Ovarian sex cord stromal tumor with annular tubules in a 7-year-old child: A case report.

A seven-year-old girl who presented with precocious puberty was diagnosed with an estrogen-secreting right ovarian tumor. Right salpingo-oophorectomy with staging was performed by gynecologic oncologists. Intraoperative frozen section reported sex cord stromal tumor. Histopathological report confirmed sex cord stromal tumor with annular tubules with brisk mitotic counts (17 per 10 high-power fields). The post-operative course was uneventful. She remained asymptomatic with normalisation of serum estradiol upon six-month follow-up.

Beyond the BRAFV600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients.

BRAF gene mutations can be found in approximately 50% of melanomas, but the most common BRAF mutation leads to substitution at residue 600 of the protein, from valine to glutamic acid. BRAFV600E occurs in up to 95% of all melanoma cases and can be successfully blocked by using a combination of BRAF- and MEK inhibitors. The wider availability of next-generation sequencing is revealing more non-V600 BRAF mutations, and the clinical implications of these mutations are widely unknown. In this review, we will discuss the biology of the MAPK pathway and the different types of BRAF mutations as well as their effect on MEK activation. Current literature will be reviewed including in vitro data, case reports and case series.

Impact of the Fukushima accident on tritium, radiocarbon and radiocesium levels in seawater of the western North Pacific Ocean: A comparison with pre-Fukushima situation.

Tritium, radiocarbon and radiocesium concentrations in water column samples in coastal waters offshore Fukushima and in the western North Pacific Ocean collected in 2011-2012 during the Ka'imikai-o-Kanaloa (KoK) cruise are compared with other published results. The highest levels in surface seawater were observed for 134Cs and 137Cs in seawater samples collected offshore Fukushima (up to 1.1 Bq L-1), which represent an increase by about three orders of magnitude when compared with the pre-Fukushima concentration. Tritium levels were much lower (up to 0.15 Bq L-1), representing an increase by about a factor of 6. The impact on the radiocarbon distribution was measurable, but the observed levels were only by about 9% above the global fallout background. The 137Cs (and similarly 134Cs) inventory in the water column of the investigated western North Pacific region was (2.7 ± 0.4) PBq, while for 3H it was only (0.3 ± 0.2) PBq. Direct releases of highly contaminated water from the damaged Fukushima NPP, as well as dry and wet depositions of these radionuclides over the western North Pacific considerably changed their distribution patterns in seawater. Presently we can distinguish Fukushima labeled waters from global fallout background thanks to short-lived 134Cs. However, in the long-term perspective when 134Cs will decay, new distribution patterns of 3H, 14C and 137Cs in the Pacific Ocean should be established for future oceanographic and climate change studies in the Pacific Ocean.

Cementless total knee replacement fixation: a contemporary durable solution--affirms.

A retrospective review was performed of patients undergoing primary cementless total knee replacement (TKR) using porous tantalum performed by a group of surgical trainees. Clinical and radiological follow-up involved 79 females and 26 males encompassing 115 knees. The mean age was 66.9 years (36 to 85). Mean follow-up was 7 years (2 to 11). Tibial and patellar components were porous tantalum monoblock implants, and femoral components were posterior stabilised (PS) in design with cobalt-chromium fibre mesh. Radiological assessments were made for implant positioning, alignment, radiolucencies, lysis, and loosening. There was 95.7% survival of implants. There was no radiological evidence of loosening and no osteolysis found. No revisions were performed for aseptic loosening. Average tibial component alignment was 1.4° of varus (4°of valgus to 9° varus), and 6.2° (3° anterior to 15° posterior) of posterior slope. Mean femoral component alignment was 6.6° (1° to 11°) of valgus. Mean tibiofemoral alignment was 5.6° of valgus (7° varus to 16° valgus). Patellar tilt was a mean of 2.4° lateral (5° medial to 28° lateral). Patient satisfaction with improvement in pain was 91%. Cementless TKR incorporating porous tantalum yielded good clinical and radiological outcomes at a mean of follow-up of seven-years.

Targeted therapy for melanoma: rational combinatorial approaches.

