Pathological findings in human autoimmune lymphoproliferative syndrome

The defects in lymphocyte apoptosis that underlie the autoimmune lymphoproliferative syndrome (ALPS) are usually attributable to inherited mutations of the CD95 (Fas) gene. In this report, we present the histopathological and immunophenotypic features seen in the lymph nodes (n = 16), peripheral blood (n = 10), bone marrow (n = 2), spleen (n = 3), and liver (n = 2) from 10 patients with ALPS. Lymph nodes showed marked paracortical hyperplasia. Interfollicular areas were expanded and populated by T cell receptor-alphabeta CD3+ CD4-CD8- (double-negative, DN) T cells that were negative for CD45RO. CD45RA+ T cells were increased in all cases studied. The paracortical infiltrate was a result of both reduced apoptosis and increased proliferation, as measured by in situ detection of DNA fragmentation and staining with MIB-1, respectively. The paracortical proliferation may be extensive enough to suggest a diagnosis of malignant lymphoma. Many of the paracortical lymphocytes expressed markers associated with cytotoxicity, such as perforin, TIA-1, and CD57. CD25 was negative. In addition, most lymph nodes exhibited florid follicular hyperplasia, often with focal progressive transformation of germinal centers; in some cases, follicular involution was seen. A polyclonal plasmacytosis also was present. The spleens were markedly enlarged, more than 10 times normal size. There was expansion of both white pulp and red pulp, with increased DN T cells. DN T cells also were observed in liver biopsies exhibiting portal triaditis. In the peripheral blood, the T cells showed increased expression of HLA-DR and CD57 but not CD25. CD45RA+ T cells were increased in the four cases studied. Polyclonal B cell lymphocytosis with expansion of CD5+ B cells was a characteristic finding. Taken together, the histopathological and immunophenotypic findings, particularly in lymph nodes and peripheral blood, are sufficiently distinctive to suggest a diagnosis of ALPS. Of note, two affected family members of one proband developed lymphoma (T-cell-rich B-cell lymphoma and nodular lymphocyte predominance Hodgkin's disease, respectively).     

Volatiles from Intact and Lygus-Damaged Erigeron annuus (L.) Pers. are Highly Attractive to Ovipositing Lygus and its Parasitoid Peristenus relictus Ruthe

Trap cropping and biological control can provide a sustainable means of controlling insect pests. Insects in the genus Lygus (Hemiptera: Miridae) are major pests on cotton and horticultural crops throughout the United States, and pesticide resistance within Lygus populations necessitates more sustainable long-term management techniques. Here, we explore behavioral responses of Lygus bugs (L. rubrosignatus Knight) and an introduced parasitoid, Peristenus relictus (Hymenoptera: Braconidae), to a common field edge plant, Erigeron annuus, which has the potential to serve as a trap host. Erigeron annuus is attractive to Lygus in the field, with Lygus preferentially moving to Erigeron patches compared to more abundant cotton plants. To determine the role of odor cues in mediating this attraction, we collected volatiles from E. annuus with and without Lygus damage, and then tested the attractiveness of these volatiles vs. those of cotton to Lygus females and female P. relictus wasps using Y-tube and wind tunnel bioassays. We found that undamaged E. annuus emits high concentrations of a complex volatile blend (60+ compounds), with novel compounds induced and constitutive compounds up-regulated in response to damage. Additionally, both female Lygus bugs and female P. relictus wasps are highly attracted to E. annuus volatiles over those of cotton in almost every combination of damage treatments. Our results suggest that Erigeron annuus would be an effective trap plant to control Lygus in cotton, since it is highly attractive to both the pest and its natural enemy.     

