A new mutation in the SQLE gene of Trichophyton mentagrophytes associated to terbinafine resistance in a couple with disseminated tinea corporis.

Trichophyton is the most common dermatophyte genus responsible for tinea corporis and topical treatment with terbinafine is effective for limited disease but extensive disease required systemic therapy. Failure of terbinafine therapy in patients infected with T. rubrum or T. mentagrophytes is associated with mutations in the gene encoding squalene epoxidase, the terbinafine target. We report two cases of tinea corporis resistant to systemic terbinafine in a 60-year-old man and his wife, a 51 year-old-woman. Both patients had multiple diffuse erythematous annular scaly plaques and T. mentagrophytes was isolated in culture. Systemic treatment with terbinafine in combination with topical terbinafine and then topical ketoconazole failed to improve the disease after 8 weeks. The broth microdilution tests performed to evaluate the antifungal sensitivity of the T. mentagrophytes isolate revealed a high MIC for terbinafine but a low MIC for posaconazole and itraconazole. An A1223T point mutation leading to a Q408L substitution was identified by DNA sequencing the SQLE gene of the isolate. Itraconazole 200mg daily was then introduced but stopped because of elevated liver transaminases in the man. Finally, complete healing was achieved only six months later for both patients and required a 3 and 2-week regimen of itraconazole with topical eberconazole in the man and woman respectively. We believe that a close monitoring and antifungal susceptibility tests should now be done more systematically in dermatophytic infections that do not respond to conventional treatment as terbinafine resistant strains are likely to spread worlwide.

Treatment efficiency and stability of skeletal Class III malocclusion with a surgery-first approach.

OBJECTIVES: To compare treatment duration in skeletal Class III malocclusion patients managed with a 2-step treatment (surgery-first approach, SFA) and conventional 3-step treatment, and to compare stability of surgical outcomes between segmentation and non-segmentation in the 2-step treatment group. SETTING AND SAMPLE POPULATION: The sample population consisted of 37 patients who completed orthognathic surgery (OGS) and orthodontic correction at the Charm Aesthetic Surgery Clinic (Taipei, Taiwan) between 2012 and 2015. Of these, 26 received 2-step treatment and 11 received 3-step treatment. MATERIALS AND METHODS: To compare treatment efficiency and stability, three time points were analysed: T0 , before treatment (before OGS in the 2-step group and before orthodontic treatment in the 3-step group); T1 , after OGS but before orthodontic correction (cone beam computed tomography (CBCT) was obtained within 2 weeks of OGS); and T2 , after orthodontic correction (CBCT was obtained on the day of bracket removal). The post-OGS (T1 ) CBCT items were individually superimposed on the pre-treatment (T0 ) CBCT items to determine the distance of B point migration. RESULTS: A significant difference was found in treatment times between 2-step treatment and conventional 3-step treatment. In addition, no significant difference was found when comparing B-X (mm) and B-Y (mm) at T2 -T1 for the segmentation and non-segmentation groups. CONCLUSIONS: Using SFA for skeletal Class III malocclusions saves approximately 6 months of treatment time over 3-step treatment; the stability of the segmentation group was comparable to that of the non-segmentation group, a result that is possibly associated with the fixation of 2 miniplates.

A safe and accurate method to perform esthetic mandibular contouring surgery for Far Eastern Asians.

A tapered mandibular contour is popular with Far Eastern Asians. This study describes a safe and accurate method of using preoperative virtual surgical planning (VSP) and an intraoperative ostectomy guide to maximize the esthetic outcomes of mandibular symmetry and tapering while mitigating injury to the inferior alveolar nerve (IAN). Twelve subjects with chief complaints of a wide and square lower face underwent this protocol from January to June 2015. VSP was used to confirm symmetry and preserve the IAN while maximizing the surgeon's ability to taper the lower face via mandibular inferior border ostectomy. The accuracy of this method was confirmed by superimposition of the perioperative computed tomography scans in all subjects. No subjects complained of prolonged paresthesia after 3 months. A safe and accurate protocol for achieving an esthetic lower face in indicated Far Eastern individuals is described.

Goserelin toxicities and preferences for ovarian suppression method in pre-menopausal women with breast cancer.

