Exome sequencing identifies SLC17A9 pathogenic gene in two Chinese pedigrees with disseminated superficial actinic porokeratosis.

BACKGROUND: Disseminated superficial actinic porokeratosis (DSAP) is a rare autosomal dominant genodermatosis characterised by annular lesions that has an atrophic centre and a prominent peripheral ridge distributed on sun exposed area. It exhibits high heterogeneity, and five linkage loci have been reported. The mevalonate kinase (MVK) gene located on 12q24 has been confirmed as one of the disease-causing genes. But, the pathogenesis of a large part of DSAP remains unclear so far. METHODS: The recruited with DSAP carried no MVK coding mutations. Exome sequencing was performed in two affected and one unaffected individual in Family 1. Cosegregation of the candidate variants was tested in other family members. Sanger sequencing in 33 individuals with familial DSAP and 19 sporadic DSAP individuals was performed for validating the causative gene. RESULTS: An average of 1.35×10(5) variants were generated from exome data and 133 novel NS/SS/indels were identified as being shared by two affected individuals but absent in the unaffected individual. After functional prediction, 25 possible deleterious variants were identified. In Family 1, a missense variant c.932G>A (p.Arg311Gln) in exon 10 of SLC17A9 was observed in cosegregation with the phenotype; this amino acid substitution was located in a highly conserved major facilitator superfamily (MFS) domain in multiple mammalian. One additional missense variant c.25C>T (p.Arg9Cys) in exon 2 of SLC17A9 was found in Family 2. CONCLUSIONS: The result identified SLC17A9 as another pathogenic gene for DSAP, which suggests a correlation between the aberrant vesicular nucleotide transporter and the pathogenesis of DSAP.

Association study of susceptibility loci with specific breast cancer subtypes in Chinese women.

To determine whether recent genome-wide association studies that reported 45 susceptibility loci in European women are also risk factors for breast cancer in Chinese women. We selected and genotyped 40 single nucleotide polymorphisms (SNPs) using the Sequenom iPlex platform in a female Chinese cohort of 2,901 breast cancer cases and 2,789 healthy controls. We evaluated these SNPs with the risk of breast cancer and further by estrogen receptor (ER) status, progestin (PR) status, human epidermal growth factor receptor-2 (HER-2) status, and four breast cancer subtypes (Luminal A type, Luminal B type, HER-2 overexpression type and Basal-like type). We first confirmed that the SNP rs9693444 on 8p12 was associated with breast cancer in Chinese women (P = 6.44 × 10(-4)). Furthermore, we identified four susceptibility loci that were associated with specific tumor subtypes. Statistically significant differences were detected with the association of rs6828523 (4q34.1/ADAM29) with ER-positive breast cancer (P = 1.27 × 10(-3)) and the association of rs4849887 (2q14.2) with PR-positive breast cancer (P = 1.29 × 10(-3)). Of the four breast cancer subtypes, the associations of rs12493607 (3p24.1/TGFBR2) with HER-2 overexpression in breast cancer (P = 1.09 × 10(-3)) and rs11075995 (16q12.2/FTO) with basal-like breast cancer (P = 1.64 × 10(-4)) were statistically significant. This study is the first to show that these 5 susceptibility loci (8p12, 4q34.1/ADAM29, 2q14.2, 3p24.1/TGFBR2, and 16q12.2/FTO) correlate with breast cancer (overall and specific subtypes) in Chinese women, which has improved our understanding of the genetic basis of specific breast cancer subtypes.

Eccrine porocarcinoma in the tempus of an elderly woman: A case report.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin tumor that mainly affects the elderly population. Tumors often present with slow growth and a good prognosis. EPCs are usually distinguished from other skin tumors using histopathology and immunohistochemistry. However, surgical management alone may be inadequate if the tumor has metastasized. However, currently, surgical resection is the most commonly used treatment modality. CASE SUMMARY: A seventy-four-year-old woman presented with a slow-growing nodule in her left temporal area, with no obvious itching or pain, for more than four months. Histopathological examination showed small columnar and short spindle-shaped cells; thus, basal cell carcinoma was suspected. However, immunohistochemical analysis revealed the expression of cytokeratin 5/6, p63 protein, p16 protein, and Ki-67 antigen (40%), and EPC was taken into consideration. The skin biopsy was repeated, and hematoxylin and eosin staining revealed ductal differentiation in some cells. Finally, the patient was diagnosed with EPC, and Mohs micrographic surgery was performed. We adapted follow-up visits in a year and not found any recurrence of nodules. CONCLUSION: This case report emphasizes the diagnosis and differentiation of EPC.

