Stucco keratoses. A clinico-pathological study.

Altered Epithelial Cell Lineage Allocation and Global Expansion of the Crypt Epithelial Stem Cell Population Are Associated with Ileitis in SAMP1/YitFc Mice

MEK Inhibition Modulates the Growth of Nf1 mutant Hematopoietic Cells and Induces Clinical Improvement in a Murine Model of Juvenile Myelomonocytic Leukemia (JMML)

This study examined temporal variation in population dynamics and size structuring of two cyprinid minnows, Pseudobarbus afer and Barbus anoplus, in relation to their proximate physical habitats. Population estimates were determined using three-pass depletion sampling during both summer and winter. The habitats were characterised by seasonal variation in all physico-chemical conditions and spatial variation in substrata compositions. Whereas significant differences in population size were noted between seasons for B. anoplus, no differences were found between seasons for density and capture probability for either species. An increase in boulders was associated with increase in population size and density for P. afer; for B. anoplus, increased percentages of bedrock and bank vegetation were associated with an increase in population size and probability of capture, respectively. According to Canonical Correspondence Analysis, size structuring in P. afer was explained predominantly by seasonality, with smaller length classes associated with the seasonal variable of summer, while larger length classes were associated with pH that was higher in winter. By comparison, for B. anoplus, the habitat variables – bank vegetation and bedrock – accounted for much of the explained variance for size structuring. Recruitment appeared to be the major driver of size structuring for the two species; refugia, especially boulders and bank vegetation, also appeared to be important. Overall, the two species were adapted to the headwater streams that were generally variable in environmental conditions. Potential invasions by non-native invasive fishes that occur within the mainstream habitats threaten these two species. Efforts should continue to protect these minnows from such invasions by constructing barriers to upstream migration of non-native fishes into these headwater habitats.

Neutrophil-to-lymphocyte ratio on admission is an independent risk factor for the severity and mortality in patients with coronavirus disease 2019

This study examined medical emergency department utilization for patterns among uninsured patients with psychiatric disorders. Billing records of 15,672 uninsured adult patients treated in the emergency department of an academic medical center in southeast Texas over a 12-month period were analyzed for information on demographic characteristics, diagnosis, number of emergency department visits, and hospitalization. Overall, 11.8% of the population was diagnosed as having at least one psychiatric disorder during an emergency department visit. Patients with psychiatric disorders had an increased risk of having multiple emergency department visits and hospitalization compared with patients without psychiatric disorders. The risk of multiple emergency department visits was particularly high for patients with either bipolar disorder or psychotic disorders. Uninsured patients with psychiatric disorders appear to be heavy users of medical emergency department services. These findings may be helpful in developing more efficient strategies to serve the mental health needs of the uninsured.

The aim of this study is to evaluate the diagnostic value of pre-operative bilirubin levels in the diagnosis of acute appendicitis and appendiceal perforation. A retrospective analysis of 557 patients undergoing emergency appendicectomy over a 24-month period at a large teaching hospital. Hyperbilirubinaemia was defined as >25µmol/L. Data were analysed using descriptive statistics. 484 of the 557 (86.9%) operated cases were found histologically to be appendicitis. 116 cases of the 484 were perforated (24%). Bilirubin levels were significantly higher in the group with appendicitis versus the group found to have a normal appendix at histology, [median (IQR) 12.0µmol/L (9.00) vs. 8.0µmol/L (7.00) respectively, p<0.001], despite being within normal serum bilirubin range. Sensitivity of hyperbilirubinaemia for acute appendicitis was only 8%, however specificity was 94%. PPV was 85% and NPV was 26%. Whilst bilirubin was higher in patients with a perforated appendix versus acute appendicitis [median (IQR) 13.0µmol/L (9.00) vs. 11.0µmol/L (9.00), respectively], statistically, there was no significant difference in pre-operative bilirubin levels between the perforated appendicitis cases and the non-perforated appendicitis cases (p=0.326). However, the specificity of hyperbilirubinaemia for perforated appendicitis was 93%, sensitivity 9.4%, PPV 24% and NPV 82%. Bilirubin levels may be high, but remain within normal range, in cases of appendicitis. Therefore, bilirubin levels may be a useful measurement when investigating a patient with suspected appendicitis. Hyperbilirubinaemia is highly specific with regards to perforation, a finding supported by other studies. However, possibly because of the few perforated cases in this study, we cannot recommend that hyperbilirubinaemia be used to predict perforation.

