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Acral melanoma (AM) and mucosal melanomas (MM) are rare clinical subtypes of melanoma. AM and MM are etiologically, biologically, and molecularly distinct from cutaneous melanoma (CM). Despite the recent development of immune checkpoint inhibitors (ICIs) for the treatment of advanced CMs, the true therapeutic efficacy of ICIs for these rare subtypes remains unclear. Since these subtypes are rare, especially in the Caucasian population, their biological features and corresponding novel therapies are underexplored than those of CM. Even in the larger phase III clinical trials for ICIs, the sample size of patients with AM and MM is limited. Consequently, establishment of standard of care for advanced AM and MM has been challenging. This review covers current update and overview on clinical efficacy of ICIs and ICI‐based therapy for advanced AM and MM, based mainly on the reported clinical trials, prospective observational studies, and retrospective studies, to provide a better understanding of the current landscape of this field. In addition, we discuss the future direction of treatment for those rare clinical subtypes, focusing on issues relevant to dermatology and medical oncology. [ABSTRACT FROM AUTHOR]

Can we clinically identify patients at risk of malignant transformation of skin tumors in Brooke-Spiegler syndrome? The enlargement of cylindroma in the present case is considered to be attributed to vasodilatation within the tumor, which may be originated from the highly vascular region of the sweat glands, or may result from a degeneration of the tumor stroma during the aging process. A magnetic resonance imaging examination revealed that the inside of the tumor was full of liquid components with no adhesion between the tumor and the skull. [Extracted from the article]

Dear Editor, A 57-year-old woman was diagnosed with sarcoidosis based on iritis, increased serum levels of angiotensin converting enzyme (ACE) and lysozyme, and bilateral hilar lymphadenopathy on chest x-ray and computed tomography scan 1 year and 3 months previously, and was under follow-up at the Respiratory Medicine and Ophthalmology Departments. Although she had been diagnosed with sarcoidosis, no skin lesions suggestive of sarcoidosis were observed. [Extracted from the article]

A biopsy specimen revealed thickened collagen bundles in the reticular dermis extending to the subcutis, with focal mononuclear cell infiltration at the dermal-subcutis junction, containing CD123-positive cells scattered (Fig. Histopathology showing fibrosis of the mid-dermis to subcutaneous tissues with mononuclear cell infiltration with focal lymphoid follicles in the lower dermis (b) (Hematoxylin-eosin stain, original magnification ×20). Histopathological features showed intense sclerosis in the mid-dermis to the subcutis with focal lymphoid follicles which contained few CD123-positive lymphocytes, and mucin deposition was observed in the lower dermis. [Extracted from the article]

Abstract: Whether a high plasma aldosterone concentration induced by strict salt restriction promotes cardiac remodeling remains controversial. Male Sprague–Dawley rats at 10weeks of age were given normal salt (NS) (1.5% NaCl) or low salt (LS) (0.05% NaCl) diets. Each animal underwent aortocaval fistula creation for volume-overloaded heart failure or sham surgery. All rats with a fistula received either vehicle or a non-hypotensive dose of spironolactone (200mg/kg/day) by gavage. Two weeks later, the LS diet significantly increased the plasma aldosterone level in the sham-operated and fistula-created rats (2677±662pg/ml and 2406±422pg/ml) compared with that in rats given the NS diet (518±18pg/ml and 362±45pg/ml, respectively). In sham-operated rats, the difference in plasma aldosterone level did not affect the extent of myocardial fibrosis (1.8±0.1% with LS diet vs. 1.5±0.3% with NS diet). However, the increase in myocardial fibrosis in fistula-created rats was more prominent with the LS diet than with the NS diet (4.7±0.3% vs. 3.4±0.1%). In addition, the fistula-created rats on the LS diet expressed significantly increased oxidative stress and transforming growth factor-beta compared with those on the NS diets (P <0.05). These increases in the fistula-created rats on the LS diet were significantly suppressed by the non-hypotensive dose of spironolactone (P <0.05). These results suggest that increased plasma aldosterone level with strict salt restriction activated the mineralocorticoid receptor signaling in volume-overloaded condition, resulting in increased myocardial fibrosis. [Copyright &y& Elsevier]

