Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.

BACKGROUND: Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations. OBJECTIVES: We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation. METHODS: Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing. RESULTS: Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. CONCLUSIONS: These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

Supermicrovascular anastomosis training using chicken wings and colored water.

Plastic surgeons require experience in supermicroscopic vascular anastomosis. Herein, we report a simple, rapid, and cost-effective training method using chicken wings and colored water. The avian ventral metacarpal artery was selected for dissection and anastomosis to mimic supermicrosurgery. Over 14 weeks (one anastomosis per day), the ulnar artery in 100 chicken wings was exposed by dissection, cut proximally, and injected with blue food dye-colored water by an inexperienced surgeon. After ligating the artery branches, it was cut and subjected to end-to-end anastomosis. Next, colored water was injected into the ulnar artery to check for suture sufficiency. The vessel was re-dissected to inspect the lumen and sutures qualitatively. Of the 100 wings, the first and last 20 wings' ventral metacarpal artery dissection, anastomosis times, and leakage frequency were compared. Avian ventral metacarpal artery diameter was recorded, and the cumulative anastomosis time where individual anastomosis times started decreasing was determined. Leakage rates before and after this point were compared. The avian ventral metacarpal artery diameter was 0.7-0.8 mm. The last 20 wings had significantly shorter median dissection times (12:27 vs. 17:45 min), anastomosis times (9:02 vs. 12:29 min), and leakage rates (15% vs. 70%); more even stitching and parallel ligature points; and less vessel layer inversion than the first 20 wings. After a cumulative anastomosis time of 10 h 26 min, individual times sharply decreased, and the leakage rate decreased significantly (58.3% vs. 23.8%). The proposed method significantly improved supermicrosurgical anastomosis. Thus, we believe that this method will help surgeons improve their supermicrosurgical skills.

Predicting delayed pressure ulcer healing using thermography: a prospective cohort study.

OBJECTIVE: To investigate whether thermography can be used to detect latent inflammation in pressure ulcers and predict pressure ulcer prognosis in a clinical setting. METHOD: For this cohort study, we recruited 35 patients with stage II-IV pressure ulcers on the torso, who underwent thermographic assessment on discovery of their pressure ulcer. The patients were followed up for at least 3 weeks. Thermography was performed immediately after dressing removal. Pressure ulcers were classified into two groups depending on whether or not the wound site temperature was lower or higher than the periwound skin: the low temperature group and the high temperature group respectively. A generalised estimation equation was used to estimate the relative risk of delayed healing of pressure ulcers, comparing wounds with high temperatures and low temperatures. RESULTS: Of the 35 patients, 21 had 'low temperature' wounds and 14 had 'high temperature' wounds at baseline. Two patients in the high temperature group presented with overt infection, and were excluded from further analysis. Twenty-two pressure ulcers were considered to heal 'normally' (that is, the wound area reduced by 30% or more within 3 weeks) and 16 did not heal. The baseline DESIGN score (a measure of gross wound status) did not differ in any subscales between the high and low temperature groups. The relative risk for delayed healing in high temperature cases was 2.25 (95% confidence intervals; 1.13-4.47, p=0.021). Sensitivity was 0.56, specificity was 0.82, positive predictive value was 0.75, and negative predictive value was 0.67. CONCLUSION: Our results indicate that using thermography to classify pressure ulcers according to temperature could be a useful predictor of healing at 3 weeks, even though wound appearances may not differ at the point of thermographical assessment. The higher temperature in the wound site, when compared with periwound skin, may imply the presence of critical colonisation, or other factors which disturb the wound healing.

Cellular and molecular features of lipoma tissue: comparison with normal adipose tissue.