BACKGROUND: Goserelin, a form of medical ovarian suppression, is an effective treatment for pre-menopausal women with breast cancer (PMBC). Meta-analysis data showed that similar efficacy is achieved with medical ovarian suppression and non-pharmacological ovarian suppression (NPOS) - oophorectomy or ovarian irradiation. The acceptance rate of NPOS remains low. AIMS: This study explored the reported toxicities of PMBC women and their preferred ovarian suppression method whilst on goserelin. METHODS: A postal survey consisting of 22 study-specific questions was sent to PMBC women who received goserelin at the Flinders Medical Centre. RESULTS: Nineteen women were identified from the database; 12 versus 7 women received goserelin in the adjuvant versus metastatic setting respectively. Thirteen (68.4%) responded to the survey. Women in the adjuvant cohort were more likely to report toxicities. The most common were hot flushes (100% vs 50% P = 0.033), myalgia/arthralgia (71.4% vs 16.7%, P = 0.048) and decreased libido (57/1% vs 16.7%, P = 0.135). NPOS was recalled to be offered to five (38.5%) women, with acceptance by one BRCA2 carrier. NPOS was declined initially due to fear of procedure, surgical/anaesthetic risk, invasiveness and planned future pregnancies. If given the option, upfront oophorectomy was indicated in seven (53.8%) women due to inconveniences with monthly goserelin. CONCLUSION: Half of PMBC women indicated a preference to NPOS, but only a minority recollected NPOS being discussed. Inconvenience with monthly goserelin is the main driver toward a preference of favouring NPOS. Clarification from larger trials that research patients' decision process and preferences regarding ovarian suppression is needed to validate our findings.

Age of diabetes diagnosis and diabetes duration associate with glycated haemoglobin.

An earlier age of diagnosis (r=-0.28, p<0.0001) and longer duration of type 2 diabetes (r=0.26, p<0.0001) were each found to correlate with higher HbA1c level, on analysis of a diabetes centre database in people under regular shared care. When combined, these biological variables strongly associate with the current HbA1c level.

Roles of type VI collagen and decorin in human mesenchymal stem cell biophysics during chondrogenic differentiation.

Human mesenchymal stem cells (hMSCs) induced towards chondrogenesis develop a pericellular matrix (PCM), rich in type VI collagen (ColVI) and proteoglycans such as decorin (DCN). Individual PCM protein functions still need to be elucidated to fully understand the mechanobiological role of this matrix. In this study we identified ColVI and DCN as important contributors in the mechanical function of the PCM and as biochemical modulators during chondrogenesis through targeted knockdown using shRNA lentiviral vectors. Gene expression, western blotting, immunofluorescence and cell deformation analysis were examined at 7, 14 and 28 days post chondrogenic induction. ColVI and DCN knockdown each affected gene expression of acan, bgn, and sox9 during chondrogenesis. ColVI was found to be of central importance in resisting applied strains, while DCN knockdown had strain dependent effects on deformation. We demonstrate that by using genetic engineering to control the biophysical microenvironment created by differentiating cells, it may be possible to guide cellular mechanotransduction.

The trend of hypertension and its relationship to the weight status among Taiwanese young adolescents.

This study evaluates prevalence of hypertension in 1996 and 2006, and examines the relationship between hypertension and weight of Taiwanese young adolescents. Two cross-sectional surveys, administered in 1996 and 2006, to junior-high school in Taipei were included. Anthropometric and blood pressure were measured using standard methods, and structured questionnaire was used to collect personal history and lifestyle characteristics. Overweight and obesity are defined based on Taiwan's Department of Health criteria and bases pre-hypertension and hypertension on the 90th and 95th percentile distribution of blood pressure of the population of both surveys. The prevalence of pre-hypertension in Taiwan between 1996 and 2006 increased from 12.0 to 14.4% for boys and decreased from 9.5 to 9.4% for girls. Hypertension increased from 22.8-29.7% and 12.5-20.7% for both boys and girls, respectively. In 1996, compared with normal young adolescents, the risk of hypertension for overweight was 1.8 times higher for boys and 3.4 times for girls. However, the risk of hypertension for overweight in 2006 was 1.7 times higher for boys and 1.5 times higher for girls compared with normal. Every unit increment of body mass index and waist circumference was associated with 17-27% and 6-11% risk of hypertension in both genders in 1996, and was associated with 9-13% and 4% risk of hypertension among young adolescents in 2006, respectively. The prevalence of hypertension has increased significantly in young adolescents, especially for overweight. It is necessary to enrol young adolescents in weight management programs to prevent hypertension-related co-morbidities.

Oncogenic AKTivation of translation as a therapeutic target.