Acquired Factor VIII (FVIII) deficiency is an uncommon but sometimes catastrophic autoimmune condition for which standard immune suppression, such as steroid or immunoglobulin infusion, is often insufficient to induce long-term remission (Dykes et al, 2001). A number of second-line therapies, such as cyclophosphamide, azathioprine and vincristine, have been used with varying success (Morrison & Ludlam, 1995). Here, we describe the use of cyclosporin A in a patient in whom conventional treatments failed to eradicate the inhibitor. At present, only limited experience exists of its use in this setting (Pfliegler et al, 1989). A 68-year-old woman with a 4-month history of easy bruising presented with life-threatening retropharyngeal haemorrhage. She had no significant past medical history, and medication consisted of aspirin and naproxen. Coagulation studies at presentation demonstrated a normal prothrombin time and fibrinogen activity but a prolonged activated partial thromboplastin time of 65 s (normal range 32–48 s). Factor assays confirmed a reduced FVIII coagulant activity (FVIII:C) at 1 iµ/dl. An inhibitor was detected and quantified at 54 Bethesda units (BU). von Willebrand factor activity and antigen were both within the normal range excluding acquired von Willebrand's disease. Her initial treatment was with high-purity plasma-derived FVIII (Liberate, Scottish National Blood Transfusion Service), commencing at 20 000 units twice daily, with prednisolone 60 mg and high-dose intravenous immunoglobulin (2 g/kg). Clinical response to treatment was excellent with no further haemorrhage. The patient's inhibitor titre remained detectable at 10–20 BU with FVIII:C remaining below 20 iµ/dl over the succeeding months. The introduction of cyclophosphamide 50 mg daily, 9 months after presentation, initially in conjunction with further prednisolone (1 mg/kg), rendered the inhibitor transiently undetectable, with FVIII:C peaking at 40 iµ/dl. However, with reduction of the prednisolone dose, the inhibitor returned, and the FVIII:C fell. After 9 months of treatment with cyclophosphamide, it was discontinued because of lack of a sustained response. Approximately 28 months after presentation, cyclosporin A (CyA) was introduced at 100 mg twice daily (3 mg/kg/d), initially with prednisolone (1 mg/kg). A target trough plasma CyA concentration of 200–250 mg/l was achieved over 3 months with a dose of 175 mg twice daily (≈ 5 mg/kg/d), during which time the prednisolone was discontinued. The inhibitor titre fell and was undetectable 3 months after the commencement of CyA. The FVIII:C rose to within the normal range following disappearance of the inhibitor (Fig 1). After 14 months of therapy with CyA, and with FVIII:C levels remaining in the normal range, cyclosporine was reduced and stopped over a 4-month period. Ten months after cessation of all immunosuppressive therapy, the FVIII:C remains in the normal range with no detectable inhibitor. Factor VIII and inhibitor levels. Permanent eradication of inhibitor without the need for continued therapy is the ultimate aim of immunosuppressive treatment for acquired haemophilia. Initial reduction in inhibitor titre may be achieved with high-dose intravenous immunoglobulin and steroids; however, long-term clearance may not be achieved with this approach alone (Hay et al, 1996). Further options include cytotoxic regimens or immunosuppressant agents such as cyclosporine. As no regime has been universally successful, and there have been no large immunomodulatory studies, no gold standard treatment has been established (Grunewald et al, 2001). Cytotoxic therapy may be associated with neutropenic sepsis; such cases have been reported in the treatment of acquired haemophilia (Lian et al, 1989). On the other hand CyA is well recognized as a precipitant of hypertension and renal impairment in addition to its anticipated immunosuppressive effects. The choice of treatment must then rest on the perceived risk of the options available. This case demonstrates a lasting response attributed to CyA that was not achieved either by first-line therapy with steroid and intravenous immunoglobulin or by second-line therapy with cyclophosphamide. Although we cannot exclude spontaneous remission of the patient's FVIII inhibitor, the reduction in inhibitor titre commensurate with the introduction of CyA makes this unlikely. We conclude that CyA warrants consideration in patients refractory to first-line therapy for this rare but serious autoimmune disorder.

