Case Report: Tuberous sclerosis complex-associated hemihypertrophy successfully treated with mTOR inhibitor sirolimus.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a mutation in either of the two tumor suppressor genes, TSC1 and TSC2. Due to dysregulated activity of the mammalian target of rapamycin (mTOR) pathway, hamartomas or benign tumors frequently occur in many organs and are often treated with mTOR inhibitors. Hemihypertrophy is a rare complication of TSC. Although not being a tumor, progressive overgrowth of the affected limb may cause cosmetic and functional problems, for which the efficacy of mTOR inhibitors has not been reported previously. We herein report a case of TSC-associated hemihypertrophy. In this case, genetic studies revealed TSC1 loss of heterozygosity as the cause of hemihypertrophy. Clinically, pharmacological treatment with an mTOR inhibitor sirolimus successfully ameliorated cosmetic and functional problems with no intolerable adverse effects.

Development and validation of an infant facial skin assessment tool: a prospective observational study.

BACKGROUND: Severe infant eczema on the face should be treated early because it may lead to allergic diseases in the future. However, caregivers find it difficult to assess. A visual tool for caregivers is needed to easily determine infants' facial skin condition severity based on the tool's scores. We developed an infant facial skin assessment tool (IFSAT) and evaluated its reliability and validity. METHODS: The IFSAT draft was developed based on results of a previous literature review and qualitative sketch. Panels including medical professionals and a caregiver checked the draft's content and face validity, and the IFSAT was finalized. To test the IFSAT's reliability and validity, caregivers and one-month-old infants were recruited. Two scoring methods were additionally created based on the relation between the items and cure period. The relationships between scores and cure period, and the ability to predict whether the infant needed medical treatment were examined by each scoring method. For the predictive validity, scores for infants requiring medical treatment and those for infants who did not were also compared. For the intra-examiner reliability analysis, two pediatricians rated the scores separately twice using photographs. Inter-rater reliabilities were analyzed among pediatricians, nurses, and caregivers. RESULTS: Altogether, 113 infant-caregiver pairs participated in the testing phase. Of the two scoring methods created (versions 1 and 2), pediatricians' and caregivers' scores using versions 1 and 2 were related to the cure period. These scores predict whether the infant needed medical treatment. We then selected version 2 based on the medical professionals' opinions. The scores of caregivers of infants requiring medical treatment were higher than those of caregivers of infants not requiring treatment (p < 0.001). The intraclass correlation coefficient (ICC) of intra-examiner reliability was 0.87. The ICC of inter-rater reliabilities between pediatricians' and caregivers' scores and between nurses' and caregivers' scores were 0.66, and 0.66, respectively. CONCLUSIONS: The proposed IFSAT may be used to assess whether infants need medical treatment and whether to extend the cure period. The tool's reliability and validity were confirmed.

A Japanese patient with RAD51-associated Fanconi anemia.

RAD51 is the only identified autosomal dominant gene to date causative of Fanconi anemia (FA) due to dominant negative effects. Only two patients with RAD51-associated FA have been reported with atypical FA phenotypes without bone marrow failure. We describe a new Asian patient with a novel RAD51 mutation, presenting with multiple congenital anomalies and atypical FA with chromosomal instability. The patient was a 9-year-old Japanese girl. She had strabismus, myopia, submucous cleft palate, bilateral hearing impairment, and scoliosis. She also had growth retardation, developmental delay, and severe intellectual disability. We performed trio whole exome sequencing and Sanger sequencing and identified a de novo RAD51 mutation (c.725A>G, p.Gln242Arg). Isolated lymphocytes from the patient were hypersensitive to chromosomal breakage induced by the DNA cross-linking agent, mitomycin C. Our detailed phenotypic analysis of the RAD51-associated atypical FA revealed clinical manifestations from the diverse population and a consistent FA phenotype characterized by chromosome instability, intellectual disability, radial ray abnormality, and microcephaly, but not bone marrow failure.

The creation and dissemination of downloadable information on dementia and driving from a social health perspective.