BACKGROUND: Involvement of adipose-derived stem/progenitor/stromal cells (ASCs) in the development of lipomas has been suggested, but the pathogenesis and pathophysiology of this tumour remain unclear. OBJECTIVES: To analyse cellular and transcriptional characteristics of lipoma tissue compared with normal adipose tissue, further to delineate differentiating features. METHODS: For lipoma or normal adipose tissues, we used a new whole-mount staining enabling three-dimensional imaging of nonfixed and nonfrozen adipose tissue. Immunohistochemistry and real-time polymerase chain reaction for obesity-related genes were performed as well as comparative assay of the proliferative and adipogenic capacity of ASCs. RESULTS: A large number of small adipocytes surrounded by CD34+/lectin- ASCs and increased numbers of Ki67+/CD34+ ASCs indicated enhanced adipogenesis in lipoma compared with normal adipose tissue. In contrast, cellular apoptosis was not enhanced in lipoma, suggesting that the enlargement of lipoma tissue may be due to a positive balance of adipocyte turnover (accelerated adipogenesis combined with nonenhanced apoptosis). Leptin mRNA was upregulated in lipoma, while adiponectin, tumour necrosis factor-alpha and glucose transporter 1 mRNA were downregulated and there were no apparent changes in hypoxia-inducible factor 1alpha, peroxisome proliferator-activated receptor-gamma and plasminogen activator inhibitor-1. These results suggested dysfunction of lipoma adipocytes similar to that in obesity, but indicated that lipoma tissue lacked several obesity-related phenomena such as ischaemia (hypoxia), macrophage infiltration, inflammatory reactions and enhanced glycolysis. ASCs from lipoma and normal adipose tissue showed similar proliferative and adipogenic capacity. CONCLUSIONS: Our findings revealed that lipoma tissue shows a positive balance of adipocyte turnover involving proliferating ASCs and several transcriptional differences from adipose tissue enlargement in obesity.

Identification of ABCG2 as an Exporter of Uremic Toxin Indoxyl Sulfate in Mice and as a Crucial Factor Influencing CKD Progression.

Chronic kidney disease (CKD) patients accumulate uremic toxins in the body, potentially require dialysis, and can eventually develop cardiovascular disease. CKD incidence has increased worldwide, and preventing CKD progression is one of the most important goals in clinical treatment. In this study, we conducted a series of in vitro and in vivo experiments and employed a metabolomics approach to investigate CKD. Our results demonstrated that ATP-binding cassette transporter subfamily G member 2 (ABCG2) is a major transporter of the uremic toxin indoxyl sulfate. ABCG2 regulates the pathophysiological excretion of indoxyl sulfate and strongly affects CKD survival rates. Our study is the first to report ABCG2 as a physiological exporter of indoxyl sulfate and identify ABCG2 as a crucial factor influencing CKD progression, consistent with the observed association between ABCG2 function and age of dialysis onset in humans. The above findings provided valuable knowledge on the complex regulatory mechanisms that regulate the transport of uremic toxins in our body and serve as a basis for preventive and individualized treatment of CKD.

IgM-producing renal plasmacytoma.

A seventy-six-year-old woman with plasmacytoma presenting as a renal mass died three months after diagnosis. Bone surveys disclosed no lytic lesions. Gallium-67 scan showed an avid uptake of the radionuclide in the renal mass. Histologic and immunofluorescence studies of resected specimens demonstrated that the renal parenchyma was destroyed by sheets of immature plasma cells producing IgM-lambda and by massive deposits of amorphous, eosinophilic substance stained with anti-mu and anti-lambda antisera. The literature is reviewed. We believe this case is the first one of well-documented IgM-producing renal plasmacytoma.

A lateral ventricular gliosarcoma arising in an ependymoma.

OBJECTIVE: We describe a 29-year-old man with gliosarcoma in the lateral ventricle. CASE: The patient presented with headache and impairment of consciousness. Computed tomography and magnetic resonance imaging localized the tumor to the right lateral ventricle and showed heterogeneous enhancement with administration of contrast agents. The tumor was partially removed via a transcallosal approach. Histologic examination disclosed gliosarcoma arising by malignant transformation of an ependymoma. POST-OPERATIVE COURSE: The patient died of tumor progression 78 days after admission, despite intensive radiotherapy and chemotherapy.

Changes of plasma concentrations of steroid hormones, prostaglandin F2 alpha-metabolite and pregnant mare serum gonadotropin during pregnancy in thoroughbred mares.