The treatment of melanoma, the most aggressive form of skin cancer, is being revolutionized by the development of personalized targeted therapy approaches. Mutant-selective BRAF inhibitors and MEK inhibitors have demonstrated impressive clinical results in molecularly selected patients. However, emerging understanding of the molecular heterogeneity of this disease and the identification of multiple mechanisms of resistance to targeted therapies strongly support the rationale for combinatorial approaches. In this review, we will discuss the preclinical and clinical studies that are testing leading hypotheses and emerging combinatorial strategies for the future.

Trace element fluxes and natural potential risks from 210Pb-dated sediment cores in lacustrine environments at the Central Mexican Plateau.

The accumulation, enrichment and provenance of selected trace metals (Ag, As, Cd, Cr, Cu, Hg, Ni, Pb, V and Zn) were studied in sediment cores collected from three lakes located in the Central Mexican Plateau, selected on the basis of their contrasting degree of urbanization: Santa Elena Lake, in a rural and remote area; El Tule Lake, in a rural and slightly urbanized area; and Chapala Lake, in a highly urbanized area. Grain size, magnetic susceptibility and sedimentary constituents such as organic carbon, calcium carbonate, as well as major (Al, Fe, Mn) and minor (Ca, Li, Rb, Sr, Th) elements were analyzed to explain the concentration trends of trace metals. Factor analysis (FA) was used to assess the provenance of the trace elements. The highest metal enrichment factor (EF) above natural concentration levels was found at Chapala Lake for Ag (EF = 3.9), although other trace element EF in all lakes was <2.0, indicating slight contamination. However, the concentration levels of Cr and Ni in all lakes, Hg and Zn in Chapala Lake, Cu in El Tule Lake and As in Santa Elena Lake were above international benchmarks for which adverse effects are expected to occur frequently, even for those metals only slightly enriched (e.g. As, Cr). Through FA, the terrigenous contribution was identified as the most important source of trace metals to the three lakes, most likely related to deforestation and erosion of the surrounding areas, followed by atmospheric transport of volcanic ashes, rather than to direct sources.

Dysmenorrhoea among Hong Kong university students: prevalence, impact, and management.

OBJECTIVE. To evaluate the prevalence of dysmenorrhoea, its impact, and management approaches in Hong Kong university students, and to compare between medical and non-medical students for any potential differences in coping strategies. DESIGN. Cross-sectional questionnaire survey. SETTING. The University of Hong Kong, Hong Kong. PARTICIPANTS. A total of 240 undergraduate (128 medical and 112 non-medical) students. MAIN OUTCOME MEASURES. Data on the presence and severity of dysmenorrhoea, its impact on daily life, management approaches, specific strategies, and their self-perceived effectiveness were obtained and analysed. RESULTS. In these subjects, the prevalence of dysmenorrhoea was 80% (95% confidence interval, 75-85%) with a mean (standard deviation) pain score of 5.0 (1.7). The most common impacts on daily life included reduced ability to concentrate and/or disturbance with study (75%) and changes in normal physical activity (60%). Only 6% sought medical advice, while 70% practised self-management. Pain scores and pain affecting normal physical activities were important predictive factors for self-management and for management based on pharmacological or non-pharmacological means. The commonest specific strategies used were a warm beverage (62%), paracetamol (57%), and sleeping (45%), while the most effective strategies were non-steroidal anti-inflammatory drugs (100%), traditional Chinese medicine (93%), and dietary/nutritional supplements (92%). Regarding the comparison of medical and non-medical students, the former used fewer pharmacological strategies among the various management approaches investigated. CONCLUSION. With data showing dysmenorrhoea as a very common condition having a significant impact in the Hong Kong community, primary care doctors should reassure young women with dysmenorrhoea that it is a common experience in the same age-group. Health education on the existence of effective treatment from medical practitioners could help women whose dysmenorrhoea was not controlled by self-management.

Parental attitudes on expanded newborn screening in Hong Kong.