BACKGROUND: Driving cessation is a likely consequence of progressive dementia. Patients and families can benefit from support through this transition, both to safeguard the patient and public and to help preserve healthy social activity of the patient. METHODS: To provide appropriate supportive information, we developed a 35-page manual ('Supporting family caregivers of older drivers with dementia') available as a free download from our department website. We then informed municipal governments of its availability, tracked website access metrics, and followed up 7 months later with a postal survey to the heads of each municipal government's department of welfare for older citizens. RESULTS: From February to September 2010, the manual was accessed 33 494 times. Of the 1750 municipalities sent surveys, we received 1067 responses (61%). The responses showed that 943 professionals (94.6%) were able to obtain information they needed from the manual, 247 (23%) had used the manual to help residents during the 7 months, and 89% of those who used the manual used it to provide relevant advice to family caregivers. The responses also showed that significantly more use occurred in towns and villages as opposed to cities, consistent with the limited public transportation options in smaller municipalities (P = 0.002). CONCLUSIONS: We anticipate that use of this manual will raise general awareness of this social health issue and facilitate collaborations to provide more social support for those with dementia and their family members.

Partial monosomy of 10p and duplication of another chromosome in two patients.

Partial monosomy of 10p is a rare chromosomal abnormality. Common features are hypoparathyroidism, deafness, renal anomalies, distinctive facies, and mental retardation, with phenotypic variability. We report two patients with chromosomal abnormalities identified on single-nucleotide polymorphism (SNP) array analysis. Although patient 1 had common features of monosomy10p, G-banding indicated a normal karyotype. SNP array and fluorescence in situ hybridization (FISH), however, indicated unbalanced translocation of a 10p terminal deletion of 11.7 Mb and a 15q terminal duplication of 8.2 Mb. In patient 2, SNP array and FISH indicated a 10p terminal deletion of 12.6 Mb and a 7q terminal duplication of 1.9 Mb. This is the first case report of monosomy 10p combined with trisomy 15q (patient 1). Because the clinical heterogeneity of the 10p deletion syndrome would be affected by duplication of another chromosome, we emphasize that SNP/microarray analysis is necessary to confirm genotype-phenotype correlation.

Laminin α2-secreting fibroblasts enhance the therapeutic effect of skeletal myoblast sheets.

Objectives: Skeletal myoblast sheet (SMB) transplantation, a method used for treating failing hearts, results in the secretion of cytokines that improve heart function. Enhancing the survival rate of implanted myoblasts should yield more continuous and effective therapies. We hypothesized that laminin-211 (merosin), a major component of skeletal muscle extracellular matrix (ECM), which mediates cell-to-ECM adhesion by binding to α -dystroglycan ( α DG) on muscle cells, could inhibit detachment of implanted myoblasts from host myocardia. Methods: Multilayered sheets composed of fibroblasts expressing laminin G-module (LG)4-5 of α 2 and skeletal myoblasts were transplanted into ischemic cardiomyopathy model rats. Animals were divided into four groups: the ligation only (Control) group, and those transplanted with SMB alone, with both myoblasts and control fibroblast sheets (SMB + normal Fb), or with myoblasts and laminin α 2 LG4-5-expressing fibroblast sheets (SMB + laminin Fb). Results: Quantitative estimation of nebulin mRNA levels indicated that the transplanted myoblasts in SMB + laminin Fb group exhibited significantly higher survival rates than those in the other groups. Consistent with these findings, the myoblasts in SMB + laminin Fb group exhibited elevated expression of growth factors, while SMB + laminin Fb rats also showed significant improvements in percent fractional shortening (%FS) and left ventricular remodelling, compared to the other groups. Conclusions: Laminin secreted by implanted fibroblasts inhibited the detachment of implanted myoblasts from grafted myocardia, resulting in more permanent therapeutic effects upon myoblast sheet transplantation.

Root Fracture of Abutment Teeth for Partial Removable Dental Prostheses.

PURPOSE: Root fracture is a common and serious cause of abutment tooth loss. No studies to date have comprehensively assessed the individual contributions of the factors that increase stress on abutment teeth. The purpose of this study was to analyze the stress distribution in abutment teeth based on a three-dimensional finite element model and to analyze the factors that affect stress distribution. MATERIALS AND METHODS: Models were generated from the computed tomography data of a single patient, consisting of a mandibular second premolar abutment tooth, bone, residual mucous membrane, and a partial removable dental prosthesis (PRDP). Four models were prepared using different types of endodontic posts and cores. Akers clasps were used for the simulated PRDPs, and a vertical load was applied to the occlusal surface of the PRDPs. Debonding between the post and root was simulated. The Young modulus of the residual ridge was reduced to simulate a poor fit between the denture base and the residual ridge. Stress distribution in the abutment tooth root was observed, and the maximum principal stress was evaluated. RESULTS: The nonmetal post model and the mesial rest model reduced stress concentration in the root. The stress increased in models simulating debonding and poor fit. The results of the multiple linear regression analysis confirmed that debonding and poor fit were significantly associated with root stress. CONCLUSION: Within the limitations of this study, it is suggested that the bonding integrity of posts and adequate fit of the denture base are important factors affecting the longevity of abutment teeth for PRDPs.