Abstract: The effect of estrogen on neointimal formation in injured rat arteries has been reported to be a sexual dimorphic effect. Recently, it has been reported that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exhibit vasoprotective effects, which are independent of their cholesterol-lowering effects. In this study, we examined the gender differences of atorvastatin''s effect on neointimal formation in balloon-injured rat arteries. Male and female Sprague Dawley rats underwent gonadectomy and balloon injury of the carotid artery. Ovariectomized female, as well as intact and castrated male, rats exhibited marked neointimal formation. Treatment with atorvastatin significantly reduced neointimal formation at day 14 (14 days after injury) and NADPH oxidase-dependent superoxide production at day 2 in ovariectomy, but not in intact and castrated males. In ovariectomized rats, 7 days of atorvastatin treatment from days −3 to 3 but not from days 7 to 14 suppressed neointimal formation at day 14. In this study, we showed that atorvastatin''s effect on neointimal formation was female-specific and was more marked in ovariectomized female rats. NADPH oxidase-dependent superoxide production may be involved in the mechanism of the sexual dimorphic response seen in response to atorvastatin treatment. Furthermore, the results suggest the importance of treatment in the early phase after vascular injury. [Copyright &y& Elsevier]

Objective: Previous studies suggest that atrial natriuretic peptide (ANP) may act as an autocrine/paracrine factor to modulate cardiac hypertrophy in response to various stimuli. The effect of ANP deficiency on the response to volume overload has not previously been studied. We hypothesised that ANP deficient mice would develop excess cardiac hypertrophy in response to volume overload stress. Methods: Male homozygous ANP deficient (Nppa−/−) and wildtype (Nppa+/+) male mice maintained on either a normal salt (0.55% NaCl) or low salt (0.05% NaCl) diet from weaning were studied after 2 weeks of volume overload from an aorto-caval fistula (ACF). Unoperated littermates served as controls. Left ventricular (LV) structure and function was evaluated by echocardiography. Heart, LV, and lung weights were determined at sacrifice. Myocyte diameter was measured by morphometric analysis of fixed sections of the left ventricle. Results: BP, heart weight, and LV weight were increased in Nppa−/− vs. Nppa+/+ unoperated mice. Nppa−/− mice developed exaggerated heart and LV weight compared to Nppa+/+ mice following ACF. Increased myocyte diameter paralleled increased echo LV wall thickness following ACF in Nppa+/+ but not Nppa−/− mice fed with 0.55% NaCl, indicating that an alternate mechanism contributed to increased wall thickness in Nppa−/− mice. Mid-wall shortening was mildly depressed in the Nppa−/− vs. Nppa+/+ genotype following ACF with fed 0.55% NaCl. A 0.05% NaCl diet from weaning normalized BP, but did not prevent exaggerated cardiac enlargement and LV hypertrophy following ACF in Nppa−/− mice. Conclusions: ANP-deficient mice exhibited an exaggerated increase in heart and LV weight in response to volume overload, which was not prevented by normalization of blood pressure. The findings suggest that ANP is an important physiologic modulator of the cardiac hypertrophy induced by volume overload. [Copyright &y& Elsevier]

The article presents a case study of an old woman, suffering from rheumatoid arthritis and being treated with tocilizumab. She had complaints of symptomless skin eruptions on the extremities and trunk after the seventh infusion of tocilizumab. Laboratory and Serological examination were done. Tocilizumab infusion was stopped and the patient was successfully treated with topical corticosteroid ointment improving the skin conditions along with normalization of eosinophil.

