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We report on the radioisotopic age, formation, and preservation of a late Pleistocene human footprint site in northern Tanzania on the southern shore of Lake Natron near the village of Engare Sero. Over 400 human footprints, as well as tracks of zebra and bovid, are preserved in a series of volcaniclastic deposits. Based on field mapping along with geochemical and grain-size analyses, we propose that these deposits originated as proximal volcanic material from the nearby active volcano, Oldoinyo L'engai, and were then fluvially transported to the footprint site. Stable isotope results (delta O-18 and delta C-13) suggest that the footprints were originally emplaced on a mudflat saturated by a freshwater spring and were later inundated by the rising alkaline waters of Lake Natron. We employed the Ar-40/Ar-39 and C-14 dating methods to investigate the age of the site and determined that the footprint level is older than 5760 +/- 30 yrs. BP and younger than 19.1 +/- 3.1 ka. These radioisotopic ages are supported by stratigraphic correlations with previously documented debris avalanche deposits and the stable isotope signatures associated with the most recent highstand of Lake Natron, further constraining the age to latest Pleistocene. Since modern humans (Homo sapiens) were present in Africa ca. 200 ka, Engare Sero represents the most abundant and best-preserved footprint site of anatomically modern Homo sapiens currently known in Africa. Fossil footprints are a snapshot in time, recording behavior at a specific moment in history; but the actual duration of time captured by the snapshot is often not well defined. Through analog experiments, we constrain the depositional window in which the prints were made, buried, and ultimately preserved to within a few hours to days or months. (C) 2016 Elsevier B.V. All rights reserved.

The mechanisms involved in the pathogenesis of ovarian cancer are poorly understood, but evidence suggests that aberrant activation of Wnt/beta-catenin signalling pathway plays a significant role in this malignancy. However, the molecular defects that contribute to the activation of this pathway have not been elucidated. Frequently rearranged in advanced T-cell lymphomas-1 (FRAT1) is a candidate for the regulation of cytoplasmic beta-catenin. In this study, we developed in situ hybridisation probes to evaluate the presence of FRAT1 and used an anti-beta-catenin antibody to evaluate by immunohistochemistry the expression levels and subcellular localisation of beta-catenin in ovarian cancer tissue microarrays. Expression of FRAT1 was found in some human normal tissues and 47% of ovarian adenocarcinomas. A total of 46% of ovarian serous adenocarcinomas were positive for FRAT1 expression. Accumulation of beta-catenin in the nucleus and/or cytoplasm was observed in 55% ovarian adenocarcinomas and in 59% of serous adenocarcinomas. A significant association was observed in ovarian serous adenocarcinomas between FRAT1 and beta-catenin expression (P0.01). These findings support that Wnt/beta-catenin signalling may be aberrantly activated through FRAT1 overexpression in ovarian serous adenocarcinomas. The mechanism behind the overexpression of FRAT1 in ovarian serous adenocarcinomas and its significance is yet to be investigated.

Loss of heterozygosity (LOH) for several tumor suppressor genes (including loci on 3p, 1p, and 17p,) has been documented in surgical specimens of adrenal cortical carcinomas (ACCA) without accompanying losses in benign hyperplastic and adenomatous adrenal cortical lesions (ACL). This disparate pattern of LOH raises the possibility of exploitation of these differences for diagnostic utilization. Cytologic differentiation of benign versus malignant ACL may be impossible based solely on fine-needle aspiration (FNA) material. The authors attempted to extrapolate the genetic findings on surgical specimens to FNA specimens of ACL to determine whether LOH studies could be utilized as a definitive diagnostic tool.Microdissection of archival material was performed on FNAs of ten ACCAs (stained with the Papanicolaou and Diff-Quik stains) with corresponding histologic material (stained with hematoxylin and eosin), one FNA of a benign ACL, and three touch preparations of benign adrenal cortex. LOH analysis was performed by polymerase chain reaction (PCR) with flanking markers for the following putative tumor suppressor genes: p53 (17p13; TP53), 1p (1p36; D1S165), and the von Hippel-Lindau gene at 3p25 (D3S1038 and D3S1110).Similar results were obtained with cytologic and histologic material. As expected, benign ACL showed no LOH for the markers examined. Of the informative ACCA cases, 70% showed LOH for at least 1 of the 3 markers tested on both FNA and histologic samples. For all cases with amplifiable DNA, there was a 100% concordance rate for LOH between cytologic and histologic material, with at least 7 of the 10 cytologic samples originating from metastatic lesions and all of the surgical material originating from the primary adrenal neoplasm.The results of this study suggest that the combination of microdissection and PCR for LOH of p53, 1p, and 3p25 from FNA material has the potential to be utilized to distinguish ACCA from benign ACL in informative cases. It also shows a 100% concordance rate between metastatic and primary ACCAs for the losses observed, a finding that can be extremely useful for the definitive identification of metastatic lesions. Archival cytologic preparations of ACCA are a reliable source of DNA for LOH studies. [See editorial counterpoint on pages 173-5 and reply to counterpoint on pages 176-7, this issue.] Cancer (Cancer Cytopathol)