This chapter defines and formulates demographic and environmental stochasticity, and illustrates statistical methods for estimating them from field data. Population fluctuations in most species are produced by demographic and environmental stochasticity, rather than by internally driven cycles or chaos. Demographic stochasticity results from chance independent events of individual mortality and reproduction, causing random fluctuations in population growth rate, primarily in small populations. Environmental stochasticity results from temporal fluctuations in mortality and reproductive rates of all individuals in a population in the same or similar fashion, causing population growth rate to fluctuate randomly in populations of all sizes. In populations much larger than the ratio of the demographic variance to the environmental variance, demographic stochasticity can be neglected. The demographic variance can be estimated from data on individual survival and reproduction, and using this, the environmental variance can then be estimated from population time series. Under density-independent growth in a random environment, the eventual rate of increase or decrease of population size is given by the long-run growth rate, the mean rate of increase of log population size, which is reduced by stochasticity. Density-dependent population growth in a stochastic environment produces temporal autocorrelation in population size, even in the absence of temporal autocorrelation in the environment. Time series for terrestrial populations of birds and mammals show little evidence of temporal environmental autocorrelation.

The influence of aluminium (20-50 micrograms/ml) on neuronal function was examined using electrophysiological techniques and neuroblastoma clone cells which offer a convenient model of differentiating and fully active neurons. Two specific questions were addressed: 1) Can differentiated cells maintain their normal excitable function when exposed to aluminium? 2) Can proper development of electrophysiological properties be achieved in its presence? We report that aluminium caused premature onset of deterioration in fully differentiated cells. Within 4-6 days they depolarized from -29.3 +/- 0.9 mV to levels lower than -15 mV; compound polyphasic action potentials were gradually replaced by slow monophasic spikes before the final loss of excitable properties and structural deformations was noticed. Developing cells followed the normal pattern of differentiation in the presence of aluminium: within 7 days they extended neurites, hyperpolarized and exhibited polyphasic spikes. These results show that neuroblastoma cells are apparently less susceptible to aluminium's toxicity during the process of development than after differentiation. Possible mechanisms by which aluminium may exert its effects are discussed in view of these observations.

Oral squamous cell carcinoma (OSCC) is associated both with the local expansion of clones of malignant cells and with their further migration to regional and distant sites. The interactions that occur between normal and malignant cells during these events are not well modelled by standard culture conditions, but organotypical cultures, in which epithelial cells are grown on a matrix containing fibroblasts, provide a suitable environment for such investigations. Cells from five cell lines, each derived from OSCC and marked by retroviral transduction with alkaline phosphatase, were incorporated as small subpopulations (0.1-5%) in uniformly differentiating organotypical cultures constructed from normal oral mucosal cells. The patterns of growth of the malignant cells within the normal epithelium were examined for 3 weeks. There was variation between the different cell lines in their rates and patterns of growth, but all cell lines produced clusters of malignant cells that had expanded within 3 weeks to replace the normal epithelium. The appearance and spacing of these clusters suggested that each was derived from a single progenitor cell. The number of malignant cells initially present within a given area of organotypical epithelium was much greater than the number of expanding cell clusters subsequently formed. Cluster-forming cells thus represented only a subpopulation of the tumour cells. The organotypical model allows examination of interactions occurring between cells derived from OSCC and normal epithelia. The three-dimensional nature of organotypical cultures, together with their more normal patterns of differentiation, provides an environment that more closely mimics the in vivo environment in which tumours develop. The finding that only a subpopulation of tumour cells forms expanding tumour colonies suggests a range of growth potentials within a tumour population and may provide preliminary evidence for some form of stem and amplifying cell pattern.