Antibiotic Resistance Profiles and MLST Typing of Staphylococcus Aureus Clone Associated with Skin and Soft Tissue Infections in a Hospital of China.

Objective: To analyze the antibiotic resistance profile, virulence genes, and molecular typing of Staphylococcus aureus (S. aureus) strains isolated in skin and soft tissue infections at the First Affiliated Hospital, Gannan Medical University, to better understand the molecular epidemiological characteristics of S. aureus. Methods: In 2023, 65 S. aureus strains were isolated from patients with skin and soft tissue infections. Strain identification and susceptibility tests were performed using VITEK 2 and gram-positive bacteria identification cards. DNA was extracted using a DNA extraction kit, and all genes were amplified using polymerase chain reaction. Multilocus sequence typing (MLST) was used for molecular typing. Results: In this study, of the 65 S. aureus strains were tested for their susceptibility to 16 antibiotics, the highest resistance rate to penicillin G was 95.4%. None of the staphylococcal isolates showed resistance to ceftaroline, daptomycin, linezolid, tigecycline, teicoplanin, or vancomycin. fnbA was the most prevalent virulence gene (100%) in S. aureus strains isolated in skin and soft tissue infections, followed by arcA (98.5%). Statistical analyses showed that the resistance rates of methicillin-resistant S. aureus isolates to various antibiotics were significantly higher than those of methicillin-susceptible S. aureus isolates. Fifty sequence types (STs), including 44 new ones, were identified by MLST. Conclusion: In this study, the high resistance rate to penicillin G and the high carrying rate of virulence gene fnbA and arcA of S.aureus were determine, and 44 new STs were identified, which may be associated with the geographical location of southern Jiangxi and local trends in antibiotic use. The study of the clonal lineage and evolutionary relationships of S. aureus in these regions may help in understanding the molecular epidemiology and provide the experimental basis for pathogenic bacteria prevention and treatment.

Associated Outcomes of Different Intravenous Antibiotics Combined with 2% Mupirocin Ointment in the Treatment of Pediatric Patients with Staphylococcal Scalded Skin Syndrome.

Purpose: To compare treatment duration, influencing factors, and costs among intravenous antibiotic groups combined with 2% mupirocin ointment for treating staphylococcal scalded skin syndrome (SSSS). Patients and Methods: Sex, age, onset days before admission, febrile status, white blood cell (WBC) count, and C-reactive protein (CRP) level were recorded as baseline characteristics for 253 included patients. The antibiotic sensitivity results were statistically compared by Cochran's Q test. Kruskal-Wallis tests were used to compare days and the total costs of hospitalization with different intravenous antibiotic applications. Mann-Whitney U-tests or Spearman's rank correlation tests were used for the univariate analysis. Finally, a multivariate linear regression model was employed to determine the variables with statistical significance. Results: The sensitivity rates of oxacillin (84.62%), vancomycin (100%), and mupirocin (100%) were significantly higher than those of clindamycin (7.69%) (p<0.0001). The duration of intravenous ceftriaxone administration was significantly longer than that of amoxicillin-clavulanic acid, cefathiamidine, and cefuroxime (p<0.01). The total hospitalization costs for cefathiamidine were significantly higher than those for amoxicillin-clavulanic acid and cefuroxime (p<0.05). According to the multiple linear regression, ages ≥60 months old were correlated with shorter treatment duration (ß=-1.48, [95% CI: -2.29, -0.66] for amoxicillin-clavulanic acid, and ß=-1.44, [95% CI: -2.06, -0.83] for cefathiamidine, and ß=-0.96, [95% CI: -1.58, -0.34] for cefuroxime) (all p<0.01). In multivariate analysis for cefathiamidine, higher WBC count (ß=0.05, [95% CI: 0.01, 0.10], p<0.05) and CRP level (ß=1.12, [95% CI: 0.14, 2.10], p<0.05) were associated with longer treatment course. Conclusion: Oxacillin resistance was rare, and clindamycin resistance was high in pediatric patients with SSSS in our district. Intravenous amoxicillin-clavulanic acid and cefuroxime combined with topical mupirocin were favorable due to a shorter intravenous treatment course and lower costs. Younger age, elevated WBC count, and CRP levels could indicate a longer course of treatment with intravenous antibiotics.

Novel IKBKG gene mutations in incontinentia pigmenti: report of two cases.

