Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

Analysis of etching mechanism and etched slope control of silicon for nanoimprinting lithography.

In the nanoimprint lithography (NIL) process, profile control of imprint masters is a very important task. Therefore, we attempted to control the etched slope of imprint masters as a function of adding O2 to CF4 plasma. Etched profile mechanisms and relationships between the etch kinetics and plasma chemistry were explored using zero-dimensional-based modeling. O2 flow rate increased to 24 sccm, the Si etch rate increased in the range of 186-393 nm/min, while the etch rate rapidly decreased as the O2 flow rate increases beyond 24 sccm. Meanwhile, change in the etch rate of SiO2 followed a similar tendency as the etch rate of Si as a function of O2 flow rate in the CF4/O2 mixing gases. The Si and SiO2 etch rate were expected to be closely dependent on the F radical intensity in CF4/O2 mixing gases. Moreover, the results of simulated normalized lateral etch critical dimension (NLECD) are in agreement with the measured NLECD as a function of O2 flow rate in the CF4/O2 mixing gases.

Osteoconductivity of Porous Titanium Structure on Implants in Osteoporosis.

In compromised bone conditions such as osteoporosis, developments of the implant surface are necessary to secure the stability of implants. This study investigated the effect of the surface porous titanium structure (PS) on the osseointegration of implants in osteoporotic bone. Bilateral ovariectomy (OVX) was performed in 4 female beagle dogs to induce osteoporosis for 32 wk. Success of induction was based on the evaluation of bone mineral density by Hounsfield units (HU) in computed tomography images. Posterior teeth in both mandibles were extracted 1 wk after OVX, and a total of 30 implants (15 implants in each group) were placed after 32 wk of osteoporosis induction. The control group implant underwent resorbable blast media (RBM) surface treatment, whereas the test group underwent RBM surface treatment in the coronal two-thirds and a PS added to the apical 3-mm portion. HU values in the mandibular trabecular bone, lumbar, and femoral head significantly decreased 32 wk after OVX, confirming osteoporotic condition after induction. Resonance frequency analysis and removal torque test showed comparable values between the 2 groups at 4 wk after implant placement. The surface topography of the implant after removal showed hard tissue integration at the PS in the test group. Bone-to-implant contact length was greater in the apical portion of the test group, although statistical significance was not found between the groups. Interthread bone area in the apical portion of the test group showed a significant increase compared to the control group (control: 0.059 ± 0.041 mm2, test: 0.121 ± 0.060 mm2, P = 0.028) with the histological feature of bone ingrowth at the PS. The findings of the study demonstrated that the surface PS could improve osteoconductivity in the osteoporotic trabecular bone by bone ingrowth at the pore space, thereby enhancing the osseointegration and stability of the implants.

Demetylation of the sex-determining region Y gene promoter and incidence of disorder of sex development in cloned dog males.

Canine cloning is occasionally accompanied by abnormal sexual development. Some male donor cells produce cloned pups with female external genitalia and complete male gonadal dysgenesis, which is classified as an XY disorder of sex development (XY DSD). In this study, we examine the potential of 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to reduce the phenotypic abnormality XY DSD in somatic cell nuclear transfer (SCNT)- derived pups. We used a 9-year-old normal male German Shepherd dog as a cell donor. Donor cells were treated with 10 nM 5-aza-dC for 4 days before being used for SCNT. At the same stage of cell development, significantly lower levels of DNA methylation of the sex-determining region Y (SRY) promoter was observed in the treated donor cells compared to that in the untreated cells (95.2% versus 53.3% on day 4 for the control and treated groups, respectively). No significant differences were observed in the control or treatment groups concerning fusion rate, pregnancy rate (30 days or entire period), the number of pups, or the incidence of XY DSD. However, more XY DSD dogs were observed in the control group (31.25%) than in the treatment group (14.29%). Hypermethylation of the SRY promoter was observed in the XY DSD cloned pups in both the treatment (84.8%) and control groups (91.1 ± 1.4%) compared to the methylation level in the phenotypically normal male pups of the treatment (23.2 ± 20.9%) and control groups (39.1 ± 20.1%). These results suggest that 5-aza-dC treatment of donor cells can reduce the methylation level of the SRY promoter in donor cells, and thus, 5-aza-dC is advantageous for reducing the incidence of XY DSD in canine cloning.

