol/min. In the control group (group B, n = 8) only ET-1 was administered (60 pmol/min). The left anterior descending coronary artery blood flow (CBF), cardiac output, electrocardiograph (ECG) and arterial blood pressure were monitored. Two monophasic action potential duration (MAPD) catheters were placed onto the left ventricular epicardium (LVEP) and into the right ventricular endocardium (RVEND) to follow electrophysiologic changes. No significant changes were observed in blood pressure (0 min vs 30 min: group A, 99.0 +/- 4.5 vs 90.0 +/- 5.2 mmHg, p = NS; group B, 103 +/- 6 vs 104 +/- 3 mmHg, p = NS), cardiac output (0 min vs 30 min: group A, 3.5 +/- 0.7 vs 3.2 +/- 0.8 l/min, p = NS; group B, 3.6 +/- 0.4 vs 3.3 +/- 0.3 l/min, p = NS), and MAPD90 (0 min vs 30 min: group A, LVEP, 241 +/- 11 vs 260 +/- 14 ms; RVEND, 233 +/- 5 vs 239 +/- 8 ms, p = NS), whereas a significant decrease was observed in CBF (deltaCBF 30 min: group A, -28 +/- 2%, p < 0.05; group B, -32 +/- 3%, p < 0.05). In group A ventricular fibrillation (VF) occurred once. Ventricular premature contractions (VPCs) and short, nonsustained ventricular tachycardias (nsVTs) were observed in seven cases. Early after depolarizations and a MAPD90 increase were observed in the control group B (0 min vs 30 min: LVEP, 244 +/- 10 vs 292 +/- 12 ms; RVEND, 255 +/- 9 vs 290 +/- 8 ms) accompanied by VPCs, incessant nsVTs. Sustained VT and VF were evident in seven cases. Our results indicate, that the applied single bolus injection of LU effectively prevents ET-1-induced major ventricular arrhythmias, whereas it has no effect on coronary vasoconstriction. These data support the notion that ET-1 possesses a direct arrhythmogenic action.

Endothelin-A-receptor antagonist LU 135.252 inhibits the formation of ventricular arrhythmias caused by intrapericardial infusion of endothelin-1.

Intrapericardial endothelin-1 (ET-1) infusion causes dose-dependent severe ventricular arrhythmias. We examined the effects of the endothelin-A- (ETA) receptor antagonist LU 135.252 (LU) on ET-1-induced arrhythmias on six open-chest mongrel dogs. Ten minutes after an intravenous bolus of LU (5 mg/kg), ET- 1 (33 pmol/kg/min) was given into the pericardial space for 30 min (LU group). Six dogs received ET-1 infusion without LU treatment (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right ventricular endocardial and epicardial (RVEND, RVEP), and left ventricular endocardial and epicardial (LVEND, LVEP) monophasic action potential durations (MAPDs) were recorded. No significant changes were observed in MAP and cardiac output. MAPD90s did not change significantly in the LU group (basic vs ET 20min: RVEP, 186 +/-7 vs 190 +/- 7; LVEP, 189 +/- 8 vs 201 +/- 11; RVEND, 191 +/- 10 vs 192 +/- 9; LVEND, 199 +/- 11 vs 203 +/- 11 ms), while significant MAPD90 prolongation was found in all investigated regions of the control group (ET start vs ET 20 min: LVEP, 174 +/- 3 vs 208 +/- 10*; RVEND, 206 +/- 9 vs 241 +/- 12* ms, *p < 0.05). No early after depolarization (EAD) was observed in the LU group, while EADs occurred in three controls. In the LU group, we have not found any significant arrhythmias except nonsustained ventricular tachycardias (nsVTs) in one animal. In the control group incessant nsVTs were observed in six, sustained VTs (sVTs) in four and ventricular fibrillation (VF) in two instances. Significant ST-elevation was observed in all animals in the LU and control groups (LU: 6.7 +/- 2.1 mV; control: 10.1 +/- 2.0 mV, p = NS). In conclusion, the arrhythmogenic action and the main electrophysiological effects of pericardial ET-1 infusion, MAPD prolongation and EAD formation, are inhibited by LU. However, LU could not prevent the ischemic changes resulting from ET-1 infusion.

Bosentan the mixed endothelin-A- and -B-receptor antagonist suppresses intrapericardial endothelin-1-induced ventricular arrhythmias.