Objectives: To examine the effect of L- and T/L-type calcium channel blockers on interstitial fibrosis in chronic unilateral ureteral obstruction (UUO). Tubulointerstitial fibrosis is a common outcome of several progressive renal diseases. Calcium channel blockers are widely used for the treatment of hypertension with renal diseases; however, the direct effect of calcium channel blockers on renal diseases independent of lowering blood pressure has not been fully elucidated. Methods: Sprague–Dawley rats were divided into 3 treatment groups: (1) vehicle control; (2) nifedipine, an L-type calcium channel blockers; and (3) efonidipine, a T/L-type calcium channel blockers. Treatment was initiated 1 day before and continued until 6 days after creation of the UUO. Results: Tubulointerstitial fibrosis in the obstructed kidney was significantly increased compared with that in the contralateral unobstructed kidney. Furthermore, the increased fibrosis was accompanied by increased fibrogenic signaling expressed by transforming growth factor β1 and connective tissue growth factor mRNA levels, increased oxidative stress expressed by p22phox, p47phox and gp91phox mRNA level. Moreover, treatment with a nonhypotensive dose of efonidipine but not nifedipine in the obstructed kidney significantly suppressed the fibrogenic signaling and the oxidative stress, resulting in reduced tubulointerstitial fibrosis. The plasma aldosterone level in efonidipine-treated animals was increased compared with vehicle-treated animals, although not significantly. The increased plasma aldosterone level did not increase sgk-1 mRNA level in efonidipine but not in nifedipine treated animals. Conclusions: Treatment with efonidipine improved tubulointerstitial fibrosis more effectively than treatment with nifedipine in UUO. The antifibrogenic effect by efonidipine was obtained through suppression of fibrogenic signaling. [ABSTRACT FROM AUTHOR]

Pemphigus foliaceus (PF) is one of the causes of erythroderma; however, to date, there have been relatively few reported cases. We herein describe 6 cases of erythrodermic PF. In all 6 cases, PF was a direct cause of erythroderma because the patients had not undergone any medical treatments and neither had any other skin diseases nor were taking any drugs that typically cause erythroderma. Serum levels of IgE and thymus and activation-regulated chemokine were elevated in 5 of the 6 cases, whereas soluble interleukin-2 receptor and squamous cell carcinoma-related antigen were markedly increased in all cases, suggesting that those markers are strong indicators of skin surface damage. All patients were treated with predonisolon (PSL), of which PSL pulse was added in 4 patients and intravenous immunoglobulin was added in 4 patients. Furthermore, all patients except for one were older adults, among whom 2 cases developed Kaposi's varicelliform eruption, and died, and another 2 patients, respectively, died of gastrointestinal bleeding and sepsis. Kaposi's varicelliform eruption is a complication of erythrodermic PF associated with poor prognosis, and thus caution is necessary when considering the diagnosis. Furthermore, elderly people are more likely to have complications due to PSL, which may result in death. Inappropriate treatment and delay in treatment may cause erythroderma, so early diagnosis and treatment are necessary. [ABSTRACT FROM AUTHOR]