Influence of Palatal Coverage and Implant Distribution on Implant Strain in Maxillary Implant Overdentures.

PURPOSE: Maxillary implant overdentures are often used in clinical practice. However, there is no agreement or established guidelines regarding prosthetic design or optimal implant placement configuration. The purpose of this study was to examine the influence of palatal coverage and implant number and distribution in relation to impact strain under maxillary implant overdentures. MATERIALS AND METHODS: A maxillary edentulous model with implants and experimental overdentures with and without palatal coverage was fabricated. Four strain gauges were attached to each implant, and they were positioned in the anterior, premolar, and molar areas. A vertical occlusal load of 98 N was applied through a mandibular complete denture, and the implant strains were compared using one-way analysis of variance (P = .05). RESULTS: The palatolabial strain was much higher on anterior implants than on other implants in both denture types. Although there was no significant difference between the strain under dentures with and without palatal coverage, palateless dentures tended to result in higher implant strain than dentures with palatal coverage. Dentures supported by only two implants registered higher strain than those supported by four or six implants. CONCLUSION: Implants under palateless dentures registered higher strain than those under dentures with palatal coverage. Anterior implants exhibited higher palatolabial strain than other implants regardless of palatal coverage and implant configuration; it is therefore recommended that maxillary implant overdentures should be supported by six implants with support extending to the distal end of the arch.

Predictors of Tooth Loss in Patients Wearing a Partial Removable Dental Prosthesis.

PURPOSE: The partial removable dental prosthesis (PRDP) is used widely to replace missing teeth, but it can disturb the ecology of the mouth. In this retrospective cohort study, the null hypothesis was that there was no difference between tooth loss and the type of edentulous spaces in participants wearing PRDPs. MATERIALS AND METHODS: Participants were selected from patients who were treated consecutively with PRDPs between January 2003 and December 2006 by undergraduate dental students at the University of British Columbia and attended the clinic for at least 5 years following placement of the PRDP. Clinical records were analyzed for 50 men and 52 women aged 19 to 85 years at baseline, before placement of the PRDP (mean age: 63.2 years). Baseline data were obtained from the records on missing teeth and edentulous spaces, and thereafter data were collected on teeth lost over the following 5-year period. Baseline data on age, sex, occlusal contacts, number of dental rests for the dentures, carious teeth, gingival attachment loss, and teeth with endodontic fillings were also obtained. RESULTS: The presence at baseline of teeth with endodontic fillings significantly (P < .05) increased the prediction of tooth loss over the 5 years, but the type of edentulous space did not. CONCLUSION: The risk of tooth loss over a 5-year period was higher in the presence of endodontically treated teeth, but no higher in participants wearing PRDPs with distally extended edentulous spaces rather than tooth-bounded edentulous spaces.

Influence of Palatal Coverage and Implant Distribution on Denture Strain in Maxillary Implant Overdentures.

PURPOSE: As maxillary implant overdentures are being increasingly used in clinical practice, prosthodontic complications related to these dentures are also reported more often. The purpose of this study was to examine the influence of palatal coverage and implant distribution on the shear strain of maxillary implant overdentures. MATERIALS AND METHODS: A maxillary edentulous model with implants inserted in the anterior, premolar, and molar areas was fabricated. Two kinds of experimental overdentures, with and without palatal coverage, were also fabricated, and two strain gauges were attached at the midline of the labial and palatal sides. A vertical occlusal load of 98 N was applied through a mandibular complete denture, and the shear strain in each denture was compared by analysis of variance (P = .05). RESULTS: In all situations, the shear strain in palateless dentures was significantly higher than in dentures with palate on both sides (P < .05). In dentures with palate, the shear strain was lower when anterior implants were present. CONCLUSION: Palateless maxillary implant overdentures exhibited much higher strain than overdentures with palate regardless of the implant distribution; this may cause more prosthodontic and implant complications. The most favorable configuration to prevent complications in maxillary implant overdentures was palatal coverage that was supported by more than four widely distributed implants.