OBJECTIVES: Classical inborn errors of metabolism (IEM) affect about 1 in 4000 in Hong Kong. Despite the widespread implementation of expanded newborn screening in most countries, Hong Kong only screen for three conditions and the awareness of public has not been evaluated. This is the first study to examine the parental knowledge and attitudes towards expanded newborn screening in Hong Kong. METHODS: A cross-sectional survey was conducted in the Princess Margaret Hospital. Parents with babies born from 1st July to 31st October 2010 were randomly recruited. Fifteen questions relating to the knowledge of newborn screening and biochemical genetic disorders, preferences about the features of newborn screening, the economic values, and attitudes toward false positive results were asked. RESULTS: In total, 172 subjects were interviewed by phone (overall response rate 97.2%). There were 87.8% parents who had never heard of expanded newborn screening; 99.4% demanded more parental education; 83.5% thought the programme should be implemented immediately; 97.7% supported population screening, even though the diseases are incurable; 93.9% accepted the possibility of false positive and false negative results; 70.4% preferred a voluntary basis; 83.2% believed that the programme should be fully government funded as basic primary care; 98.8% agreed that Hong Kong should follow mainland China's policy on expanded newborn screening; 98.2% required pre-test counseling; and 96.4% required an explicit parental consent before blood sampling. CONCLUSIONS: The response from parents overwhelmingly favoured having expanded newborn screening in Hong Kong. Parental tolerance was high. Parents valued the parental autonomy with informed consent and pre-test counseling the most. The success of any screening programme requires the public participation and this study is the first to prove the parental call for an expanded newborn screening in Hong Kong.

Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma.

To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.

Isotopic, geophysical and biogeochemical investigation of submarine groundwater discharge: IAEA-UNESCO intercomparison exercise at Mauritius Island.

Submarine groundwater discharge (SGD) into a shallow lagoon on the west coast of Mauritius Island (Flic-en-Flac) was investigated using radioactive ((3)H, (222)Rn, (223)Ra, (224)Ra, (226)Ra, (228)Ra) and stable ((2)H, (18)O) isotopes and nutrients. SGD intercomparison exercises were carried out to validate the various approaches used to measure SGD including radium and radon measurements, seepage rate measurements using manual and automated meters, sediment bulk conductivity and salinity surveys. SGD measurements using benthic chambers placed on the floor of the Flic-en-Flac Lagoon showed discharge rates up to 500 cm/day. Large variability in SGD was observed over distances of a few meters, which were attributed to different geomorphological features. Deployments of automated seepage meters captured the spatial and temporal variability of SGD with a mean seepage rate of 10 cm/day. The stable isotopic composition of submarine waters was characterized by significant variability and heavy isotope enrichment and was used to predict the contribution of fresh terrestrially derived groundwater to SGD (range from a few % to almost 100%). The integrated SGD flux, estimated from seepage meters placed parallel to the shoreline, was 35 m(3)/m day, which was in reasonable agreement with results obtained from a hydrologic water balance calculation (26 m(3)/m day). SGD calculated from the radon inventory method using in situ radon measurements were between 5 and 56 m(3)/m per day. Low concentrations of radium isotopes observed in the lagoon water reflected the low abundance of U and Th in the basalt that makes up the island. High SGD rates contribute to high nutrients loading to the lagoon, potentially leading to eutrophication. Each of the applied methods yielded unique information about the character and magnitude of SGD. The results of the intercomparison studies have resulted a better understanding of groundwater-seawater interactions in coastal regions. Such information is an important pre-requisite for the protection and management of coastal freshwater resources.

Severe community-acquired pneumonia caused by macrolide-resistant Mycoplasma pneumoniae in a 6-year-old boy.

Mycoplasma pneumoniae is the commonest agent causing atypical pneumonia in children. Macrolides have long been used in the treatment of community-acquired pneumonia not responsive to beta-lactams alone. In this report, we describe the first locally acquired paediatric patient with severe community-acquired pneumonia caused by macrolide-resistant Mycoplasma pneumoniae, possessing an A-to-G transition at position 2063 of the 23s rRNA gene. In addition, we have detected two more strains of macrolide-resistant Mycoplasma pneumoniae out of a total of 10 cases with chest infection that were confirmed by polymerase chain reaction. Therefore macrolide-resistant Mycoplasma pneumoniae accounted for 33% (3 out of 10 patients) of the polymerase chain reaction-confirmed cases.