Plasma concentrations of estrogens, gestagens, cortisol (F), 13, 14-dihydro, 15-keto PGF2 alpha (PGFM) and pregnant mare serum gonadotropin (PMSG) in 10 Thoroughbred mares were measured for a 11-month pregnancy period. Estrone (E1) and estradiol-17 beta (E2) levels gradually increased as the pregnancy advanced, showing a peak around Month 8 and decreased thereafter. Progesterone (P) levels increased on Months 3 and 11, and 17 alpha-OH-progesterone (17 alpha-OHP) levels peaked on Month 3, whereas 20 alpha-OH-progesterone (20 alpha-OHP) levels increased sharply after Month 6. PGFM indicated peaks on Months 2 and 11. F and PMSG levels peaked on Months 2 and 3. From factor analysis, Month, E1, E2 and 20 alpha-OHP were discriminated as Factor 1, increasing with the progress of pregnancy, PMSG, 17 alpha-OHP and P as Factor 2, showing a relation with the secondary corpus luteum, and PGFM and F as Factor 3, affecting PGFM change on Month 2 by F. P also related to both Factors 1 and 3, showing an inverse relation against PGFM. In conclusion E1, E2 and 20 alpha-OHP contained in Factor 1 were suggested to be important especially as parameters of placental function after Month 6.

[A patient with limb-girdle type myasthenia gravis and atopic dermatitis, both of which improved after thymectomy].

We herein report a patient with myasthenia gravis (MG) and atopic dermatitis (AD). Heretofore, there have been no reports of patients with MG and AD. Nine years ago, a 25-year-old man noted muscle weakness of upper and lower extremities on physical labor, and the muscle weakness was gradually exacerbated. Two years ago, he noted acute skin eczema with itching on his hands and feet. Neurological examination revealed mild left ptosis, facial muscle weakness and proximal muscle weakness of upper and lower extremities, but no diplopia, ophthalmoplegia or dysphagia. Although anti-nicotinic acetylcholine receptor antibody was negative, edrophonium test was positive and 54% waning in the thenar muscles was observed on Harvey-Masland test. Thus, he was diagnosed as limb-girdle type MG. IgE level in his serum elevated (1,818 U/ml). After thymectomy, the muscle weakness markedly improved as well as waning in the thenar muscles (11%). Simultaneously, AD markedly improved and serum IgE level was decreased (1,245 U/ml). Thus, MG and AD in this case may be derived from some common immunological aberrancy in the thymus.

[Small epidermoid induced trigeminal neuralgia unrecognized by conventional CT and MRI for over 25 years].

A 65-year-old woman had been conservatively treated as idiopathic trigeminal neuralgia for over 25 years, because conventional computed tomography (CT) and magnetic resonance imaging(MRI) showed no abnormality in the cerebello-pontine(CP) angle cistern. She received a detailed MRI by constructive interference in steady state and diffusion weighted image(DWI) sequences. Those sequences on MRI well demonstrated a epidermoid tumor in the CP angle cistern, and the removal of the tumor completely resolved the neuralgia. Since a small epidermoid in the CP angle cistern seems to be unrecognized by conventional CT and MRI, detailed evaluation by DWI sequence, which has been widespread recently, is required for patients with trigeminal neuralgia.

[Temporary placement of inferior vena cava filter prior to transcatheter arterial embolization (TAE) for hepatocellular carcinoma with IVC tumor thrombus--prevention of pulmonary tumor emboli after TAE].

A 66-year-old-man with a right huge hepatocellular carcinoma (HCC) extending into both the right portal vein and the right atrium underwent transcatheter arterial embolization (TAE) via the right hepatic artery. Prior to the TAE, a temporary inferior vena cava (IVC) filter was placed suprarenally for prevention of pulmonary tumor emboli. When we replaced the temporary IVC filter with a new one 7 days after the TAE, the filter which was pulled out of the IVC captured a fragment of the tumor thrombus. A histopathological specimen demonstrated only ghost cells. The patient has been followed at our outpatient clinic without any tumor thrombus or pulmonary infarction for 13 months after this procedure.