Melanoma beyond the skin: A case of anorectal melanoma

Anorectal melanoma is a rare cancer with a very poor prognosis. Symptoms on presentation include rectal bleeding, anal pain, an appreciable anorectal mass, change in bowel habits, pruritis, and tenesmus. Current surgical treatment options include abdominoperineal resection and wide local excision (WLE). However, recent reports suggest that WLE is adequate for disease control while minimizing the morbidity associated with surgery. We present a case of a 63 year old female with an initial diagnosis of an unspecified rectal tumour found to be anorectal melanoma.     

Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: a two-year study

BACKGROUND/AIMS: The aim of this study was to evaluate long term safety and antiviral activity of different doses of emtricitabine given once daily to patients chronically infected with hepatitis B. METHODS: Eligible patients were randomized in a double-blind, parallel study to evaluate 25, 100 or 200 mg once daily doses of emtricitabine for 48 weeks. Patients were then followed for an additional 48 weeks on open-label 200 mg emtricitabine. Serum HBV DNA, ALT, and hepatitis B serology were measured at regular intervals over the 2 years. Resistance surveillance was performed after 1 and 2 years on viremic samples, i.e. > 4700 copies/mL. RESULTS: Emtricitabine was well tolerated and produced a dose proportional antiviral response. After 2 years, 53% of the patients had serum HBV DNA < or = 4700 copies/mL, 33% seroconverted to anti-HBe and 85% had normal ALT. Eighteen percent of the patients who had received 200 mg emtricitabine for 2 years developed resistance mutations. CONCLUSIONS: Emtricitabine was well tolerated and demonstrated a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection. Based on these data, 200 mg emtricitabine once daily was chosen as the optimal dose for future hepatitis B studies.     

Idh1 mutations contribute to the development of T-cell malignancies in genetically engineered mice

Gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant Idh1. We observed the development of a spontaneous T-cell acute lymphoblastic leukemia (T-ALL) in these animals. The disease was transplantable and maintained expression of mutant IDH1. Whole-exome sequencing revealed the presence of a spontaneous activating mutation in Notch1, one of the most common mutations in human T-ALL, suggesting Idh1 mutations may have the capacity to cooperate with Notch1 to drive T-ALL. To further investigate the Idh1 mutation as an oncogenic driver in the T-cell lineage, we crossed Idh1-KI mice with conditional Trp53 null mice, a well-characterized model of T-cell malignancy, and found that T-cell lymphomagenesis was accelerated in mice bearing both mutations. Because both IDH1 and p53 are known to affect cellular metabolism, we compared the requirements for glucose and glutamine in cells derived from these tumors and found that cells bearing the Idh1 mutation have an increased dependence on both glucose and glutamine. These data suggest that mutant IDH1 contributes to malignancy in the T-cell lineage and may alter the metabolic profile of malignant T cells.Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently observed in a number of malignancies, including glioma, cholangiocarcinoma, chondrosarcoma, and several hematological malignancies (1). IDH1 is a cytoplasmic enzyme that catalyzes the NADP-dependent conversion of isocitrate to α-ketoglutarate (αKG). Mutations in IDH1 at arginine 132 (R132) cause an enzymatic gain of function that results in the NADPH-dependent conversion of αKG to d-2-hydroxyglutarate (2HG) (2). This metabolite is normally maintained at very low levels in cells and tissues and is not part of any known productive metabolic pathway. However, in cells and tissues of patients with IDH1 mutant tumors, 2HG builds up to high levels and is thought to contribute to tumorigenesis by inhibiting a class of αKG-dependent enzymes (1). The precise effects important for driving tumorigenesis downstream of IDH1 mutations are not fully understood and may differ between disease states.In the hematopoietic system, IDH1 mutations are most often associated with myeloid diseases, where they are commonly found in myelodysplastic syndrome and acute myeloid leukemia (3). However, IDH1 mutations are also found in a small proportion of adult T-cell acute lymphoblastic leukemia (T-ALL) (4, 5). T-ALL is an aggressive malignancy of developing T cells and is responsible for ∼25% of adult ALL (6, 7). T-ALL is thought to arise via a multistep process of oncogenic mutation that leads to the transformation of immature T cells. The genetic landscape of the disease has been characterized, and a large number of driver mutations have been identified (6). The most common genetic feature of T-ALL is the presence of activating mutations in Notch1, which are present in more than 50% of patients (8). Interestingly, IDH1 mutations seem to be confined to a subset of adult patients with T-ALL bearing an immature T-cell gene expression signature and harboring other oncogenic mutations in genes more commonly associated with myeloid malignancy, including Flt3 and DNMT3A (4, 9). This subset of T-ALL has recently been recognized as a distinct disease entity called early T-cell precursor T-ALL and is associated with therapy resistance and a particularly poor outcome (10). The role of IDH1 mutations in this subset of T-ALL is not understood.Using a myeloid lineage-specific conditional Idh1-R132-KI mouse model, we previously showed that mutant IDH1 partially blocks differentiation and produces a hematopoietic phenotype similar to human myelodysplastic syndrome (11). In this study, we crossed the Idh1-R132-KI mouse with Vav-cre animals to introduce the IDH1 R132 mutation into the entire hematopoietic system to investigate the role of Idh1 mutations in T-cell malignancy.     