Incontinentia pigmenti (IP), an X-chromosome dominant genodermatosis caused by mutations in the IKBKG/NEMO gene, is a rare disease affecting the skin, teeth, eyes, and central nervous system. Here, we report two pedigrees of IP and detection of two novel mutations in the IKBKG gene associated with IP via genetic analysis. In addition, different gene mutation types can present with different clinical phenotypes, and the same gene mutation type can show different clinical phenotypes. This study provides clinical cases for further study of the genotype and phenotype of IP and enriches the mutation spectrum of IKBKG gene, which provides a basis for genetic counseling and genetic diagnosis of IP in the future.

The Effect of Amoxicillin Pre-Exposure on Treatment Outcomes and Antimicrobial Susceptibility in Patients with Urogenital Chlamydia trachomatis Infection.

Purpose: We investigated the influence of amoxicillin pre-exposure on treatment outcomes, Chlamydia trachomatis (CT) culture, the presence of drug-resistant genes, minimum inhibitory concentrations (MICs), and fractional inhibitory concentrations (FICs) in CT clinical strains. Additionally, we explored the effect of different antimicrobial combinations on CT. Patients and Methods: Clinical data of 62 patients with CT infection were recorded. Of these, 33 had pre-exposure to amoxicillin and 29 did not. Among patients with pre-exposure, 17 received azithromycin and 16 received minocycline. Among the patients without pre-exposure, 15 received azithromycin and 14 received minocycline. All patients underwent microbiological cure follow-ups one month after completing the treatment. 23S rRNA gene mutations, acquisition of tet(M) and tet(C) were detected using reverse transcription PCR (RT-PCR) and PCR, respectively. The MICs and FICs of azithromycin, minocycline, and moxifloxacin, alone or in combination, were determined using the microdilution and checkerboard methods, respectively. Results: More cases of treatment failure occurred in pre-exposed patients, in both treatment groups (P <0.05). No 23S rRNA gene mutations or tet(M) and tet(C) acquisitions were found. More inclusion bodies were cultured from patients without amoxicillin pre-exposure than from those with pre-exposure (P <0.0001). The MICs of all antibiotics were higher in pre-exposed patients than in those without pre-exposure (P <0.01). The FICs of azithromycin plus moxifloxacin were lower than those of the other antibiotic combinations (P <0.0001). The synergy rate of azithromycin plus moxifloxacin was significantly higher than those of azithromycin plus minocycline and minocycline plus moxifloxacin (P <0.001). The FICs of all antibiotic combinations were comparable between isolates from the two patient groups (all P >0.05). Conclusion: Pre-exposure to amoxicillin in CT patients may inhibit CT growth and decrease sensitivity of CT strains to antibiotics. Azithromycin plus moxifloxacin may be a promising treatment regimen for genital CT infections with treatment failure.

Hidrotic ectodermal dysplasia in a Chinese pedigree: A case report.

BACKGROUND: We report on a large family of Chinese Han individuals with hidrotic ectodermal dysplasia (HED) with a variation in GJB6 (c.31G>A). The patients in the family had a triad of clinical manifestations of varying degrees. Although the same variation locus have been reported, the clinical manifestations of this family were difficult to distinguish from those of congenital thick nail disorder, palmoplantar keratosis, and congenital hypotrichosis. CASE SUMMARY: This investigation involved a large Chinese family of 46 members across five generations and included 12 patients with HED. The proband (IV4) was a male patient with normal sweat gland function and dental development, no skeletal dysplasia, no cognitive disability, and no hearing impairments. His parents were not consanguineously married. Physical examination of the proband revealed thinning hair and thickened grayish-yellow nails and toenails with some longitudinal ridges, in addition to mild bilateral palmoplantar hyperkeratosis. GJB6, GJB2, and GJA1 have been reported to be the causative genes of HED; therefore, we subjected the patient's samples to Sanger sequencing of these three genes. In this family, the variation locus was at GJB6 (c.31G>A, p.Gly11Arg). Overexpression vectors of wild-type GJB6 and its variants were established and transfected into HaCaT cell models, and the related mRNA and protein expression changes were determined using real-time reverse transcriptase-polymerase chain reaction and Western blot, respectively. CONCLUSION: We report another HED phenotype associated with GJB6 variations, which can help clinicians to diagnose HED despite its varying presentations.

The study of GSDMB in pathogenesis of psoriasis vulgaris.