Size changes in muscle fibers of subjects with chronic heart disease (CHD) have been reported, although a consensus has not been achieved. The aims of the present study were to investigate a possible association between CHD and fiber size changes in the brachial biceps compared to subjects without heart disease. Forty-six muscle samples were obtained in autopsies of individuals (13 to 84 years) without neuromuscular disorders, 19 (10 males and 9 females) with, and 27 (14 males and 13 females) without CHD. In all cases muscle sections were stained with hematoxylin and eosin and processed for the visualization of myofibrillar ATPase activity. The lesser diameter of type 1 and type 2 fibers was obtained tracing their outlines (at least 150 fibers of each type per sample) onto an image analyzer connected to a computer. The results were analyzed statistically comparing males and females with and without CHD. Type 1 fiber mean lesser diameters were 51.51 and 54.52 microm in males (normal range 34-71 microm) and 45.65 and 55.42 microm in females (normal range 34-65 microm) without and with CHD, respectively; type 2 fibers measured 54.31, 58.23, 41.15, and 49.57 microm, respectively (normal range 36-79 microm for males and 32-59 microm for females). No significant difference in fiber size was detected in 24 males with and without CHD, while in 22 females there was a significant increase in size in those with cardiomyopathy. We concluded that CHD does not determine significant changes in fiber size. However, in females, there is some hypertrophy which, despite within normal range, may reflect morphologic heterogeneity of the sample, or the daily life activities in the upper limbs as a compensatory mechanism to fatigability that affect predominantly the lower limbs in subjects with CHD.

During infections, naive CD8 T cells differentiate into terminal effector cells (TE) and long-lived memory CD8 T cells that recirculate through lymphoid organs using the vasculature (TCIRC), and tissue resident memory (TRM) cells that do not recirculate. The transcriptional control that delineates differentiation of TE cells from memory cell subsets is still unclear. DNA motifs recognized by ETS-family transcription factors (TFs) are highly frequent in cis-regulatory regions that become chromatin accessible in naïve CD8 T cells 24 hours after TCR stimulation, and in mature memory T cell subsets. The ETS-family is encoded by 27 genes, and expression analyses revealed Ets1 is the most highly expressed member. Ets1 is transiently downregulated during activation and is re-expressed in TCIRC cells, but remains lower in intestinal TRM cells. P14 CD8 T cells responding to acute LCMV infection that were depleted of Ets1 using retrovirally-delivered shRNAmirs preferentially became KLRG1hi CD127lo TE-like cells, and their numbers in the circulation rapidly declined, resulting in an absence of long-lived effector cells and residual numbers of central memory-like cells. Concomitantly, Ets1-depleted cells re-distributed into the gut TRM compartment and had increased fractions of CD69hi CD103hi cells. Early after infection in the spleen, a larger fraction of Ets1-depleted P14 cells express CCR9 and α4β7. Depletion or overexpression of Ets1 in P14 cells both indicate it negatively regulates CD25 and Prdm1 expression, and promotes Tcf7 and Bcl6 expression. These results suggest that Ets1 functions early during CD8 T cell activation to establish the normal pattern of TCIRC and TRM cell differentiation during acute viral infection.