Clinical algorithms for malaria diagnosis lack utility among people of different age groups

We conducted a study to determine whether clinical algorithms would be useful in malaria diagnosis among people living in an area of moderate malaria transmission within Kilifi District in Kenya. A total of 1602 people of all age groups participated. We took smears and recorded clinical signs and symptoms (prompted or spontaneous) of all those presenting to the study clinic with a history of fever. A malaria case was defined as a person presenting to the clinic with a history of fever and concurrent parasitaemia. A set of clinical signs and symptoms (algorithms) with the highest sensitivity and specificity for diagnosing a malaria case was selected for the age groups /=15 years. These age-optimized derived algorithms were able to identify about 66% of the cases among those <15 years of age but only 23% of cases among adults. Were these algorithms to be used as a basis for a decision on treatment among those presenting to the clinic, 16% of children /=5000 parasites/microl of blood would be sent home without treatment. Clinical algorithms therefore appear to have little utility in malaria diagnosis, performing even worse in the older age groups, where avoiding unnecessary use of anti-malarials would make more drugs available to the really needy population of children under 5 years of age.     

Use of DNA probes to identify Trypanosoma congolense and T. simiae in tsetse flies from The Gambia

Species- and strain-specific DNA probes were used to identify patent midgut infections in Glossina morsitans submorsitans and G. palpalis gambiensis captured at four sites in The Gambia. 52% of mature Nannomonas infections and 12% of immature infections were identified. Trypanosoma (Nannomonas) simiae accounted for the majority of identified infections in G.m. submorsitans, indicating the importance of distinguishing this species from the closely related T.(N) congolense when assessing the trypanosomiasis challenge to cattle. Both the savannah and riverine-forest groups of T. congolense were present, although the riverine-forest form was found only in G.p. gambiensis at Pirang, an isolated area of forest. Two-thirds of the samples remain unidentified by probes specific for: Trypanozoon; T. congolense savannah, riverine-forest and Kenya coast forms; T. simiae; and T. vivax, probably owing in part to low numbers of trypanosomes. However, the failure to identify several heavy Nannomonas infections, strongly suggests the presence of a further, as yet unknown, kind of Nannomonas.     

Proteoglycans: Road Signs for Neurite Outgrowth

Proteoglycans in the central nervous system play integral roles as ＂traffic signals＂ for the direction of neurite outgrowth. This attribute of proteoglycans is a major factor in regeneration of the injured central nervous system. In this review, the structures of proteoglycans and the evidence suggesting their involvement in the response following spinal cord injury are presented. The review further describes the methods routinely used to determine the effect proteoglycans have on neurite outgrowth. The effects of proteoglycans on neurite outgrowth are not completely understood as there is disagreement on what component of the molecule is interacting with growing neurites and this ambiguity is chronicled in an historical context. Finally, the most recent findings suggesting possible receptors, interactions, and sulfation patterns that may be important in eliciting the effect of proteoglycans on neurite outgrowth are discussed. A greater understanding of the proteoglycan-neurite interaction is necessary for successfully promoting regeneration in the iniured central nervous system.     