Clinical and angiographic follow-up of spontaneous isolated superior mesenteric artery dissection.

OBJECTIVES: To observe the clinical features and angiographic findings in patients with a spontaneous isolated superior mesenteric artery dissection (SISMAD) and to identify any correlation between them. METHODS: From a single institution, 32 patients (22 symptomatic patients at presentation; mean age 54years; men 97%) with SISMAD were retrospectively reviewed. All patients were available for clinical follow-up after treatment (conservative, n=28, 88%, open or endovascular superior mesenteric artery (SMA) reconstruction, n=4, 12%), and follow-up CT scans were available in 28 patients (mean 22months, range 1-80months). RESULTS: We found a positive correlation between pain severity and dissection length (p=0.03, rho=0.50, Spearman's partial correlation analysis). After conservative treatment, only one patient (3%) required bowel resection, and there was no difference in outcome between patients who were treated with anticoagulation or anti-platelet therapy and those who were not (p=1.00, Fisher's exact test). No patients had progression of their lesion on the follow-up CT angiography. CONCLUSIONS: In SISMAD patients, dissection length is positively associated with more severe clinical symptoms. After conservative treatment, we observed a benign clinical course and no CT progression of the dissection, even without anticoagulation or anti-platelet therapy. Based on our observation, patients with SISMAD can be treated conservatively without anticoagulation therapy.

Effect of proximal arterial occlusion on the progression of the distal arterial disease.

PURPOSE: To test the hypothesis that a proximal arterial occlusion has a protective effect on the progression of distal arterial disease, assessed by distal runoff resistance score (DRRS). MATERIALS AND METHODS: One hundred and nineteen patients (median age 64 y, male 96%) with a unilateral iliac and/or femoral arterial occlusion caused by atherosclerosis were analyzed retrospectively. DRRS was assessed on arteriograms of the test limb (with proximal arterial occlusion) and control limb (contralateral limb). Multivariate analysis was performed to determine if a proximal arterial occlusion was an independent risk factor for the development of a difference in the DRRS between the test and control limbs. RESULTS: The clinical features of the subjects were claudication in 85%, ankle brachial index 0.52 (median), diabetes in 30% and smoker in 76%. The upper leg DRRS of the test limb was significantly lower in the iliac occlusion group than in the control limb (1.87+/-1.69 vs 2.85+/-2.75, p=0.032). However, multivariate analysis failed to identify any risk factors associated with the difference in DRRS in both limbs. CONCLUSION: There was no evidence that a proximal arterial occlusion was associated with a slower progression of distal arterial disease.

The 'four-in-one' procedure for habitual dislocation of the patella in children: early results in patients with severe generalised ligamentous laxity and aplasis of the trochlear groove.

We describe our experience with the 'four-in-one' procedure for habitual dislocation of the patella in five children (six knees). All the patients presented with severe generalised ligamentous laxity and aplasia of the trochlear groove. All had a lateral release, proximal 'tube' realignment of the patella, semitendinosus tenodesis and transfer of the patellar tendon. The mean age at the time of the operation was 6.1 years (4.9 to 6.9), and the patients were followed up for a mean of 54.5 months (31 to 66). The clinical results were evaluated using the Kujala score. There has been no recurrence of dislocation. All the patients have returned to full activities and the parents and children were satisfied with the clinical results. The mean Kujala score was 95.3 (88 to 98). Two patients had marginal skin necrosis which healed after debridement and secondary closure. These early results in this small group have shown that the 'four-in-one' procedure is effective in the treatment of obligatory dislocation of the patella in children with severe ligamentous laxity and trochlear aplasia.