The AKT signalling pathway is a major regulator of protein synthesis that impinges on multiple cellular processes frequently altered in cancer, such as proliferation, cell growth, survival, and angiogenesis. AKT controls protein synthesis by regulating the multistep process of mRNA translation at every stage from ribosome biogenesis to translation initiation and elongation. Recent studies have highlighted the ability of oncogenic AKT to drive cellular transformation by altering gene expression at the translational level. Oncogenic AKT signalling leads to both global changes in protein synthesis as well as specific changes in the translation of select mRNAs. New and developing technologies are significantly advancing our ability to identify and functionally group these translationally controlled mRNAs into gene networks based on their modes of regulation. How oncogenic AKT activates ribosome biogenesis, translation initiation, and translational elongation to regulate these translational networks is an ongoing area of research. Currently, the majority of therapeutics targeting translational control are focused on blocking translation initiation through inhibition of eIF4E hyperactivity. However, it will be important to determine whether combined inhibition of ribosome biogenesis, translation initiation, and translation elongation can demonstrate improved therapeutic efficacy in tumours driven by oncogenic AKT.

Graft-versus-host disease presenting with pancytopenia after en bloc multiorgan transplantation: case report and literature review.

Graft-versus-host disease (GVHD) is a dreaded complication of bone marrow and solid organ transplantation. Commonly affected organs include skin, liver, and the gastrointestinal tract, with bone marrow and renal involvement occurring more rarely. GVHD is less commonly seen with solid organ transplants. Fewer than 100 cases of GVHD have been reported in the literature following liver transplantation. We report a case of a 53-year-old woman who required a multiorgan transplant after a complicated postoperative course following paraduodenal hernia repair. She developed isolated pancytopenia approximately 4 months after receiving an en bloc transplant involving the liver, kidney, small bowel, and pancreas. No evidence of skin, gastrointestinal, or hepatic involvement was discovered. HLA typing of the peripheral blood revealed that 28% of patient peripheral blood was composed of donor lymphocytes. Bone marrow biopsy showed a markedly hypocellular marrow with 23% donor lymphocytes and 80% of the T-cell population from the donor as well. The patient began treatment for GVHD, including high-dose steroids, basiliximab, and rituximab. Unfortunately, she developed overwhelming sepsis and subsequently died. This case describes an instance of GVHD manifested by isolated pancytopenia after en bloc transplantation of multiple solid organs. GVHD is a rare, but serious complication of solid organ transplantation that can result in death. Although isolated bone marrow involvement is uncommon, it must be considered early to avoid a delay in diagnosis. This case also highlights an association of GVHD with multiorgan transplants, although this is incompletely characterized in the current literature.

Biochemical and white blood cell profiles of baboon neonates consuming formulas with moderate and high dietary long-chain polyunsaturated fatty acids.

BACKGROUND: Clinical chemistry and complete blood count (CBC) values were determined in 14 term baboons (Papio species) consuming formula with moderate or high levels of dietary long-chain polyunsaturated fatty acids (LCPUFA) from 2-12 weeks of age. METHOD: Neonates were randomized to three groups: C: Control, no LCPUFA; L: 0.33% docosahexaenoic acid (DHA)/0.67% arachidonic acid (ARA) (w/w); L3:1.00% DHA/0.67% ARA (w/w). Blood chemistries were assessed at 6 and 12 weeks and CBC parameters were measured at 2, 4, 8, 10, 12 weeks of age. RESULTS: Dietary LCPUFA had significant effects on serum triglyceride (C > L,L3) and calcium (L > C,L3). No other significant effects of diet were detected; pooled values are presented for all other parameters. CONCLUSION: These data provide longitudinal biochemical and white cell/platelet/immunological data on LCPUFA-fed baboons over the first 12 weeks of life. Data ranges are similar to reference data in cases for which values exist and hematological changes reflect trends observed during human neonatal development.

Targeting HER proteins in cancer therapy and the role of the non-target HER3.