Underwater in situ measurements of radionuclides in selected submarine groundwater springs, Mediterranean Sea.

The application of the in situ measurement system 'KATERINA' for monitoring of radon progenies in submarine groundwater discharge (SGD) was investigated at different locations in the Mediterranean Sea (Chalkida, Stoupa, Korfos and Cabbé). At Chalkida and Stoupa radon progenies concentration exhibited almost constant values of 1.2 ± 0.1 and 2.5 ± 0.2 Bq l(-1), respectively. At Korfos these activities ranged between 1.4 ± 0.1 and 2.3 ± 0.2 Bq l(-1) exhibiting inverse relationship with salinity. At Cabbé the in situ measured data were compared with radon measurements obtained by liquid scintillation counter. The system also resolved radon progeny variations of SGD on time scales above 1 h. The radioactivity levels of radon progenies from all sites were found considerably lower (approximately 2 orders of magnitude) than the commonly accepted limits for radon in drinking water.

Production and characterization of two monoclonal antibodies to bovine tumour necrosis factor alpha (TNF-alpha) and their cross-reactivity with ovine TNF-alpha.

Tumour necrosis factor alpha (TNF-alpha) is an innate pro-inflammatory cytokine involved in protection against intracellular pathogens. Existing methods for measuring TNF-alpha production and function in ruminants are limited to ELISA and many rely on polyclonal antisera. With a view to developing improved detection methods for bovine (bov) TNF-alpha, monoclonal antibodies (mAb) were produced by immunising mice with a plasmid encoding bov TNF-alpha. Two of the resulting mAb, termed CC327 and CC328, were used to develop a sandwich ELISA capable of detecting both native and recombinant bov TNF-alpha. This ELISA did not detect recombinant ovine (ov) TNF-alpha. A luminometric method was applied to the ELISA to improve sensitivity for detection of native bov TNF-alpha in culture supernatants derived from bovine monocyte-derived dendritic cells (DC) infected with Mycobacterium bovis. Both CC327 and CC328 detected intracytoplasmic expression of TNF-alpha in mitogen-activated bovine T lymphocytes. However, only CC328 detected intracytoplasmic ovine TNF-alpha in transfected cells, explaining the failure of the sandwich ELISA to detect recombinant ov TNF-alpha. These mAbs have generated the capability to study the role of TNF-alpha in host immune protection and disease pathogenesis in ruminants.

Role of LPS/CD14/TLR4-mediated inflammation in necrotizing enterocolitis: pathogenesis and therapeutic implications.

AIM: To establish the roles of lipopolysaccharide (LPS)/CD14/toll-like receptor 4 (TLR4)-mediated inflammation in a rat model of human necrotizing enterocolitis (NEC). METHODS: Six pairs of intestinal samples from human NEC were collected before and after recovery for histological and molecular analysis of inflammatory cytokines and signaling components. In the rat NEC model, we isolated 10-cm jejunum segments and divided them into six groups (n = 6) for sham operation, treatment with LPS, bowel distension, combined bowel distension and LPS stimulation, and two therapeutic groups. The potential efficacy of a recombinant CD18 peptide and a monoclonal CD14 antibody was evaluated in the latter two groups. The serum and tissue levels of several inflammatory mediators were quantified by real-time polymerase chain reaction, ELISA and immunoblotting. RESULTS: Human acute phase NEC tissues displayed significant increases (P < 0.05) in levels of TLR4, CD14, myeloid differentiation protein (MD)-2, tumor necrosis factor (TNF)-alpha and nuclear factor-kappaB when compared to those after recovery. The histological and inflammatory picture of human NEC was reproduced in rats that were treated with combined bowel distension and LPS, but not in the sham-operated and other control rats. Serum levels of interleukin-6 and TNF-alpha were also elevated. The NEC pathology was attenuated by treating the NEC rats with a monoclonal CD14 antibody or an LPS-neutralizing peptide. CONCLUSION: LPS and distension are required to produce the histological and inflammatory features of NEC. A potential treatment option is blocking LPS activation and leukocyte infiltration.