Truncation and microdeletion of EVC/EVC2 with missense mutation of EFCAB7 in Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is a ciliopathy with cardiac anomalies, disproportionate short stature, polydactyly, dystrophic nails and oral defects. To obtain further insight into the genetics of EvC, we screened EVC/EVC2 mutations in eight Vietnamese EvC patients. All the patients had a congenital heart defect with atypical oral and/or skeletal abnormalities. One had compound heterozygous EVC2 mutations: a novel mutation c.769G > T-p.E177X in exon 6 inherited from father and another previously reported c.2476C > T-p.R826X mutation in exon 14 inherited from mother. The EVC2 mRNA expression level was significantly lower in the patient and her parents compared to controls. Another case had a novel heterozygous EVC mutation (c.1717C > G-p.S572X) in exon 12, inherited from his father. Of note, the mother without any EVC mutation on Sanger sequencing showed a lower expression level of EVC mRNA compared with controls. SNP array analysis revealed that the patient and mother had a heterozygous 16.4 kb deletion in EVC. This patient also had a heterozygous novel variant in exon 9 of EFCAB7 (c.1171 T > C-p.Y391H), inherited from his father. The atypical cardiac phenotype of this patient and the father suggested that EFCAB7 may modify the phenotype by interacting with EVC. In conclusion, we detected two novel nonsense mutations and a partial deletion of EVC/EVC2 in two Vietnamese families with EvC. Moreover, we found in one family a missense mutation of EFCAB7, a possible modifier gene in EvC and its related disorders.

Improvement of cardiac function after implanting the osteopontin-derived peptide SVVYGLR in a hamster model of dilated cardiomyopathy.

OBJECTIVES: Osteopontin is a multifunctional cytokine that can modulate a variety of cellular activities, such as fibrotic response and inflammation. Osteopontin-derived peptide Ser-Val-Val-Tyr-Gly-Leu-Arg (SVVYGLR; SV) induces angiogenesis and the expression of smooth muscle actin (SMA) in fibroblasts. In this study, we determined the effects of SV peptide on dilated cardiomyopathy (DCM). METHODS: Gels containing SV peptide (SV group), a random SV peptide (GYRVLSV) (random group) or a simple phosphate-buffered saline solution (PBS group) were transplanted on to the left ventricular (LV) anterior wall of a DCM hamster model. A control group simply underwent chest opening and closing. We used echocardiography to measure cardiac function before gel implantation (week 0) and 2, 4, 6 and 8 weeks after gel implantation. Changes in histology and myocardial remodelling were evaluated 8 weeks after the gel implantation. RESULTS: At 8 weeks post-treatment, the SV group had significantly better maintained cardiac function compared with the other groups. Histological analysis showed that LV chamber dilatation and cardiomyocyte hypertrophy were significantly attenuated, and the distribution of SMA-positive cells in the LV anterior wall area was greater in the SV group. The capillary density in the epicardial aspect of the anterior wall in the SV group was also significantly increased, indicating that the SV peptide released from the implanted gel had promoted angiogenesis. Furthermore, Western blotting and histological analyses showed that the level of expression of collagen type III at the gel-implanted anterior wall in the SV group was significantly increased, and the type III/type I collagen ratio was higher in the SV group than in the control or PBS groups. CONCLUSIONS: SV peptide treatment improved cardiac function, and inhibited the dilatation of the LV chamber and cardiomyocyte hypertrophy. By inducing the differentiation of fibroblasts to SMA-positive muscle-like cells and increasing type III collagen, SV peptide conferred a contractile property on the gel-implanted wall. We believe that the SVVYGLR peptide treatment could be used as a bridge to a left ventricular assist device and heart transplantation and for cardiac regeneration therapy without cell transplantation in the future.

Metal reinforcement of a complete maxillary denture without a palate: a preliminary report.

This preliminary study examined laboratory-simulated differences between maxillary complete dentures with and without a palate (palateless) as well as the effect of reinforcement of the latter design. Five types of experimental dentures and three types of reinforcements were made. Strain gauges were attached, and a vertical load was applied. The strain was statistically compared using analysis of variance (P = .05). Strain recordings on the palatal side of palateless dentures without reinforcement were significantly higher than in complete dentures and palateless dentures with reinforcement (P < .05). These preliminary observations suggest that such reinforcement with a palatal bar or metal-based palate may reduce the risk of fracture and deformation.

Depression among family caregivers of community-dwelling older people who used services under the Long Term Care Insurance program: a large-scale population-based study in Japan.