Intestinal water and solute absorption studies: comparison of in situ perfusion with chronic isolated loops in rats

The effects of lumenal glucose on jejunal water transport and the influence of glucose-induced water absorption on solute uptake from single-pass perfusions are compared in anesthetized rats in situ and isolated chronic loops in unanesthetized rats in vivo. While the magnitudes of solute membrane permeabilities are consistently higher in the chronic loop system, the effects on water transport and its promotion of jejunal solute uptake are comparable between the two experimental systems. The effect of glucose-induced water absorption on the enhanced/baseline jejunal uptake ratio of the hydrophilic drug, acetaminophen, is greater than that for the lipophilic drug, phenytoin, in both experimental systems. The fact that chronic loop effective solute permeabilities were equivalent to solute membrane permeabilities in situ is consistent with greater lumenal fluid mixing in vivo. In addition, in situ body temperature affects the uptake of phenytoin but not acetaminophen, water, or glucose. This suggests that active and paracellular solute transport is not compromised in situ, while membrane partitioning and diffusion of lipophilic species are more sensitive to experimental conditions.     

Anesthetic management and perioperative surveillance

The intraoperative management of the high-risk patient has received a great deal of attention and research during the past decade. Based on the available evidence, there appears to be no one best anesthetic technique or agent. More importantly, the goals of intraoperative management are to avoid myocardial ischemia, which include preventing tachycardia, and maintaining normothermia and adequate hematocrit. Perioperative monitoring includes transesophageal echocardiography, pulmonary artery catheter and ST segment monitoring. Perioperative pharmacological treatment with alpha-2 agonists and beta-adrenergic blocking agents are associated with a reduced incidence of perioperative myocardial ischemia and improved long-term survival, respectively. Future research will be required to determine whether prophylactic therapy or early treatment of perioperative myocardial ischemia will lead to improved outcome.     

Sequence alterations of insulin-like growth factor binding protein 3 in neoplastic and normal gastrointestinal tissues

Insulin-like growth factor binding protein 3 (IGFBP-3) is an important regulator of normal and malignant cell growth. It modulates the mitogenic effects of insulin-like growth factors (IGFs) by inhibiting growth through mechanisms both dependent on and independent of IGF binding. IGF-I and IGF-II levels are regulated by binding to the IGF-II receptor, which is inactivated by mutation in human gastrointestinal (GI) tumors. We have previously demonstrated elevated IGF-II ligand expression in IGF-II receptor-mutant GI tumors, implicating the IGF signaling system in GI tumorigenesis. Therefore, to investigate the potential involvement of IGFBP-3 in human GI carcinogenesis, direct DNA sequencing of exons 1-4 and intron-exon boundaries of the IGFBP-3 gene was performed in 10 colorectal cancers, 10 gastric cancers, and 10 esophageal cancers. Four distinct sequence alterations were identified: (a) in one gastric and one esophageal tumor, an A to C transversion occurred at nucleotide 5795 (CAC-->CCC), leading to a His-->Pro substitution at codon 179; (b) a second esophageal tumor had a C to T transition at nucleotide 8291 (ACC-->ATC), leading to a Thr-->Ile substitution at codon 277 of IGFBP-3; (c) one alteration comprised a G to C transversion in exon 1 at nucleotide 2132 (GGG-->GCG), leading to a Gly-->Ala substitution at codon 32 in two gastric cancers, seven esophageal cancers, and nine colon cancers; and (d) a C to G transversion located 17 nucleotides from the 3' splice site in intron 1 was observed in three colon cancers and four esophageal cancers. All of these DNA sequence alterations were present in matched normal DNA from the same subjects, which suggests that some or all of them may represent polymorphisms. However, we cannot exclude the possibility that the germ-line nonconservative amino acid substitutions predicted to occur as a result of these alterations result in subtle changes to IGFBP-3 protein function and a predisposition to developing GI malignancy.     