A new Certified Reference Material for radionuclides in Irish sea sediment (IAEA-385).

A new Certified Reference Material (CRM) for radionuclides in sediment (IAEA-385) is described and the results of the certification process are presented. Eleven radionuclides ((40)K, (137)Cs, (226)Ra, (228)Ra, (230)Th, (232)Th, (234)U, (238)U, (238)Pu, (239+240)Pu and (241)Am) have been certified and information mass activities with 95% confidence intervals are given for seven other radionuclides ((90)Sr, (210)Pb((210)Po), (235)U, (239)Pu, (240)Pu and (241)Pu). Results for less frequently reported radionuclides ((60)Co, (99)Tc, (134)Cs, (155)Eu, (224)Ra and (239)Np) and information on some activity and mass ratios are also reported. The CRM can be used for quality assurance/quality control of the analysis of radionuclides in sediment samples, for the development and validation of analytical methods and for training purposes.

Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use.

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.

Atm is a negative regulator of intestinal neoplasia.

The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc(Min/+) and Apc(1638N/+). These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability.

A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology.

Mutations in the progranulin (GRN) gene have recently been reported as a cause of the frontotemporal dementia (FTD) syndrome. We performed a clinical, neuropathological and molecular genetic study of two families with FTD and the same novel mutation in GRN. Age of onset ranged from 35 to 75 years and all individuals progressed to a severe dementia syndrome with a mean disease duration of approximately 6-10 years. Variable clinical presentations included language impairment, behaviour change or parkinsonism. Seven total autopsies in the families (five in Family 1, two in Family 2) showed gross and microscopic evidence of neuronal loss in the neocortex, striatum, hippocampus and substantia nigra. All cases with material available for immunohistochemistry had cytoplasmic and intranuclear ubiquitin positive, tau negative inclusions that stained best with an antibody to the TDP43 protein. In addition, all but one had evidence of distinctive tau pathology. Two cases in Family 1 also had alpha-synuclein (SNCA) pathology, one with diffuse neocortical inclusions and neurites and unusual striatal cytoplasmic inclusions. Affected persons in both families had the same mutation in GRN (c.709-2A>G). A minigene construct showed that this mutation alters splicing of exon 7 and results in reduced mRNA message in brain. A single GRN mutation in these two families was associated with variable clinical presentations consistent with the FTD syndrome. All cases had ubiquitin/TDP43 immuno-positive inclusions and most had additional tau pathology. Two cases had SNCA pathology. These findings suggest a link between mutations in GRN and aggregation of tau, TDP43 and SNCA.

Certified reference material for radionuclides in fish flesh sample IAEA-414 (mixed fish from the Irish Sea and North Sea).

A certified reference material (CRM) for radionuclides in fish sample IAEA-414 (mixed fish from the Irish Sea and North Seas) is described and the results of the certification process are presented. Nine radionuclides (40K, 137Cs, 232Th, 234U, 235U, 238U, 238Pu, 239+240Pu and 241Am) were certified for this material. Information on massic activities with 95% confidence intervals is given for six other radionuclides (90Sr, 210Pb(210Po), 226Ra, 239Pu, 240Pu 241Pu). Less frequently reported radionuclides (99Tc, 129I, 228Th, 230Th and 237Np) and information on some activity and mass ratios are also included. The CRM can be used for quality assurance/quality control of the analysis of radionuclides in fish sample, for the development and validation of analytical methods and for training purposes. The material is available from IAEA, Vienna, in 100 g units.

BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.

BACKGROUND: BAY 59-7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. METHODS: In a multicenter, parallel-group, double-blind, double-dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59-7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6-8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12-24 h postsurgery). Treatment was continued until mandatory bilateral venography 5-9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non-fatal pulmonary embolism and all-cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. RESULTS: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59-7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59-7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5-10 mg b.i.d. doses compared with higher doses of BAY 59-7939. CONCLUSIONS: Oral administration of 2.5-10 mg b.i.d. of BAY 59-7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.