The bcl-2 proto-oncogene suppresses apoptosis in a variety of cell types and is essential for normal renal development. PAX8 is a member of the paired box class of transcription factors and is developmentally regulated. bcl-2 and PAX8 are both expressed in the kidney during development and throughout life, demonstrating a nearly identical pattern of expression. We used transient transfection reporter assays and electrophoretic mobility shift assays to test PAX8 transcriptional regulation of bcl-2. PAX8 transcriptionally activates the bcl-2 promoter and binds to promoter sequences in vitro. These findings establish that PAX8 can transcriptionally regulate bcl-2 and suggest that suppression of apoptosis is an important event in the development and maintenance of renal tubular epithelial structures.

The Wilms' tumor gene WT1 encodes a zinc-finger transcription factor that functions as a tumor suppressor gene and repress transcription of a number of growth factors and proto-oncogenes. In the developing kidney, WT1 expression peaks at the onset of the mesenchyme-to-epithelium transition and is required for epithelial differentiation. WT1 mRNA undergoes alternative splicing at two sites, resulting in four mRNA species and proteins expressed in constant ratios. The first alternative splice results in the presence or absence of exon 5, which is 51 nucleotides long and encodes 17 amino acids between the amino-terminal, proline-rich transcriptional repression domain and the carboxy-terminal DNA-binding zinc-fingers. We used cell-proliferation assays to determine the effect of exon 5 on WT1 function. Isoforms of WT1 without exon S repressed cell growth. WT1 isoforms with exon 5 slowed cell growth to a lesser extent but resulted in altered cellular morphology. These results provide evidence that WT1 splice isoforms differentially regulate cell proliferation and initiate the mesenchyme-to-epithelium transition during metanephric development.

The organisation of on-site medical personnel and facilities is described for an open air rock concert attended by 62,000 people. Care of the majority of patients was completed on site, avoiding an increased workload for local hospitals and general practitioners. Many of the head injuries could have been avoided by preventing the distribution of promotional items and large drinks containers which were thrown as missiles.

The Wilms' tumor gene WT1 functions as a tumor suppressor gene, repressing transcription of several growth factors and growth factor receptors. The bcl-2 and c-myc proto-oncogenes are essential for regulation of apoptosis and cell proliferation with roles in development and oncogenesis. We found that WT1 can repress transcription of both the bcl-2 and c-myc promoters. This suggests that WT1 regulates bcl-2 and c-myc during renal development, and the loss of functional WT1 results in deregulation of bcl-2 and c-myc, contributing to tumor formation.