OBJECTIVE: To identify predictors for depression among family caregivers of community-dwelling older people under the Long Term Care Insurance (LTCI) program in Japan through a large-scale population-based survey. METHOD: All 5938 older people with disabilities, using domiciliary services under the LTCI in the city of Toyama, and their family caregivers participated in this study. Caregiver depression was defined as scores of ≥16 on the Center for Epidemiological Studies Depression Scale (CES-D). Other caregiver measures included age, sex, hours spent caregiving, relationship to the care recipient, income adequacy, living arrangement, self-rated health, and work status. Care recipient measures included age, sex, level of functional disability, and severity of dementia. The data from 4128 pairs of the care recipients and their family caregivers were eligible for further analyses. A multiple logistic regression analysis was used to examine the predictors associated with being at risk of clinical depression (CES-D of ≥16). RESULTS: Overall, 34.2% of caregivers scored ≥16 on the CES-D. The independent predictors for depression by logistic regression analysis were six caregiver characteristics (female, income inadequacy, longer hours spent caregiving, worse subjective health, and co-residence with the care recipient) and one care-recipient characteristic (moderate dementia). CONCLUSION: This is one of the first population-based examinations of caregivers of older people who are enrolled in a national service system that provides affordable access to services. The results highlighted the importance of monitoring caregivers who manifest the identified predictors to attenuate caregiver depression at the population level under the LTCI.

Incorporating couples-based approaches into HIV prevention for gay and bisexual men: opportunities and challenges.

Thirty years after the beginning of the HIV epidemic, gay, bisexual, and other men who have sex with men (collectively called MSM) bear a disproportionate burden of HIV in the United States and continue to acquire a distressingly high number and proportion of new infections. Historically, HIV prevention for MSM has been focused on individual-level behavior change, rarely intervening with MSM as part of a couple. Yet, an estimated 33­67% of HIV infections among MSM are acquired from primary sexual partners, suggesting that work with MSM as couples could be an important contributor to prevention. Given the emergence of high impact combination HIV prevention, it is timely to consider how work with the broad variety of male couples can improve both personal and community health. Couples HIV testing and counseling for MSM is an important advance for identifying men who are unaware that they are HIV-positive, identifying HIV-discordant couples, and supporting men who want to learn their HIV status with their partner. Once men know their HIV status, new advances in biomedical prevention, which can dramatically reduce risk of HIV transmission or acquisition, allow men to make prevention decisions that can protect themselves and their partners. This paper highlights the present-day challenges and benefits of using a couples-based approach with MSM in the era of combination prevention to increase knowledge of HIV status, increase identification of HIV discordant couples to improve targeting prevention services,and support mutual disclosure of HIV status.

Mechanical analysis of a palateless denture.

The purpose of this study was to compare the strain of complete dentures with and without full palatal coverage and to determine the effect of reinforcement. Three types of maxillary complete dentures (with palate, without palate, and without palate but with reinforcement) were fabricated, and reinforcements were made from a cobaltchromium alloy. Strain gauges were attached to the polished surface, and a vertical load was applied in the region of the first premolar and first molar. The strains were statistically compared. The greatest strain occurred on the anterior palatal surface and was tensile in the denture with palatal coverage and compressive in the denture without palatal coverage. Significantly less strain occurred in dentures with reinforcement than without reinforcement.

A novel SOS1 mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways.

CONTEXT: Pathological upregulation of the RAS/MAPK pathway causes Costello, Noonan and cardio-facio-cutaneous (CFC) syndrome; however, little is known about PI3K/AKT signal transduction in these syndromes. Previously, we found a novel mutation of the SOS1 gene (T158A) in a patient with Costello/CFC overlapping phenotype. OBJECTIVE: The aim of this study was to investigate how this mutation affects RAS/MAPK as well as PI3K/AKT pathway signal transduction. MATERIALS AND METHODS: Wild-type and mutant (T158A) Son of Sevenless 1 (SOS1) were transfected into 293T cells. The levels of phospho- and total ERK1/2, AKT, p70S6K and pS6 were examined under epidermal growth factor (EGF) stimulation. RESULTS: After EGF stimulation, the ratio of phospho-ERK1/2 to total ERK1/2 was highest at 5 min in mutant (T158A) SOS1 cells, and at 15 min in wild-type SOS1 cells. Phospho-AKT was less abundant at 60 min in mutant than in wild-type SOS1 cells. Phosphorylation at various sites in p70S6K differed between wild-type and mutant cells. Eighteen hours after activation by EGF, the ratio of phospho-ERK1/2 to total ERK1/2 remained significantly higher in mutant than in wild-type SOS1 cells, but that of phospho-AKT to total AKT was unchanged. DISCUSSION: T158A is located in the histone-like domain, which may have a role in auto-inhibition of RAS exchanger activity of SOS1. T158A may disrupt auto-inhibition and enhance RAS signaling. T158A also affects PI3K/AKT signaling, probably via negative feedback via phospho-p70S6K. CONCLUSION: The SOS1 T158A mutation altered the phosphorylation of gene products involved in both RAS/MAPK and PI3K/AKT pathways.