Introduction: Inadequate vaccine response is a common concern among healthcare workers at the frontlines of the COVID-19 pandemic. We aimed to investigate if healthcare workers with history of weak immune response to HBV vaccination are more likely to have weak responses against the BioNTech/Pfizer's BNT162b2 mRNA SARS-CoV-2 vaccine. Methods: We prospectively tested 954 healthcare workers for the Anti-SARS-CoV-2 spike (S) protein antibody titers prior to the first and second BNT162b2 vaccination doses and after four weeks after the second dose using Roche's Elecsys® assay. We calculated the percentage of patients who seroconverted after the first and second doses. We estimated the relative risk of non-seroconversion after the first BNT162b2 vaccine (defined as anti-SARS-CoV-2-S titer <15 U/mL) among HBV vaccine non-responders (HBs-Ab titer <10 mIU/mL) and weak responders (≥10 and <100 mIU/mL) compared to normal responders (≥100 mIU/mL). Results: Among 954 healthcare workers recruited between March 9 and March 24, 2021 at Osaka Medical and Pharmaceutical University, weak and normal HBV vaccine responders had comparable S-protein titers after the first BNT162b2 dose (51.4 [95% confidence interval 25.2–137.0] versus 59.7 [29.8–138.0] U/mL, respectively). HBV vaccine non-responders were more likely than normal responders to not seroconvert after a single dose (age and sex-adjusted relative risk 1.85 95% confidence interval [1.10–3.13]) although nearly all participants seroconverted after the second dose. After limiting the analysis to 382 patients with baseline comorbidity data, the comorbidity-adjusted relative risk of non-seroconversion among HBV vaccine non-responders to normal responders was 1.32 (95% confidence interval [0.59–2.98]). Discussion: Long term follow-up studies are needed to understand if protective immunity against SARS-CoV-2 wanes faster among those with history of HBV vaccine non-response and when booster doses are warranted for these healthcare workers. [ABSTRACT FROM AUTHOR]

Aims The effects of hormone replacement therapy with estrogen on cardiovascular disease in postmenopausal women are still controversial. In the present study, we examined the effects of an endothelin (ET) receptor antagonist (ERA) and/or angiotensin receptor blocker (ARB) on neointimal formation following vascular injury in ovariectomized (OVX) female rats. Main methods Female rats were divided into intact female and OVX groups. The right carotid artery was subjected to balloon injury, and harvested 2 weeks later. Key findings In the intact female groups, treatment with ARB (L-158809; 1 mg/kg/day) for two weeks after the injury significantly decreased neointimal formation, whereas treatment with the ERA (J-104132; 10 mg/kg/day) did not affect neointimal formation. On the other hand, the ERA markedly decreased neointimal formation after the injury in the OVX groups; however, neointimal formation was not significantly improved by the ARB treatment. In addition, the combined treatment with 17β-estradiol (20 μg/kg/day) or the ERA and ARB markedly suppressed neointimal formation after the balloon injury in the OVX groups, whereas no combinational effects were observed due to the combined treatment with 17β-estradiol and the ERA. Significance These results suggest that ERAs have estrogen-like vasoprotective effects on neointimal formation following balloon injury in OVX rats. ERAs may be useful as an alternative therapy to prevent vascular disease in postmenopausal women. [ABSTRACT FROM AUTHOR]

We present the case of a woman with IgA nephropathy and concomitant Fabry’s disease. She was referred to our hospital with proteinuria and haematuria. A renal biopsy showed findings indicating IgA nephropathy under light and immunofluorescence microscopy. Electron microscopy, however, showed laminated inclusion bodies characteristic of Fabry’s disease. The α-galactosidase activity in her serum was low, and the diagnosis of Fabry’s disease was confirmed by genetic analysis. Fabry’s disease in a patient with IgA nephropathy is a very rare occurrence, and Fabry’s disease diagnosed only by electron microscopy has not been previously reported. [ABSTRACT FROM PUBLISHER]