Members of the human epidermal growth factor receptor (HER) family have been of considerable interest in the cancer arena due to their potential to induce tumorigenesis when their signalling functions are deregulated. The constitutive activation of these proteins is seen in a number of different common cancer subtypes, and in particular EGFR and HER2 have become highly pursued targets for anti-cancer drug development. Clinical studies in a number of different cancers known to be driven by EGFR or HER2 show mixed results, and further mechanistic understanding of drug sensitivity and resistance is needed to realise the full potential of this treatment modality. Signalling in trans is a key feature of HER family signalling, and the activation of the PI3K/Akt pathway, so critically important in tumorigenesis, is driven predominantly through phosphorylation in trans of the kinase inactive member HER3. An increasing body of evidence shows that HER3 plays a critical role in EGFR- and HER2-driven tumours. In particular, HER3 lies upstream of a critically important tumorigenic signalling pathway with extensive ability for feedback and cross-talk signalling, and targeting approaches that fail to account for this important trans-target of EGFR and HER2 can be undermined by its resiliency and resourcefulness. Since HER3 is kinase inactive, it is not a direct target of kinase inhibitors and not presently an easily drugable target. This review presents the current evidence highlighting the role of HER3 in tumorigenesis and its role in mediating resistance to inhibitors of EGFR and HER2.

Influence of Raman susceptibility on optical parametric amplification in optical fibers.

The real part of the Raman susceptibility is shown to have a strong influence on the peak parametric gain of single-pump parametric amplifiers. This results in a 35% variation in the peak parametric gain over the frequency range 0-30 THz. We are able to experimentally demonstrate this effect in a photonic crystal fiber and obtain good agreement between the experimentally measured and theoretically predicted gains.

Combined effect of Raman and parametric gain on single-pump parametric amplifiers.

We investigate the combined effect of Raman and parametric gain on single-pump parametric amplifiers. The phasematched parametric gain is shown to depend strongly on the real part of the complex Raman susceptibility. In fused silica fibers this results in a significant reduction in the available parametric gain for signal detunings beyond 10 THz. We are able to experimentally measure this effect for signal detunings ranging from 7 to 22 THz. Finally we discuss the implications of these results for the design of broadband optical parametric amplifiers.

Mechanobiology in intervertebral disc degeneration and regeneration.

The intervertebral disc is an avascular, pliant, composite structure that separates spinal vertebrae and, in health, serves to support compression and facilitate movement. Its morphological organization is directed by fluid pressure and consists of a central swelling gel (nucleus), surrounded peripherally by a constraining ligament (annulus fibrosus), and separated from adjacent vertebrae by semi-permeable membranes (endplate). These three tissues serve differing structural roles, are subjected to differing mechanical environments, and are composed of unique matrices and cells. Viewing disc cells as mechanosensors, we use in vivo models of disc loading to identify spatial and temporal relationships between stress/strain and cell function that define normal morphology and drive the architectural changes attributed to normal aging and degeneration. Intra-discal stress patterns consistent with disc health can then be elucidated based on these relationships, and in turn, help us develop spine-loading criteria that parameterize injury tolerance. This same perspective is critical for tissue engineering approaches for disc repair. Cells and matrices meant to guide healing need to withstand the demanding mechanical forces in the acute phases, and differentiate/remodel along the appropriate trajectory in the long-term. Because of their unique potential for adaptation, we are exploring the mechanoplasticity of mesenchymal stem cells (MSCs) and their use in disc repair strategies. Our data demonstrate that these cells respond differentially to pressure and distortion, and can be delivered, retained, and survive in the disc's demanding mechanical/biochemical environment. Because of these features, MSCs are qualified as an intriguing autograft cell type for disc repair.

Haematological effects among silk screening workers exposed to 2-ethoxy ethyl acetate.

BACKGROUND: 2-Ethoxy ethyl acetate (2-EEA) is a solvent with broad industrial and commercial applications. It has been reported to cause hematological toxicity, infertility, and teratogenesis. AIMS: To investigate the haematological effects in 2-EEA exposed workers. METHODS: Workers from one silk screening shop (n = 29), using 2-EEA as the major cleaning and printing solvent, were recruited as a high exposure group. Workers with indirect and non-exposure to 2-EEA (n = 56) were recruited as the comparison group. Venous blood was collected for blood routine examination. Air concentration of 2-EEA in this plant was measured by eight hour personal sampling. RESULTS: The geometric mean (GM) of air concentration of 2-EEA in the high exposure group was 7.41 ppm (range 1.35-16.5 pppm). The mean exposure of female workers (GM = 9.34 ppm) was significantly higher than that of male workers (GM = 4.87 ppm). The GM of air 2-EEA concentration in the comparison group was 0.07 ppm (range: non-detectable to 3.62 ppm, n = 26). The haemoglobin and haematocrit in the female high 2-EEA exposure workers were significantly lower than those of female workers in the comparison group. No difference was found between male 2-EEA high exposure and comparison group workers. The haemoglobin, haematocrit, and RBC count in the study population had a significant dose-response relation with air 2-EEA levels. CONCLUSION: Results suggest that 2-EEA is a haematological toxicant, which leads to anaemic status in high exposure female workers.