Soft Tissue Stability around Single Implants Inserted to Replace Maxillary Lateral Incisors: A 3D Evaluation.

Purpose. To evaluate the soft tissue stability around single implants inserted to replace maxillary lateral incisors, using an innovative 3D method. Methods. We have used reverse-engineering software for the superimposition of 3D surface models of the dentogingival structures, obtained from intraoral scans of the same patients taken at the delivery of the final crown (S1) and 2 years later (S2). The assessment of soft tissues changes was performed via calculation of the Euclidean surface distances between the 3D models, after the superimposition of S2 on S1; colour maps were used for quantification of changes. Results. Twenty patients (8 males, 12 females) were selected, 10 with a failing/nonrestorable lateral incisor (test group: immediate placement in postextraction socket) and 10 with a missing lateral incisor (control group: conventional placement in healed ridge). Each patient received one immediately loaded implant (Anyridge®, Megagen, Gyeongbuk, South Korea). The superimposition of the 3D surface models taken at different times (S2 over S1) revealed a mean (±SD) reduction of 0.057 mm (±0.025) and 0.037 mm (±0.020) for test and control patients, respectively. This difference was not statistically significant (p = 0.069). Conclusions. The superimposition of the 3D surface models revealed an excellent peri-implant soft tissue stability in both groups of patients, with minimal changes registered along time.

A novel H1 mutation in the keratin 1 chain in epidermolytic hyperkeratosis.

We report a novel mutation in a case of epidermolytic hyperkeratosis that results in a proline for arginine substitution in the penultimate residue position of the H1 subdomain of the keratin 1 chain, which is near the beginning of the rod domain. This causes a severe clinical disease classified as PS-2. Therefore, the H1 subdomain is probably equally important for the maintenance of keratin intermediate filament integrity as the rod domain. Since earlier concepts had implied that mutations in the H1 subdomain produce milder disease, this case suggests that attempts to correlate mutations with disease presentation remain problematic.

The effect of external electron beam on neointima in rat carotid artery injury model.

PURPOSE: Endovascular irradiation with either a gamma or a beta source has shown to reduce neointimal proliferation. However, the effect of external-beam radiation on neointimal hyperplasia is controversial. The objective of this study was to determine the effect of external-beam irradiation with different doses on neointimal hyperplasia in the rat carotid artery injury model. METHODS AND MATERIALS: Twenty-seven Sprague-Dawley rats underwent endothelial denudation injury by 2F Fogarty balloons on carotid artery. Immediately after the injury, rats were irradiated externally using 6-MeV electrons. Rats were grouped according to the radiation doses, 0 Gy as controls (n = 5), 5 Gy (n = 5), 10 Gy (n = 5), 15 Gy (n = 6), and 20 Gy (n = 6). Then, rats were sacrificed after 2 weeks and the carotid arteries were perfusion-fixed in paraformaldehyde. External elastic lamina (EEL) area, lumen area, maximal intimal thickness (MIT), and intimal area (IA) of the injured segments were measured on the basis of histomorphometry. RESULTS: In EEL and lumen area, there was no statistically significant difference between the irradiated groups and the controls. In MIT and IA, low-dose radiation (5 Gy and 10 Gy) did not induce any significant reduction. High-dose radiation (15 Gy and 20 Gy), however, reduced MIT and IA significantly. CONCLUSION: External electron beam reduced the intimal area, and the inhibition of neointimal proliferation was dependent upon radiation doses. This study suggests that the minimal effective dose for the inhibition of neointimal hyperplasia following denudation injury in the rat carotid model is between 10 Gy and 15 Gy.

Biodistribution and kinetics of holmium-166-chitosan complex (DW-166HC) in rats and mice.