BACKGROUND: Gasdermin (GSDM) B is a member of the GSDM family, which is a protein that may be involved in the cell pyroptosis process and is associated with inflammatory diseases. OBJECTIVE: To explore the correlation between GSDMB and psoriasis vulgaris. METHODS: Skin lesions from 33 patients with psoriasis vulgaris and 69 normal controls were collected. ELISA and Western blot were adopted to detect proteins. The HaCaT cell line was transfected with 3 sets of interfering sequence siRNA, and the mRNA and protein levels before and after the transfection were measured by qPCR and Western blot respectively, so as to establish a cell model with low GSDMB gene expression; the MTT method was used to detect cells viability, flow cytometry to detect cell apoptosis. RESULTS: The level of GSDMB protein in the skin lesions of patients with psoriasis vulgaris was lower than that in normal skin tissues (P < 0.05). The mRNA and protein expression levels of the target gene in the siRNA-GSDMB-3 group were lower than those in the control group (P < 0.05). The proliferation of HaCaT cells was decreased by MTT method and flow cytometry, and the apoptosis rate was increased (P < 0.05). CONCLUSION: The expression level of GSDMB in psoriasis vulgaris lesion tissue is lower than that of normal skin tissue. The down-regulation of GSDMB expression can inhibit cell proliferation and promote cell apoptosis. GSDMB may play a role in the pathogenesis of psoriasis by affecting the differentiation of keratinocytes and the function of T cells.

Ant sting-induced whole-body pustules in an inebriated male: A case report.

BACKGROUND: Many ant species can harm humans; however, only a few cause life-threatening allergic reactions. Normally, reactions caused by ants occur in patients who come into contact with ant venom. Venom contains various biologically active peptides and protein components, of which acids and alkaloids tend to cause anaphylaxis. Ant venom can cause both immediate and delayed reactions. The main histopathological changes observed in ant hypersensitivity are eosinophil recruitment and Th2 cytokine production. CASE SUMMARY: A 70-year-old man was bitten by a large number of ants when he was in a drunken stupor and was hospitalized at a local hospital. Five days later, because of severe symptoms, the patient was transferred to our hospital for treatment. Numerous pustules were observed interspersed throughout the body, with itching and pain reported. He had experienced fever, vomiting, hematochezia, mania, soliloquy, sleep disturbances, and elevated levels of myocardial enzymes since the onset of illness. The patient had a history of hypertension for more than 1 year, and his blood pressure was within the normal range after hypotensive drug treatment. He had no other relevant medical history. Based on the clinical history of an ant bite and its clinical manifestations, the patient was diagnosed with an ant venom allergy. The patient was treated with 60 mg methylprednisolone for 2 d, 40 mg methylprednisolone for 3 d, and 20 mg methylprednisolone for 2 d. Oral antihistamines and diazepam were administered for 12 d and 8 d, respectively. Cold compresses were used to treat the swelling during the process. After 12 d of treatment, most pustules became crusts, whereas some had faded away. No symptoms of pain, itching, or psychological disturbances were reported during the follow-up visits within 6 mo. CONCLUSION: This case report emphasizes the dangers of ant stings.

Novel compound heterozygous mutation of SLC12A3 in Gitelman syndrome co-existent with hyperthyroidism: A case report and literature review.

BACKGROUND: Gitelman syndrome (GS) is a rare inherited autosomal recessive tubulopathy, characterized clinically by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis, and is caused by an inactivating mutation in SLC12A3. GS is prone to misdiagnosis when occurring simultaneously with hyperthyroidism. It is important to consider the possibility of other diseases when hyperthyroidism is combined with hypokalemia, which is difficult to correct. CASE SUMMARY: A female patient with hyperthyroidism complicated with limb weakness was diagnosed with thyrotoxic hypokalemic periodic paralysis for 4 mo. However, the patient's serum potassium level remained low despite sufficient potassium replacement and remission of hyperthyroidism. GS was confirmed by whole exome and Sanger sequencing. Gene sequencing revealed compound heterozygous mutations of c.488C>T (p.Thr163Met), c.2612G>A (p.Arg871His), and c.1171_1178dupGCCACCAT (p.Ile393fs) in SLC12A3. Protein molecular modeling was performed to predict the effects of the identified missense mutations. All three mutations cause changes in protein structure and may result in abnormal protein function. All previously reported cases of GS coexisting with autoimmune thyroid disease are reviewed. CONCLUSION: We have identified a novel compound heterozygous mutation in SLC12A3. The present study provides new genetic evidence for GS.

Antibiotic-resistant profile and the factors affecting the intravenous antibiotic treatment course of generalized Staphylococcal Scalded Skin Syndrome: a retrospective study.