Pseudothrombocytopenia associated with infectious mononucleosis.

A 22-year-old man was hospitalized for assessment of thrombocytopenia and fever. Examination showed that he had infectious mononucleosis and moderately severe thrombocytopenia that was asymptomatic. Examination of blood smears revealed that the thrombocytopenia was caused by the clumping of platelets. We made a diagnosis of ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia after excluding other infectious mononucleosis-related mechanisms of thrombocytopenia. When the patient recovered from infectious mononucleosis 2 months later, his thrombocytopenia improved, and no platelet clumping in peripheral blood smears was noted. Ethylenediaminetetraacetic acid-dependent pseudothrombocytopenia should always be considered as a possible cause of reported low platelet counts, even in patients with infectious mononucleosis and splenomegaly.

Follow up study of haematological effects in workers exposed to 2-methoxyethanol.

AIMS: To examine the association between 2-methoxyethanol (2-ME) exposure and haematological effects, as well as the recovery from these haematological effects with continuous reduction in exposure to 2-ME. METHODS: Twenty nine exposed and 90 non-exposed workers were recruited. Haematological parameters, eight hour full shift personal exposure to 2-ME, and urinary 2-methoxyacetic acid (MAA) were repeatedly measured in three consecutive surveys within six months. RESULTS: Results of haematological examination in the first exposure survey showed that haemoglobin, packed cell volume, and red blood cell count in the male exposed workers were significantly lower than those in the comparison workers. The frequency of anaemia in the exposed group (42%) was significantly higher than that in the comparison group (3%). The haematological effects were significantly associated with the urinary MAA of exposed workers. The haematological effects had returned to normal in the first follow up survey 2.5 months later, when a reduction in 2-ME exposure was noted. Haematological results of the second follow up examination six months later remained normal. The mean airborne exposure of 2-ME in the three surveys dropped from 35.7 to 2.65, then to 0.55 ppm. The mean urinary MAA of exposed workers in the three surveys was reduced from 57.7 to 24.6, then to 13.5 mg/g creatinine (n = 29). The reduction in exposure through both inhalation and potential dermal contact with 2-ME might account for the haematological recovery. CONCLUSION: 2-ME is a haematological toxin which leads to anaemia in exposed workers. However, the toxic haematological effects of 2-ME persist for only a short period of time after cessation or reduction of exposure.

Mechanobiology of the intervertebral disc.

Intervertebral disc degeneration has been linked in humans to extreme spinal loading regimens. However, mechanisms by which spinal force influences disc cellularity, morphology and consequently biomechanical function are unclear. To gain insight into mechanobiological interactions within the disc, we developed an in vivo murine tail-compression model. Results from this model demonstrate how deviations in spinal stress induce a cycle of altered cell function and morphology as the disc remodels to a new homoeostatic configuration.

Adenoviral delivery of osteoprotegerin ameliorates bone resorption in a mouse ovariectomy model of osteoporosis.

Osteoprotegerin (OPG) regulates bone resorption by inhibiting osteoclast formation, function, and survival. The current studies employed a mouse ovariectomy (OVX) model of estrogen deficiency to investigate gene therapy with OPG as a means of preventing osteoporosis. Young adult females injected with a recombinant adenoviral (Ad) vector carrying cDNA of either full-length OPG or a fusion protein combining the hOPG ligand-binding domain with the human immunoglobulin constant domain (Ad-hOPG-Fc) developed serum OPG concentrations exceeding the threshold needed for efficacy. However, elevated circulating OPG levels were sustained for up to 18 months only in mice given Ad-hOPG-Fc. Administration of Ad-hOPG-Fc titers between 10(7) and 10(9) pfu yielded dose-dependent increases in serum OPG. Mice subjected to OVX or sham surgery followed by immediate treatment with Ad-hOPG-Fc had significantly more bone volume with reduced osteoclast numbers in axial and appendicular bones after 4 weeks. In contrast, animals given OVX and either a control vector or vehicle had significantly less bone than did comparably treated sham-operated mice. This study demonstrates that a single adenoviral gene transfer can produce persistent high-level OPG expression and shows that gene therapy to provide sustained delivery of OPG may prove useful in treating osteoporosis.