Localization of enkephalin immunoreactivity in the spinal cord of the long-tailed ray Himantura fai

Enkephalin-like immunoreactivity (ENK-LI) was found throughout the spinal cord of the long-tailed ray Himantura fai. The densest ENK-LI was in the superficial portion of lamina A of the dorsal horn. Lamina B and the deeper parts of lamina A contained radially oriented, labelled fibres. Laminae C, D, and E contained many longitudinally orientated fascicles which were surrounded by a reticulum of transversely orientated, labelled fibres, some of which projected into the ventral and lateral funiculi. Labelled fibres were found in the dorsal commissure and around the central canal, but the later did not cross the midline. One-third of all enkephalinergic cells were found throughout laminae A and B, while two-thirds were located in the medial half of C, D, and E. Occasionally a labelled cell was located in the lateral funiculus. The ventral horn (laminae F and G) contained many enkephalinergic fibres but no labelled nuclei. A few dorsal column axons contained ENK-LI. In the lateral funiculus there were two groups of labelled axons, a superficial, dorsolateral group, and a deeper group, occupying a crescent-shaped region. The ventral funiculus also contained many labelled axons. The central projection of the dorsal root passed through the substantia gelatinosa and divided into rostrally and caudally projecting fascicles within lamina C. The root, and these fascicles, both lacked ENK-LI. In contrast, the fascicles in laminae D and E did contain enkephalinergic fibres. The origin of the various fibre systems and the role of enkephalin in the regulation of sensory processing and motor output are discussed. © 1996 Wiley-Liss, Inc.     

Monoclonal antibody U36, a suitable candidate for clinical immunotherapy of squamous-cell carcinoma,recognizes a CD44 isoform

At present, tumor-targeting with monoclonal antibodies (MAbs) is among the most promising novel adjuvant-therapy modalities for the treatment of patients with minimal residual disease of head-and-neck squamous-cell carcinoma (HNSCC). For this purpose we developed MAb U36, recognizing a 200-kDa antigen expressed on the outer cell surface of squamous-cell carcinomas and their normal counterparts. Clinical radioimmunoscintigraphy (RIS) and biodistribution studies have shown that the MAb-U36-defined antigen is a suitable target molecule for antibody-based therapy of head-and-neck cancer. In the present study we further characterized the antigen by cDNA cloning. The cDNA was isolated by expression cloning in COS-7 cells. Sequence analysis and database searching revealed that the MAb-U36-defined antigen is identical to the squamous-cell-specific CD44 splice variant epican. The epitope recognized by MAb U36 was mapped by screening overlapping synthetic peptides of the epican-specific region encoded by exon 7–11 (v3–v7), and appeared to be located in the v6 domain. The applicability of MAb U36 for targeting human tumors of various origin expressing the CD44v6 domain is discussed. © 1996 Wiley-Liss, Inc.     

Problem-solving task performance in brain-damaged subjects

Investigated the relationship between the Halstead Category Test and the Wisconsin Card Sorting Test. A correlational analysis revealed a statistically significant but modest relationship between the two variables in separate samples of brain-damaged and non-brain-damaged individuals (N = 156). Thus, in spite of the apparent similarity of the two measures, their relationship is not sufficiently close to suggest that in fact they are measuring the same abilities. However, the combination of hit rates of the two measures and the high base rate of brain dysfunction in the present sample yielded good diagnostic accuracy for decisions with regard to the presence of brain damage.     

Narrative language skills of maltreated children living in out-of-home care

Abstract

Purpose: Children’s narrative accounts of their experiences are central to the prosecution of perpetrators of alleged maltreatment. We describe the narrative language skills of children who were placed in out-of-home care (OOHC) following substantiated maltreatment. It was hypothesised that (i) children with such histories would display narrative language skills that fall significantly below published age-expected norms, (ii) narrative language skills and core language skills would be positively correlated and (iii) narrative language skills would be associated with measures of socio-economic disadvantage.

Method: Eighty-three children (40 males and 43 females) aged 5;3 to 12;10 (M?=?7.9, SD = 2.3) from English-speaking home backgrounds were assessed using the Test of Narrative Language and the Clinical Evaluation of Language Fundamentals (CELF-4) Core Language Score. The Raven’s Coloured Progressive Matrices, a measure of nonverbal intelligence, was employed as a covariate.

Result: Forty-two percent of children scored in the below-average range on the Narrative Language Index Ability Index. The same proportion scored at/above age-expected levels on the Narrative Comprehension subtest, and 19% scored at/above age-expected levels on Oral Narration. There was a significant correlation between CELF-4 Core Language Scores and the Narrative Language Index Ability Index. Female carers’ education was significantly positively associated with overall narrative language scores; however, household income and index of socio-economic disadvantage were not significantly associated with narrative language scores.

Conclusion: Children who are victims of substantiated maltreatment should be considered at-risk for compromised ability to provide a narrative account of their experiences. The heterogeneity and often scant oral narrative language skills of these children highlights the importance of police/human services training on best-practice forensic interviewing. Policy and practice implications for speech-language pathology early intervention to support the needs of at-risk children are also discussed.