The Royal College of Surgeons of England recently published guidelines for sedation by non-anaesthetists. The report emphasizes sedation for endoscopy and dental surgery, but the recommendations are equally relevant to accident and emergency (A&E) medicine. Current sedation practice for orthopaedic manipulations was determined by questionnaire in 58 A&E and orthopaedic junior staff in one teaching and one district general hospital. Of the 50 doctors who completed the questionnaire, 14 (28%) respondents made an inadequate pre-sedation assessment. Over half were unable to name the antagonist to benzodiazepine drugs. Eleven (22%) doctors administered supplemental oxygen to all their patients, 12 (24%) did not consider it necessary. Pulse oximetry was used for patient monitoring by one respondent (2%). None of the junior staff had received any formal training in sedation techniques. Thirty-one (62%) had attended a resuscitation refresher course within the last year. These results emphasize the need for training in sedation techniques for A&E and orthopaedic juniors and the importance of appropriate supervision.

The Wilms' tumor gene, WT1, is expressed in few tissues, mainly the developing kidney, genitourinary system, and mesothelium, and in immature hematopoietic cells. To develop an understanding of the role of WT1 in development and tumorigenesis, we have identified transcriptional regulatory elements that function in transient reporter gene constructs transfected into kidney and hematopoietic cell lines. We found three transcription start sites of the WT1 gene and have identified an essential promoter region by deletion analysis. The WT1 promoter is a member of the GC-rich, TATA-less, and CCAAT-less class of polymerase II promoters. Whereas the WT1 promoter is similar to other tumor suppressor gene promoters, the WT1 expression pattern (unlike Rb and p53) is tissue-restricted. The WT1 GC-rich promoter is promiscuous, functioning in all cell lines tested, independent of WT1 expression. This finding suggests that the promoter is not tissue-specific, but that tissue-specific expression of WT1 is modulated by additional regulatory elements. Indeed, we have identified a transcriptional enhancer located 3' of the WT1 gene50 kilobases downstream from the promoter. This orientation-independent enhancer increases the basal transcription rate of the WT1 promoter in the human erythroleukemia cell line K562, but not in any of the other cell lines tested.

The case of a fit young man who developed rhabdomyolysis after a short period of immobilization following acute alcohol intoxication is described. Rhabdomyolysis should be considered in an intoxicated patient presenting with muscle tenderness, particularly after immobilization.

Using ascitic fluid or pleural effusion obtained from 13 ovarian or metastatic breast cancer patients, we separated tumor cells from effusion-associated lymphocytes (EAL) with Percoll density centrifugation. Lymphocytes were incubated with recombinant interleukin 2 (IL-2) for 3-4 days and then assessed for tumoricidal activity in a 51chromium-release assay. The IL-2-activated EAL were found to lyse autologous fresh tumor cells, as well as allogeneic fresh tumor cells and FMEX tumor cells, a melanoma cell line which is resistant to natural killer cell activity but is sensitive to lysis by lymphokine-activated killer cells. There was little or no tumoricidal activity seen in freshly isolated EAL or in EAL which were cultured in medium without IL-2. Phenotypically, the IL-2-activated EAL were largely CD3-, although some cytolytic activity was found in CD3+ populations. Also, most activity was found in cells positive for CD2 (OKT11) and CD16 (Leu 11b), and negative for the monocyte marker Leu M3. These results indicate that the activated cell types found in EAL were predominantly natural killer/lymphokine-activated killer-like with a small contribution from T-cells. Finally, EAL were readily activated by IL-2 in medium containing autologous effusion fluid, indicating that in situ activation of tumoricidal activity by IL-2 can occur in the face of potentially inhibitory substances or cells that may exist in the effusions. Direct introduction of IL-2 may therefore be a potential therapeutic modality of effusion-forming cancers.

The ECC tool development and audit experiences indicated that there is promise in developing a process audit tool to monitor quality of care in nursing homes; moreover, the tool selected required only one hour per resident. Focusing on the care process and resident needs provided useful information for care providers at the unit level as well as for administrative personnel. Besides incorporating a more interdisciplinary focus, the revised tool needs to define support services most appropriate for nursing homes, includes items related to discharge planning and increases measurement of significant others' involvement in the care process. Future emphasis at the ECC will focus on developing intervention plans to maintain strengths and correct deficiencies identified in the audits. Various strategies to bring about desired changes in the quality of care will be evaluated through regular, periodic monitoring. Having a valid and reliable measure of quality of care as a tool will be an important step forward for LTC facilities.