UNLABELLED: The fate of 166Ho-chitosan complex, a radiopharmaceutical drug for cancer therapy, was determined by studying its absorption, distribution and excretion in rats and mice. METHODS: Holmium-166-chitosan complex [0.75 mg of Ho(NO3)3 x 5H2O and 1 mg chitosan/ head] was administered intrahepatically to male rats. Radioactive concentrations in blood, urinary and fecal excretion and radioactive distribution in tissues were examined. To determine the effects of chitosan in 166Ho-chitosan complex, 166Ho alone [0.75 mg of Ho(NO3)3 x 5H2O/head] was intrahepatically administered to male rats, and radioactive concentrations in blood, urinary and fecal excretion and radioactive distribution were examined. In B16 melanoma-transplanted nude mice, radioactive distribution after intratumoral administration of 166Ho-chitosan complex [0.075 mg of Ho(NO3)3 x 5H2O and 0.10 mg chitosan/head] was investigated also. RESULTS: After administration of 166Ho-chitosan complex, the radioactive concentrations in blood were low, and cumulative urinary and fecal excretions over a period of 0-72 hr were 0.53% and 0.54%, respectively. The radioactive concentrations in tissues and the whole-body autoradiography images showed that most of the administered radioactivity was localized at the administration site, and only slight radioactivity was detected from the liver, spleen, lungs and bones. On the other hand, results of intrahepatic administration of 166Ho alone showed high radioactive concentrations in the blood, and the whole-body autoradiographs showed that the administered radioactivity was distributed in many organs and tissues. These results strongly suggest that 166Ho is retained at the administration site only when it forms a chelate complex with chitosan. Autoradiographs after intratumoral administration of 166Ho-chitosan complex showed that radioactivity was localized at the site of administration without distribution to the other organs and tissues. CONCLUSION: Administered 166Ho-chitosan complex is retained at the administration site after either intrahepatic or intratumoral administration to rats or tumor-transplanted nude mice.

Radionuclide therapy of skin cancers and Bowen's disease using a specially designed skin patch.

UNLABELLED: Skin cancer is the most common malignancy in humans. Therapeutic modalities for skin cancer are local destruction, radiotherapy and surgery. External radiation therapy leads to good results, however, generally 5-6 wk of treatment is needed to deliver optimal radiation dose to tumors. In this study, a beta-emitting radionuclide, 166Ho, impregnated in a specially designed patch, was used on superficial skin cancers and Bowen's disease for local irradiation. METHODS: Ten mice with chemically induced skin tumors were studied. Five-millimeter size patches containing 22.2-72.15 MBq (0.6-1.95 mCi) 166Ho were applied to the tumor surface for 1-2 hr. In a human trial, patients with squamous-cell carcinoma (n = 3), basal cell carcinoma (n = 1) and Bowen's disease (n = 1) were treated with patches containing 273.8-999 MBq (7.4-27 mCi) of 166Ho for 30 min to 1 hr. Pathologic examination was performed 4-7 wk after treatment in an animal model. Skin biopsy was performed 8 wk post-treatment in four patients. RESULTS: Tumor destruction was seen 1 wk post-treatment, however, radiation dermatitis or ulceration developed at the site of radionuclide application. Those reactions healed gradually with fibrosis or epithelialization, which was confirmed pathologically. No significant adverse reaction to radiation except subcutaneous fibrosis was found. CONCLUSION: Superficial skin tumors could be successfully treated by topical application of beta-emitting radionuclides.

Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells.