&lt;div&gt;Abstract&lt;p&gt;Early-life exposure to estrogenic chemicals can increase cancer risk, likely by disrupting normal patterns of cellular differentiation. Female mice exposed neonatally to the synthetic estrogen diethylstilbestrol (DES) develop metaplastic and neoplastic uterine changes as adults. Abnormal endometrial glands express the oncofetal protein sine oculis homeobox 1 (SIX1) and contain cells with basal [cytokeratin (CK)14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;−&lt;/sup&gt;] and poorly differentiated features (CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;+&lt;/sup&gt;), strongly associating SIX1 with aberrant differentiation and cancer. Here, we tested whether SIX1 expression is necessary for abnormal endometrial differentiation and DES-induced carcinogenesis by using &lt;i&gt;Pgr-cre&lt;/i&gt; to generate conditional knockout mice lacking uterine &lt;i&gt;Six1&lt;/i&gt; (&lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;d/d&lt;/sup&gt;). Interestingly, corn oil (CO) vehicle-treated &lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;d/d&lt;/sup&gt; mice develop focal endometrial glandular dysplasia and features of carcinoma &lt;i&gt;in situ&lt;/i&gt; as compared with CO wild-type &lt;i&gt;Six1&lt;/i&gt; (&lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;+/+&lt;/sup&gt;) mice. Furthermore, &lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;d/d&lt;/sup&gt; mice neonatally exposed to DES had a 42% higher incidence of endometrial cancer relative to DES &lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;+/+&lt;/sup&gt; mice. Although DES &lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;d/d&lt;/sup&gt; mice had &gt;10-fold fewer CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;−&lt;/sup&gt; basal cells within the uterine horns as compared with DES &lt;i&gt;Six1&lt;/i&gt;&lt;sup&gt;+/+&lt;/sup&gt; mice, the appearance of CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;+&lt;/sup&gt; cells remained a feature of neoplastic lesions. These findings suggest that SIX1 is required for normal endometrial epithelial differentiation, CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;+&lt;/sup&gt; cells act as a cancer progenitor population, and SIX1 delays DES-induced endometrial carcinogenesis by promoting basal differentiation of CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;+&lt;/sup&gt; cells. In human endometrial biopsies, 35% of malignancies showed CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;+&lt;/sup&gt; expression, which positively correlated with tumor stage and grade and was not present in normal endometrium.&lt;/p&gt;Implications:&lt;p&gt;Aberrant epithelial differentiation is a key feature in both the DES mouse model of endometrial cancer and human endometrial cancer. The association of CK14&lt;sup&gt;+&lt;/sup&gt;/18&lt;sup&gt;+&lt;/sup&gt; cells with human endometrial cancer provides a novel cancer biomarker and could lead to new therapeutic strategies.&lt;/p&gt;&lt;/div&gt;

The extensive research done on the interrelationship between different social factors such as social class, gender and age and different linguistic variables has shown that these factors have important effects on the way language is used. Among these factors a special importance can be placed on age due to the role it plays in revealing different patterns of language use, such as the age-grading pattern, the normal pattern of age differentiation and the important patterns of language change which can inform us about the emergence of a linguistic form or the death of some old form. This paper is intended to examine the interrelationship between age and the usage of Shirazi vocabulary or lexical items. Sixty respondents belonging to 6 age groups of Shirazi speakers answered a 60-item questionnaire. Each item included one Shirazi word with its definition and sometimes a short example to clarify its meaning. The respondents had to choose between two choices: either they used the item or they did not. The analysis of the results showed that age was an influencing factor on the speech of the speakers as the older people had a large collection of active Shirazi words (they actively used all the words) while the younger generation had two collections of more active and less active Shirazi words and as the age of the subjects increased their mean scores which represented their usage of Shirazi vocabulary items also increased. These words were also used less among the more educated Shirazi speakers.

We characterized the distribution of CD40 and CD40 ligand (CD40-L) in the adult and developing murine thymus. Before birth, CD40 was almost exclusively localized to scattered foci of medullary cells. By birth there was a dramatic upregulation of CD40 expression by cortical epithelial cells, which was accompanied by a consolidation of medullary epithelial foci. CD40-L+ thymocytes displayed a medullary location. Analysis of mice deficient in CD40-L expression indicated that CD40-L/CD40 interactions were not required for development of the medullary compartment. Overexpression of CD40-L targeted to thymocytes altered thymic architecture, as reflected by a dramatic loss of cortical epithelial cells, expansion of the medullary compartment, and extensive infiltration of the capsule with a mixture of CD3+ cells, B-cells, and macrophages/dendritic cells. Reconstitution of lethally irradiated normal mice with lck CD40-L bone marrow cells also resulted in loss of cortical epithelium and expansion of the medullary compartment. Disruption of the normal pattern of thymic architecture and epithelial differentiation as a consequence of increased intrathymic levels of CD40-L expression points to a role for CD40-L/CD40 interactions in the normal pattern of epithelial compartmentalization/differentiation within the thymic environment.