Ixazomib-induced cutaneous necrotizing vasculitis.

Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti-cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life.

Pityriasis rubra pilaris-like erythroderma secondary to phosphoinositide 3-kinase inhibition.

BACKGROUND: Phosphoinositide 3-kinase (PI3K) inhibitors are a class of small-molecule inhibitors approved for the treatment of certain leukaemias and lymphomas. Their dermatological adverse event profile is poorly described. AIM: To characterize a rare cutaneous adverse event from PI3K inhibitors in order to help dermatologists and oncologists identify and effectively manage such eruptions. METHODS: This was a retrospective analysis of patients receiving PI3K inhibitors referred to the Skin Toxicities Program in The Center for Cutaneous Oncology. RESULTS: Three patients on PI3K inhibitors for treatment of malignancy developed diffuse erythroderma and keratoderma. Clinical and histopathological findings were consistent with pityriasis rubra pilaris (PRP)-like reactions. All patients improved with topical and oral corticosteroids, oral acitretin, and drug discontinuation. CONCLUSIONS: PRP-like cutaneous eruptions may develop secondary to PI3K inhibition. Early dermatological evaluation of cutaneous toxicities to PI3K inhibitors as well as rapid initiation of disease-specific treatments may help keep patients on life-prolonging anti-cancer therapies.

The catalase gene promoter and 5'-untranslated region variants lead to altered gene expression and enzyme activity in vitiligo.

BACKGROUND: Oxidative stress is considered to be the initial event in the course of vitiligo. The enzyme catalase (CAT) is mainly involved in cellular defence against oxidizing agents through detoxifying H2 O2 . OBJECTIVES: The aims were (i) to assess erythrocyte CAT enzyme activity and lipid peroxidation (LPO) levels as well as CAT mRNA expression in skin and blood; (ii) to investigate CAT gene promoter rs7943316, rs1001179, 5'-untranslated region rs1049982, and exon (rs17886350, rs11032709, rs17880442, rs35677492) polymorphisms; and (iii) to perform genotype/haplotype-phenotype correlation analyses in patients with vitiligo and controls from Gujarat. METHODS: CAT activity and LPO levels were measured spectrophotometrically. CAT mRNA levels were estimated using real-time polymerase chain reaction (PCR) by the SYBR Green method. Single-nucleotide polymorphism genotyping was performed using PCR-restriction fragment length polymorphism and amplification-refractory mutation system-PCR analyses. RESULTS: Patients with vitiligo showed significantly decreased CAT mRNA expression in lesional and nonlesional skin and in blood, with reduced CAT activity compared with that of controls. CAT -89A/T and -20T/C polymorphisms were significantly associated with patients, especially with active and generalized vitiligo, whereas no association was observed for -262G/A and exon polymorphisms. The A-262 T-89 C-20 haplotype with variant alleles was found to be associated with 6·4-fold risk of vitiligo. Genotype/haplotype-phenotype correlation analyses revealed that individuals with susceptible genotypes/haplotype for CAT -89A/T and -20T/C polymorphisms showed significantly decreased CAT mRNA/activity, and only -89A/T polymorphisms showed significantly increased LPO levels compared with wild-type genotypes/haplotype. CONCLUSIONS: The present study proposes the crucial role of CAT and its allelic variants in oxidative stress-mediated pathogenesis of vitiligo.

The subsurface lesion in erosive tooth wear.

OBJECTIVES: This study compared the surface change on natural and polished enamel exposed to a joint mechanical and chemical wear regimen. METHODS: Human enamel samples were randomly assigned to natural (n = 30) or polished (n = 30) groups, subjected to erosion (n = 10, 0.3% citric acid, 5 min), abrasion (n = 10, 30 s), or a combination (n = 10). Wear in the form of step height was measured with a non-contact profilometer, and surface changes were inspected with SEM on selected sections. Data was normalised and underwent repeated measures MANOVA, accounting for substrate and erosive challenge as independent variables, with Bonferroni correction for significant post hoc interactions. RESULTS: After four cycles, polished samples had mean step heights of 3.08 (0.40) µm after erosion and 4.08 (0.37) µm after erosion/abrasion. For natural samples, these measurements were 1.52 (0.22) µm and 3.62 (0.39) µm, respectively. Natural surfaces displayed less wear than polished surfaces under erosion-only conditions (p<0.0001), but the difference disappeared with added abrasion. SEM revealed a shallow subsurface layer for polished surfaces and natural ones undergoing only erosion. However, natural surfaces exposed to both erosion and abrasion showed deeper subsurface changes up to 50 µm. CONCLUSION: Natural enamel, when exposed to erosion alone, showed less wear and minimal subsurface alterations. But with added abrasion, natural enamel surfaces saw increased wear and notable subsurface changes compared to polished ones. CLINICAL SIGNIFICANCE: The pronounced subsurface lesions observed on eroded/abraded natural enamel surfaces highlight how combined wear challenges may accelerate tooth tissue loss.

The early wear susceptibility of cementum, enamel and dentine in vitro.