1. Hypersensitivity to the drug sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NHOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). SMX-NO covalently modifies self proteins which in turn might be recognized as neo-antigens by T-cells. The antioxidant glutathione (GSH) is known to protect cells from reactive metabolites by conjugation and subsequent dissociation to SMX-NHOH and/or SMX. 2. To study the reactivity of T-cells to SMX metabolites and their respective role in the generation of drug-specific T-cells, we analysed the effect of GSH on the response of PBMC to SMX and its metabolites SMX-NHOH and SMX-NO. Furthermore, we monitored the proliferative response of drug-specific T-cell clones in the presence or absence of GSH. 3. We found that addition of GSH to peripheral blood mononuclear cells had no effect on the SMX-specific response but enhanced the proliferation to SMX-metabolites. The response of SMX-NO-specific T-cell clones was abrogated when GSH was present during the covalent haptenation of antigen presenting cells (APC). Conversely, SMX-specific T-cell clones gained reactivity through the conversion of SMX-NO to the parent drug by GSH. While GSH had no effect on the initial activation of T-cell clones, it prevented covalent binding to APCs, reduced toxicity and thereby led to proliferation of drug-specific T-cells to non-reactive drug metabolites. 4. Our data support the concept that in allergic individuals T-cells recognize the non-covalently bound parent drug rather than APC covalently modified by SMX-NO.

A study of skin responses to follow-up, rechallenge and combined effects of irritants using non-invasive measurements.

Irritant contact dermatitis is a common clinical problem. Primary irritation can be easily recognized, but cumulative irritation by daily exposure is hard to be diagnosed and the condition may fail to be clear even away from work. The mechanism of irritant dermatitis produced by repeated or combined exposure to clinical or subclinical doses of irritants is still poorly understood. In order to find out whether the subclinical doses of irritants affect each other by repeated or combined exposure according to their concentrations, non-invasive measurements, transepidermal water loss and laser Doppler flowmetry were used. Sodium lauryl sulfate, sodium hydroxide and benzalkonium chloride were serially diluted and patch-tested with large Finn chambers on Scanpor tape on the back of normal human volunteers and responses were followed up for 7 days. Twice repeated exposure with subclinical doses of irritants at 1 day intervals were also performed. Repeated daily applications for 5 days with subclinical doses of single or premixed irritants were performed to know the combined irritating effect. The irritant response was well correlated to the concentration of the irritants. However, increased response was not observed when subclinical doses were rechallenged on the previously patch tested sites. Twice-repeated exposure of subclinical doses of irritants increased skin irritancy when measured by transepidermal water loss and laser Doppler flowmetry. Some correlation and some discrepancies were observed between different evaluation methods in combined and repeated application tests with irritants of subclinical doses. Responses of skin irritancy induced by subclinical doses showed somewhat different pattern from that given strong irritants.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum concentration of the soluble interleukin-2 receptor in vitiligo patients.

Serum levels of sIL-2R can be used to monitor in vivo immune activation and its elevation have been shown to be correlated with T cell mediated immune disease such as atopic dermatitis, psoriasis, lymphoma and systemic sclerosis. Vitiligo is the disease of depigmentation caused by destruction of melanocytes, and there have been extensive studies on the immune pathogenesis. If the pathogenesis of vitiligo is correlated with the activation of T lymphocytes, the change of IL-2R will be detected compared with that of normal control. Therefore we sought the change in sIL-2R to determine whether T lymphocytes from patients with vitiligo show abnormal biological behavior. The quantitation of sIL-2R was done by sandwich enzyme-linked immunosorbent assay (ELISA) from the sera of 79 vitiligo patients and 40 normal controls. The results were summarized as following. The sIL-2R level in vitiligo patients (671.91 +/- 368.59 U/ml) was significantly increased compared with that of controls (370.8 +/- 71.8 U/ml; P < 0.005). According to clinical types, sIL-2R level in focal type of vitiligo patients was significantly higher than those in other types (segmental or generalized; P < 0.05). The sIL-2R level in patients less than 1 year duration was significantly higher than in patients more than 1 year duration (P < 0.05). The sIL-2R levels were not significantly different between active and inactive group. There was no significant differences among sIL-2R levels according to sex or age of onset. Our study showed that sIL-2R level was higher in vitiligo patients compared with that of normal controls, so the activation of T lymphocytes would be an important component in the pathogenesis of vitiligo. The higher sIL-2R levels in recent onset group would suggest that sIL-2R level might be an acute immunologic marker in vitiligo patients.