Heterotrimeric G proteins physically associated with the lipopolysaccharide receptor CD14 modulate both in vivo and in vitro responses to lipopolysaccharide

Septic shock induced by lipopolysaccharide (LPS) triggering of cytokine production from monocytes/macrophages is a major cause of morbidity and mortality. The major monocyte/macrophage LPS receptor is the glycosylphosphatidylinositol (GPI)-anchored glycoprotein CD14. Here we demonstrate that CD14 coimmunoprecipitates with Gi/Go heterotrimeric G proteins. Furthermore, we demonstrate that heterotrimeric G proteins specifically regulate CD14-mediated, LPS-induced mitogen-activated protein kinase (MAPK) activation and cytokine production in normal human monocytes and cultured cells. We report here that a G protein binding peptide protects rats from LPS-induced mortality, suggesting a functional linkage between a GPI-anchored receptor and the intracellular signaling molecules with which it is physically associated.     

Crohn's disease and acute leukocytoclastic vasculitis of skin

A 39-yr-old white male with a prolonged history of Crohn's disease presented with worsening diarrhea associated with an increasingly painful rash of both lower extremities as well as left ankle swelling. A skin biopsy revealed an acute leukocytoclastic vasculitis. Intravenous hydrocortisone followed by oral prednisone achieved a rapid remission of the both cutaneous and gastrointestinal manifestations. Long-term remission has been maintained with 6-mercaptopurine and mesalamine. The rare association between cutaneous vasculitis and Crohn's disease is discussed and earlier reported cases reviewed.     

A generalized two-threshold detection procedure

A modified sequential procedure for testing binary hypotheses with different means, proposed by C.C. Lee and J.B. Thomas (ibid., vol.IT-30, no.1, p.16-23, Jan. 1984), is generalized for application to the case of multiple hypotheses with different means/variances of the Gaussian distribution. The method constitutes a two-threshold test for fixed-size packages of samples with a sequential procedure of discarding the package for which no decision is reached and subsequently testing a new package. The objective is to find an optimum package size N₀ which leads to the minimum overall average sample number (ASN) for a given overall error probability. An optimization algorithm is developed to extend the application of the Lee-Thomas procedure to the M-ary case. Performance characteristics of the generalized two-threshold (GTT) test procedure are compared with those of conventional sequential as well as fixed-sample-size (FSS) methods. It is shown for the M-ary different means/variances cases that for low error rates the number of samples required by the GTT test is, on the average, approximately half that needed by a FSS test. However, it is somewhat more than the ASN obtained with a conventional sequential test. With decreasing error probabilities the GTT test performance approaches that of conventional sequential methods     

Reply to comments on "Derivation of numerical values for the World Health Organization guidelines for recreational waters"

The contribution addressed reveals an optimistic design philosophy likely to systematically underestimate risk in epidemiologic studies into the health effects of bathing water exposures. The authors seem to recommend that data on the 'exposure' measure (i.e. water quality) in such studies should be acquired in a similar manner to that used for regulatory sampling. This approach may compromise the quality of the epidemiologic investigations undertaken. It may result in imprecise estimates of exposure because it ignores the fact that regulatory timescales and spatial resolution (even if artificially compressed to a bathing day) can mask large spatial and temporal variability in water quality. If this variability is ignored by taking some mean value and attributing that to all of those exposed in a period at a study location, many bathers may be misclassified and the studies may be biased to a 'no-effect' conclusion. A more appropriate approach is to maximise the precision of the epidemiologic investigations by measurement of individual exposure (or water quality) at the place and time of the exposure, as has been done in randomised volunteer studies in the UK and Germany. The precise epidemiologic relationships linking 'exposure' with 'illness' can then be related to the probability of exposure to particular water quality by a 'normal bather' using the known probability distribution of the exposure variable (i.e. faecal indicator concentration) in the regulated bathing waters. We suggest that any research protocol where poor sampling design for water quality assessment is justified because regulatory monitoring is equally imprecise may be fundamentally flawed. The rationale for this assessment is that the epidemiology is the starting point and evidence-base for 'standards'. If precision is not maximised at this stage in the process it compromises the credibility of the standards design process. The negative effects of the approach advocated in this 'comment' are illustrated using published research findings used to derive the figures illustrated in Wymer et al. [2005. Comment on derivation of numerical values for the World Health Organization guidelines for recreational waters. Water Research 39, 2774-2777].