Abstract: Aims: Recurrent hypoxia due to sleep apnea syndrome is implicated in cardiovascular events, especially in diabetic patients, but the underlying mechanisms remain controversial. We previously reported that angiotensin II receptor blockers can improve hypoxia-induced left ventricular remodeling. The aim of this study was to examine the effect on left ventricular remodeling of adding a calcium channel blocker to angiotensin II receptor blocker therapy in diabetic mice exposed to recurrent hypoxia. Main methods: Male db/db mice (8-week-old) and age-matched control db/+ mice were fed a Western diet and subjected to recurrent hypoxia (oxygen at 10±0.5% for 8h daily during the daytime) or normoxia for 3weeks. Hypoxic db/db mice were treated with the vehicle, olmesartan (3mg/kg/day), nifedipine (10mg/kg/day), or both drugs. Key findings: Recurrent hypoxia caused hypertrophy of cardiomyocytes, interstitial fibrosis, and a significant increase in expression of the oxidative stress marker 4-hydroxy-2-nonenal (4-HNE) in the left ventricular myocardium. Treatment with olmesartan, nifedipine, or both drugs had no effect on systolic blood pressure, and each treatment achieved similar suppression of 4-HNE expression. Olmesartan and the combination with olmesartan and nifedipine significantly prevented cardiomyocyte hypertrophy more than treatment with nifedipine alone. On the other hand, olmesartan combined with nifedipine significantly reduced cytokine expression, superoxide production and matrix metalloproteinase (MMP)-9 activity, and significantly suppressed interstitial fibrosis in the left ventricular myocardium. Significance: The combination with olmesartan and nifedipine, as well as a monotherapy with olmesartan, exerts preferable cardioprotection in diabetic mice exposed to recurrent hypoxia. [Copyright &y& Elsevier]

Summary 1. Homozygous deletion of the pro-atrial natriuretic peptide (Nppa ) gene (ANP–/–) has been associated with both cardiac hypertrophy and salt-sensitive hypertension in mice, suggesting that cardiac hypertrophy in ANP–/– mice may be related, at least in part, to increased afterload. 2. To test the hypothesis that cardiac hypertrophy in ANP–/– mice is independent of blood pressure, male ANP–/– and wild-type ANP+/+ mice were fed a low (0.05%) or basal (0.55%) NaCl diet. Five weeks later, mean arterial pressure (MAP) was measured in conscious mice; the whole heart, atria, left and right ventricles (LV and RV, respectively), brain, lung, kidney, liver and spleen were weighed and fixed for histological analysis. Separate groups of mice were subjected to echocardiographic examination under tribromoethanol anaesthesia. 3. Mean arterial pressure and atrial, LV and RV mass were greater in ANP–/– mice than in ANP+/+ mice fed the basal salt diet. Salt depletion equalized MAP in the two genotypes, but did not alter the relative cardiac hypertrophy in ANP–/– mice. The ANP–/– mice had significant LV cardiomyocyte hypertrophy when fed either basal or low-salt diets. 4. Left ventricle chamber dimensions did not differ between genotypes, but were significantly reduced in mice fed the low-salt diet; LV posterior wall and septal thickness were greater in ANP–/– than ANP+/+ mice and were not altered by diet, indicating a concentric pattern of LV hypertrophy in ANP–/– mice. Left ventricle function (cardiac output, stroke volume, ejection fraction, circumferential wall stress and velocity of circumferential wall shortening) did not differ between strains on either diet; circumferential wall stress was reduced in the low-salt groups; other functional parameters were not altered by diet. 5. These findings indicate that ANP deletion results in... [ABSTRACT FROM AUTHOR]

Sleep apnea syndrome increases the risk of cardiovascular morbidity and mortality. We previously reported that intermittent hypoxia increases superoxide production in a manner dependent on nicotinamide adenine dinucleotide phosphate and accelerates adverse left ventricular (LV) remodeling. Recent studies have suggested that hydrogen (H2) may have an antioxidant effect by reducing hydroxyl radicals. In this study, we investigated the effects of H2 gas inhalation on lipid metabolism and LV remodeling induced by intermittent hypoxia in mice. Male C57BL/6J mice (n = 62) were exposed to intermittent hypoxia (repetitive cycle of 1-min periods of 5 and 21% oxygen for 8 h during daytime) for 7 days. H2 gas (1.3 vol/100 vol) was given either at the time of reoxygenation, during hypoxic conditions, or throughout the experimental period. Mice kept under normoxic conditions served as controls (n = 13). Intermittent hypoxia significantly increased plasma levels of low- and very low-density cholesterol and the amount of 4-hydroxy-2-nonenal-modified protein adducts in the LV myocardium. It also upregulated mRNA expression of tissue necrosis factor-α, interleukin-6, and brain natriuretic peptide, increased production of superoxide, and induced cardiomyocyte hypertrophy, nuclear deformity, mitochondrial degeneration, and interstitial fibrosis. H2 gas inhalation significantly suppressed these changes induced by intermittent hypoxia. In particular, H2 gas inhaled at the timing of reoxygenation or throughout the experiment was effective in preventing dyslipidemia and suppressing superoxide production in the LV myocardium. These results suggest that inhalation of H2 gas was effective for reducing oxidative stress and preventing LV remodeling induced by intermittent hypoxia relevant to sleep apnea. [ABSTRACT FROM AUTHOR]