OBJECTIVES: To assess the differential early wear susceptibility of cementum, enamel and dentine at a micron level. METHODS: Whole human molar buccal surfaces incorporating natural enamel and cementum (n = 20) confirmed by imaging (digital microscopy: Keyence, VHX-7000 Milton Keynes, UK), were mounted, scanned (profilometry: XYRIS 4000, Taicaan, Southampton, UK), and allocated to receive erosion (citric acid, pH 2.7, 30 min (n = 10)) or erosion/abrasion challenges (3 cycles of (citric acid, pH 2.7, 10 min, 60 300 g linear abrasion strokes), n=10). Samples were polished and the experiment repeated on polished enamel, and polished coronal and radicular dentine within the same tooth. Profilometric wear data were obtained using superimposition: GeoMagic (3Dsystems, Darmstadt, Germany) and subtraction: MountainsMap (DigitalSurf, Besancon, France). Data were normal. A general linear model was used to assess differences between groups and substrates. RESULTS: The mean step height (SD) for natural enamel was 8.82 µm (2.53) for erosion and 11.48 µm (2.95) for erosion/abrasion. For natural cementum, the mean step height was 6.00 µm (2.29) for erosion and 4.67 µm (1.58) for erosion/abrasion. Dentine step heights ranged from 7.20 µm (1.53) for erosion and 9.79 µm (1.01) for erosion/abrasion with no statistical differences in dentine wear. Natural cementum surfaces had the lowest wear (p<0.001). Dentine had significantly less wear than natural enamel (p<0.02). CONCLUSIONS: Cementum surfaces demonstrated the most wear resistance, followed by dentine under erosion dominant conditions in this in vitro study. Further in-vivo investigations are needed to confirm the intraoral stability of cementum. CLINICAL SIGNIFICANCE: Cementum may be the least susceptible of dental substrates to wear and dentine does not wear at a faster rate than enamel under erosive conditions. This adds to our knowledge on the development of non-carious cervical lesions and questions whether wear rates will accelerate once dentine is exposed.

Phosphodiesterase 8B Polymorphism rs4704397 Is Associated with Infertility in Subclinical Hypothyroid Females: A Case-Control Study.

BACKGROUND: Subclinical hypothyroidism (SCH) remains largely unnoticed as a major cause of infertility due to asymptomatic. Polymorphisms of phosphodiesterase 8B gene (PDE8B) have been linked with various diseases, including female infertility. Hence, we aimed to study prevalence of SCH, in infertile females, explore association of PDE8B rs4704397 A/G and rs6885099 G/A polymorphisms with infertility in females suffering from SCH and genotype-phenotype correlation of the polymorphisms with thyroid stimulating hormone (TSH) levels in Gujarat population. MATERIALS AND METHODS: In this retrospective study, TSH level was estimated from plasma of 230 infertile and 100 control females by enzyme-linked fluorescence immunoassay (ELFA) to find out the prevalence of SCH. Further, based on TSH levels, thyroid function test (TFT) was performed in controls and infertile females with subclinical hypothyroidism (IF-SCH). PDE8B rs4704397 and rs6885099 polymorphisms were genotyped by PCR-RFLP and ARMS-PCR, respectively in 74 controls and 60 IF-SCH females. RESULTS: We observed i. significantly high prevalence of SCH (32%) in the infertile females, ii. significantly lower frequency of 'G' allele (P=0.006), while the frequency of 'A' allele (P<0.0001) was higher in IFSCH females, compared to the controls, for rs4704397 A/G SNP, iii. no significant difference in the genotype (P=0.214; OR=2.51; CI=0.74-8.42) and the allele frequency (P=0.129; OR=1.51; CI=0.92-2.47) of rs6885099 G/A SNP, iv) low linkage disequilibrium for the polymorphisms, v. significantly higher frequency of 'AA' haplotype (P=0.0001; OR=3.84; CI=1.86-8.01),while the 'GG' haplotype (P=0.0023; OR=0.33; CI=0.16-0.69) was significantly lower in IF-SCH females and vi. no significant difference in the TSH level of IF-SCH females with respect to the genotypes. CONCLUSION: The present study reports an association of PDE8B rs4704397 polymorphism with infertility in SCH females. The study categorically shows a higher prevalence of SCH in infertile females of Gujarat and advocates the importance of screening for SCH in infertility management.

Molecular study of 33 families with Fraser syndrome new data and mutation review.

Fraser syndrome (FS) is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract. FS is considered to be the human equivalent of the murine blebbing mutants: in the mouse mutations at five loci cause a phenotype that is comparable to FS in humans, and thus far mutations in two syntenic human genes, FRAS1 and FREM2, have been identified to cause FS. Here we present the molecular analysis of 48 FS patients from 18 consanguineous and 15 nonconsanguineous families. Linkage analysis in consanguineous families indicated possible linkage to FRAS1 and FREM2 in 60% of the cases. Mutation analysis identified 11 new mutations in FRAS1 and one FREM2 mutation. Manifestations of these patients and previously reported cases with an FRAS1 mutation were compared to cases without detectable FRAS1 mutations to study genotype-phenotype correlations. Although our data suggest that patients with an FRAS1 mutation have more frequently skull ossification defects and low insertion of the umbilical cord, these differences are not statistically significant. Mutations were identified in only 43% of the cases suggesting that other genes syntenic to murine genes causing blebbing may be responsible for FS as well.