Arginine in the beginning of the 1A rod domain of the keratin 10 gene is the hot spot for the mutation in epidermolytic hyperkeratosis.

Keratin intermediate filaments are expressed in specific type I/type II pairs in the stage of differentiation of keratinocytes. The mutations in the keratin genes expressed in the epidermis are etiologically responsible for several epidermal genetic skin diseases, such as epidermolysis bullosa simplex, epidermolytic hyperkeratosis (EHK), ichthyosis bullosa of Siemens, palmoplantar keratoderma, pachyonchia congenita and white sponge nevus. The mutations of keratins 1/10 which are expressed in spinous and granular layers are confirmed to cause EHK. There are several trials to correlate between the clinical phenotypes and sites of mutations of the keratin genes. One of these is that EHK is divided into two groups: the palms and soles involvement (PS) group and the non-palms and soles (NPS) group. So far the PS group had the mutations in the keratin 1 and the NPS group in keratin 10. Most of the mutations of the NPS group were reported in the beginning of the 1A rod domain and over 2/3 of the mutations in the 1A rod domain were the base pair substitution of arginine. Here we find two different mutations in two unrelated Korean kindreds classified as NPS group-R156C and R156H-in the 1A rod domain of keratin 10. Our results are compatible with the above classification and suggest that the arginine in the beginning of the 1A rod domain is the hot spot for the mutation of the keratin 10 gene.

Loss of heterozygosity on the short arm of chromosome 17 in uterine cervical carcinomas.

DNA samples from 26 cervical carcinoma and normal tissue pairs were studied by restriction fragment length polymorphism (RFLP) analysis to determine the frequency of loss of heterozygosity (LOH) on 17p. Allelic loss in the p13.1 region of chromosome 17, known to contain the TP53 locus, was not detected in any of 10 informative cases. Instead, LOH was detected on 17p13.3 in eight (40%) of 20 informative cases with at least one of two 17p13.3 markers. Examination of the intragenic region of p53 in the same samples using polymerase chain reaction (PCR)-RFLP analysis showed no LOH in the gene (none of 16 informative individuals).

p53 mutation in epithelial ovarian carcinoma and borderline ovarian tumor.

We have investigated a series of 19 human ovarian carcinomas and 17 borderline ovarian tumors to determine the loss of heterozygosity on chromosome 17p and possible concurrent p53 mutations. Allelic losses were assessed using restriction fragment length polymorphism study, and p53 gene mutations were detected by single strand conformation polymorphism analysis and by direct sequencing. In addition, we stained the same tumor sections immunohistochemically to detect p53 protein in tissues. Among 19 ovarian malignant tumor samples tested, we identified 17p allelic deletions in 12 (63.2%) of 19 informative cases. The p53 gene mutation was observed in 7 of 19 (36.8%) malignant ovarian tumors, and it was predominantly observed in tumors with allelic loss on 17p (six of seven tumors, 85.7%). Although 9 cases of 17 borderline ovarian tumors showed shifted bands on single strand conformation polymorphism analysis, only one case was proved to have a point mutation in direct sequencing. We also obtained six cases (31.6%) of positive immunoreactivity from 19 ovarian cancers and 3 cases (17.6%) from 17 borderline ovarian tumors. We conclude that loss or inactivation of tumor suppressor gene function by chromosome 17p allelic deletions or p53 mutations are important genetic changes in ovarian cancer.

Preparation of 153Sm-chitosan complex for radiation synovectomy.

A samarium 153-chitosan complex was prepared by simply mixing acidic solutions of chitosan and (153)SmCl(3). When a solution of this complex was injected into the knee joints of rabbits, minimal extra-articular leakage was observed. This can be attributed to the rapid change in the pH of the complex solution from acidic to neutral, resulting in the formation of gel followed by the subsequent retention in the administered site. Thus, the complex solution represents a promising candidate for radiation synovectomy.