In earlier studies severe ventricular arrhythmias developed during intrapericardial (i.p.) endothelin-1 (ET-1) infusion. Monophasic action potential duration (MAPD90) increase and significant ST segment elevation preceded the onset of arrhythmias. The aim of this study was to test the antiarrhythmic and anti-ischemic efficacy of the mixed endothelin-A- and -B- (ETA/B) receptor antagonist bosentan (BOS) on ET-1-induced arrhythmias on six mongrel dogs. Ten minutes after an intravenous bolus dose of BOS (10 mg/kg), ET-1 (33 pmol/kg/min) was given into the pericardial space for 30min (BOS group). Six control dogs received only ET-1 infusion (control group). Mean arterial blood pressure (MAP), cardiac output, electrocardiograph (ECG), right and left ventricular endo- and epicardial (RVEND, RVEP, LVEND, LVEP) MAPD90s were recorded. MAP and cardiac output did not change significantly in the BOS group. Significant MAPD90 prolongation was found in all investigated regions of the control group (ET start vs ET 20 min: LVEP, 174 +/- 3 vs 208 +/- 10*; RVEND, 206 +/- 9 vs 241 +/- 12* ms, *p < 0.05), while significant MAPD90 alterations were not observed in the BOS group (basic vs ET 20 min: RVEP, 189 +/- 5 vs 196 +/- 5; LVEP, 199 +/- 5 vs 199 +/- 4; RVEND, 194 +/- 5 vs 195 +/- 6; LVEND, 209 +/- 3 vs 213 +/- 5 ms). Early after depolarizations (EADs) were observed in three control dogs. Severe ventricular arrhythmias [incessant nonsustained ventricular tachycardias (nsVTs) in all cases, sustained VTs (sVTs) in four, ventricular fibrillation (VF) in two instances] were present in the control group, whereas nsVTs were observed only in two dogs in the BOS group. ST segment elevation was more pronounced in the control group than in the BOS group (1.01 +/- 0.2 vs 0.41 +/- 0.07 mV, p < 0.05). In summary, bosentan effectively inhibits intrapericardial ET- 1-induced ventricular arrhythmias, moreover it may have a protective effect against epimyocardial ischemia.

Increased monophasic action potential dispersion in endothelin-1-induced ventricular arrhythmias.

The aim of this study was to investigate the changes in monophasic action potentials (MAP) from different sites in the heart and to determine MAP dispersion during endothelin-1 (ET-1) infusion. Standard ECG, left ventricular anterior, right ventricular lateral, right ventricular septal, and right ventricular apical MAPs and intra-arterial blood pressure were monitored in seven anesthetized open-chest mongrel dogs. After radiofrequency atrioventricular node ablation, ventricular pacing (70/min) was performed and intracoronary ET-1 (60 pmol/min) was administered into the left anterior descending coronary artery. Both MAPd90 and MAPd90 dispersion increased significant during ET-1 infusion. The onset of spontaneous monomorphic and polymorphic sustained ventricular tachycardias (sVT) was observed in five dogs (around 40 min), and nonsustained VTs (nsVT) developed in another two dogs. The increases in MAP and MAP dispersion lasted until the appearance of polymorphic nsVTs and sVTs, but at the time of these VTs this difference decreased. At the termination of the experiments, ventricular fibrillation occurred in six cases. In four cases third-phase early afterdepolarizations were recorded. Our results suggest that increased MAP dispersion and development of EAD contribute to the arrhythmogenic action of ET-1, and these phenomena might explain the pathogenesis of a wide variety of ventricular arrhythmias with different morphology observed in this study.

Mechanism of endothelin-induced malignant ventricular arrhythmias in dogs.