BACKGROUND: Staphylococcal Scalded Skin Syndrome (SSSS) is caused by a special type of Staphylococcus aureus (S.aureus) which can produce exfoliative toxins. The generalized SSSS is recommended to be admitted and treated with intravenous antibiotics. However, there were limited reports on whether personal and clinical factors can have impacts on the duration of intravenous antibiotic application for pediatric patients with generalized SSSS. We performed a study to assess the factors affecting intravenous antibiotic treatment course of SSSS patients. Additionally, the positive culture rates of S.aureus in different samples and the antibiotic-resistant profile were investigated. METHODS: Two hundred nineteen patients with generalized SSSS were included. Gender, age, area, season, maximum axillary temperature, white blood cell (WBC) count, C-reactive protein (CRP) level, types of intravenous antibiotics, and types of external antibiotics were recorded as the baseline. Simple linear regression was applied in the univariate analysis to determine the variables with statistical significance and then these variables were further examined in multivariate linear regression model. The positive culture rates of S.aureus in different sample sources were calculated and the drug sensitivity results were statistically compared by pairwise Chi square test. RESULTS: According to the multiple linear regression, older ages (ß = - 0.01, p < 0.05) and external application of fusidic acid (ß = - 1.57, p < 0.05) were associated with shorter treatment course, elevated leukocytes (ß = 0.11, p < 0.001) and CRP level (ß = 1.64, p < 0.01) were associated with longer treatment course. The positive culture rates of periorificial swabs, throat swabs, and blood samples were 54.55, 30.77, and 5.97% respectively. The resistant rates of levofloxacin (8.33%), gentamycin (8.33%), tetracycline (25%), oxacillin (8.33%), vancomycin (0%) were significantly lower than the ones of erythromycin (100%), trimethoprim-sulfamethoxazole (TMP/SMX) (83.33%), clindamycin (91.67%), penicillin G(100%) (p < 0.001). CONCLUSION: Elevated leukocytes and CRP level indicated prolonged intravenous antibiotic treatment course. Older ages and external application of fusidic acid helped to reduce the treatment course. Compared with blood samples, the culture positive rates of S.aureus in periorificial and throat swabs were higher. Oxacillin and vancomycin resistance was rare and clindamycin resistance was common. Clindamycin monotherapy for SSSS should be avoided.

Author Correction: Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.

This corrects the article DOI: 10.1038/ncomms7793.

Genotype combination contributes to psoriasis: An exhaustive algorithm perspective.

Researchers have learned that nearly all conditions and diseases have a genetic component. With the benefit of technological advances, many single-nucleotide polymorphisms (SNPs) have been found to be associated with the risk of complex disorders by using genome wide association studies (GWASs). Disease-associated SNPs are sometimes shared by healthy controls and cannot clearly distinguish affected individuals from unaffected ones. The combined effects of multiple independent SNPs contribute to the disease process, but revealing the relationship between genotype and phenotype based on the combinations remains a great challenge. In this study, by considering the disease prevalence rate, we conducted an exhaustive process to identify whether a genotype combination pattern would have a decisive effect on complex disorders. Based on genotype data for 68 reported SNPs in 8,372 psoriasis patients and 8,510 healthy controls, we found that putative causal genotype combination patterns (CGCPs) were only present in psoriasis patients, not in healthy subjects. These results suggested that psoriasis might be contributed by combined genotypes, complementing the traditional modest susceptibility of a single variant in a single gene for a complex disease. This work is the first systematic study to analyze genotype combinations based on the reported susceptibility genes, considering each individual among the cases and controls from the Chinese population, and could potentially advance disease-gene mapping and precision medicine due to the causality relationship between the candidate CGCPs and complex diseases.

Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis.

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR, SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27 (P<5.00 × 10(-08)). In addition, we also replicate four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D-LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis.

Construction of circular miRNA sponges targeting miR-21 or miR-221 and demonstration of their excellent anticancer effects on malignant melanoma cells.

microRNA sponges antagonizing the oncogenic microRNAs are potential candidates for RNA-based cancer therapies. Although the constructed sponges so far are to some extent suitable for biological experiments, they can only express at relative low levels in cells, because they are sensitive to microRNA-mediated activation of deadenylation and subsequent exonucleolytic degradation. Since circular RNA molecules are resistant to exonuclease degradation, we report the production of circular microRNA sponges against miR-21 or miR-221 in cell lines using the self-splicing permuted intron-exon sequences derived from T4 bacteriophage gene td. The circularized microRNA sponges withstand enzymatic degradation and are completely resistant to microRNA-mediated degradation. They are more effective than typical linear microRNA sponges and microRNA inhibitors in derepressing microRNA targets. They also display superior anti-cancer activities compared to the linear sponges in malignant melanoma cell lines. We have provided an alternative method for circular microRNA sponge production and malignant melanoma treatment.