A 74-year-old man was diagnosed with nephrotic syndrome due to focal segmental glomerulosclerosis, and steroid therapy was initiated. Subsequently, he was affected by deep mycosis, and hence, voriconazole (VRCZ) was administered. On the 16th day, he was transferred to our hospital because of somnolence and malaise. His systolic blood pressure was approximately 80 mmHg, and he showed decreased skin turgor, indicating volume depletion. Laboratory analysis revealed hyponatremia and liver dysfunction. Discontinuation of VRCZ and drip infusion of normal saline improved the consciousness disorder, hyponatremia, and liver dysfunction. The levels of antidiuretic hormone (ADH) and plasma renin activity were elevated. This patient showed high excreted urine sodium, despite volume depletion and low serum osmolality. Therefore, this patient was diagnosed with salt-losing nephropathy (SLN). SLN should be considered for treatment of VRCZ-associated hyponatremia, together with syndrome of inappropriate secretion of ADH. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia due to sleep apnea syndrome is associated with cardiovascular diseases. However, the precise mechanisms by which intermittent hypoxic stress accelerates cardiovascular diseases are largely unclear. The aim of this study was to investigate the role of gp91phox-containing NADPH oxidase in the development of left ventricular (LV) remodeling induced by intermittent hypoxic stress in mice. Male gp91phox-deficient (gp91-/-) mice (n = 26) and wild-type (n = 39) mice at 7-12 wk of age were exposed to intermittent hypoxia (30 s of 4.5-5.5% 02 followed by 30 s of 21% 02 for 8 h/day during daytime) or normoxia for 10 days. Mean blood pressure and LV systolic and diastolic function were not changed by intermittent hypoxia in wild-type or gp91-/- mice, although right ventricular systolic pressure tended to be increased. In wild-type mice, intermittent hypoxic stress significantly increased the diameter of cardiomyocytes and interstitial fibrosis in LV myocardium. Furthermore, intermittent hypoxic stress increased superoxide production, 4-hydroxy-2-nonenal protein, TNF-α and transforming growth factor-β mRNA, and NF-δB binding activity in wild-type, but not gp91-/-, mice. These results suggest that gp91phox-containing NADPH 'oxidase plays a crucial role in the pathophysiology of intermittent hypoxia-induced LV remodeling through an increase of oxidative stress. [ABSTRACT FROM AUTHOR]

Abstract: A new DNA modified electrode for the electrochemical detection of 16S rDNA extracted from Escherichia coli (JCM1649) is proposed. The electrodes were fabricated by screen printing a fullerene-impregnated carbon ink onto a poly(methylmethacrylate) substrate and immobilizing a probe DNA on the surface after activating the electrode with air plasma. The results indicated a dramatic improvement in the surface coverage of the immobilized probe DNA, and of the reduction peak of the redox indicator (Co(phen)3 3+) due to the incorporation of fullerene. By immobilizing the probe onto the fullerene-impregnated screen-printed electrodes, the PCR product of the 16S rDNA extracted from E. coli was directly detected without any pretreatment. A well defined signal difference was observed between the perfectly matching oligonucleotide and the mismatching one, and it was possible to detect the target at the modified electrode. This method enabled us to clearly detect the two base mismatches in the ca. 1500-bases long 16S rDNA sequence. [Copyright &y& Elsevier]