The development of ventricular tachyarrhythmias caused by low-dose intracoronary infusion of endothelin-1 (ET-1) has recently been observed in dogs. The aim of the present study was to investigate the pathomechanism of ET-1-induced ventricular arrhythmias in 32 anesthetized, open-chest mongrel dogs in group A (n = 14) without, in group B (n = 14), and in group C (n = 4 control) with atrioventricular node ablation. The coronary blood flow (CBF) was measured in the left anterior descending (LAD) coronary artery by an electromagnetic flowmeter. Standard ECG, atrial and ventricular electrograms, and in groups B and C endocardial and epicardial monophasic action potentials (MAPs) were recorded. ET-1 was administered into the LAD at a low dose (30-60 pmol/min). At the time of the appearance of premature beats, CBF was only slightly decreased. The effective ventricular refractory period did not change significantly. Onset of spontaneous polymorphic and monomorphic sustained ventricular tachycardia (sVT) was observed in five dogs without bradycardia and in nine dogs with bradycardia. VTs in dogs with complete AV block were longer and slower. In most of the cases, ventricular fibrillation occurred. ET-1 treatment resulted in a significant increase in MAP 90% duration (255 +/- 9 vs. 290 +/- 8 ms endocardial, 244 +/- 10 vs. 292 +/- 12 epicardial; p < 0.05) at 70 beats/min ventricular pacing. In eight cases (group B), third-phase early afterdepolarization could be recorded. According to our results, the mechanism of ET-1-induced arrhythmias appears to be based on prolongation of MAP duration and development of afterdepolarizations.

Optimizing the geometry of implantable leads for recording the monophasic action potential with fractally coated electrodes.

This study investigates the influence of various lead geometry on intracardial signals like the monophasic action potential (MAP) to optimize the geometry of implantable MAP leads. The experimental results were compared with a field theoretical approach to the origin of MAP from the transmembrane potential (TAP). During the experiments several lead geometries (tip surface: 1.3 to 12 mm2; tip-ring distance: 0.8 mm to 25 cm; ring surface: 1.8 mm2 to 40 mm2) were investigated in endo- and epicardial positions in 12 dogs (17 +/- 9 kg). The electrodes were fixed passively (tines) or actively (screws). MAP was recorded during several interventions and correlated with MAP measured using an Ag-AgCl MAP catheter. The experimental results showed that small tips provided high MAP amplitudes with less pressure. No difference was observed using active and passive fixations. A tip-ring distance smaller than 5 mm with a ring surface smaller than the tip (< 5 mm2) avoided artifacts in the repolarization course. For the theoretical approach the quasistatic, anisotropic bidomain model was calculated in small unity volumes Vi where the TAP phi mi was constant and represented by the current density Ji. Two solutions for electrode positions at and outside the heart were achieved. By superposition of each solution phi ei the summed potential at the electrode position was calculated. The theoretical findings show in good correlation with the experimental results that a larger distance than 10 mm leads to distortions in repolarization course by signals proportional to phi out.

Simultaneous recordings of the monophasic action potential with silver chloride- and Ir-coated electrodes.

Ag/AgCl and Ir-coated electrodes allow the recording of the monophasic action potential (MAP) due to their electrical properties like non-polarisability. This study investigates the correlation of MAP recorded with both types of electrodes. In 20 mongrel dogs (18 +/- 6 kg) an Ag/AgCl and an Ir-coated catheter (Ir) were placed endocardially in the apex of the right ventricle. The effects of isoproterenol and verapamil were investigated during spontaneous rhythm and stimulation simultaneously recorded with both types of electrodes in 10 dogs without AV-node ablation. The correlation at different heart rates were investigated in 10 other dogs with complete AV-block. The morphology and amplitudes of MAP were comparable (AgCl: 15 +/- 7 mV; Ir: 13 +/- 8 mV). Following an i.v. bolus of 2 micrograms/kg isoproterenol the spontaneous rate increased (175 +/- 18 to 245 +/- 25 bpm). During stimulation with 250 ms cycle length the duration shortened (MAPd90: AgCl: 160 +/- 11 to 130 +/- 12 ms; Ir: 154 +/- 18 to 128 +/- 15 ms). The alterations reversed after 20 min. An i.v. bolus of 0.2 mg/kg verapamil decreased the spontaneous rate (167 +/- 11 to 104 +/- 23 bpm) and lengthened the MAPd90 (AgCl: 182 +/- 14 to 220 +/- 13 ms; Ir: 174 +/- 16 to 216 +/- 21 ms) at 300 ms stimulation. The correlation between the MAPd90 of both lead types was r = 0.98 during all measurements. Under the effect of beta-agonist and Ca(2+)-antagonist medication MAP showed a strong correlation recorded with both types of electrodes. Thus, both leads allow the recording of MAP but only the Ir-electrodes with their long-term stability are implantable and allows us to control the effects of drugs with implantable devices.