Adoptive immunotherapy for posttransplantation viral infections.

Viral diseases are a major cause of morbidity and mortality after hemopoietic stem cell transplantation. Because viral complications in these patients are clearly associated with the lack of recovery of virus-specific cellular immune responses, reconstitution of the host with in vitro expanded cytotoxic T lymphocytes is a potential approach to prevent and treat these diseases. Initial clinical studies of cytomegalovirus and Epstein-Barr virus in human stem cell transplant patients have shown that adoptively transferred donor-derived virus-specific T cells may restore protective immunity and control established infections. Preclinical studies are evaluating this approach for other viruses while strategies for generating T cells specific for multiple viruses to provide broader protection are being evaluated in clinical trials. The use of genetically modified T cells or the use of newer suicide genes may result in improved safety and efficacy.     

Autoimmune hepatitis associated with the use of black cohosh: a case study

Herbal remedies generate more than 1.8 billion dollars in annual sales in the United States. Herbal products have been associated with a wide spectrum of hepatic toxicities. With the recent Women's Health Initiative Study demonstrating increased risk of breast cancer and cardiovascular events associated with hormone therapy, many women may resort to herbal remedies for persistent menopause symptoms. We report a case of autoimmune hepatitis likely triggered by the use of black cohosh (Actaea racemosa), an agent marketed to treat menopause symptoms. Given this case report, we recommend close monitoring of women using this herbal preparation.     

Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses

Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans.     

Treatments of pelvic girdle pain in pregnant women: adverse effects of standard treatment,acupuncture and stabilising exercises on the pregnancy,mother, delivery and the fetus/neonate

Background  

Previous publications indicate that acupuncture is efficient for the treatment of pelvic girdle pain, PGP, in pregnant women. However, the use of acupuncture for PGP is rare due to insufficient documentation of adverse effects of this treatment in this specific condition. The aim of the present work was to assess adverse effects of acupuncture on the pregnancy, mother, delivery and the fetus/neonate in comparison with women that received stabilising exercises as adjunct to standard treatment or standard treatment alone.     

Belief in the harmfulness of antidepressants: results from a national survey of the Australian public

BACKGROUND: Surveys of the public in several countries have found that negative attitudes towards antidepressants are common. However, there has been little research into the factors associated with these attitudes. METHODS: A national survey of 999 Australian adults assessed beliefs about the helpfulness or harmfulness of antidepressants for a person with depression and suicidal thoughts. Associated factors investigated were as follows: sociodemographic characteristics, exposure to depression, ability to recognize depression, beliefs about other depression interventions, beliefs about long-term outcomes with and without treatment, beliefs about causes, and stigmatizing attitudes. RESULTS: Around a quarter of Australian adults believe that antidepressants would be harmful for a person who is depressed and suicidal. This group was less educated, had less exposure to depression, showed poorer recognition of depression, was less favorable about other standard interventions including psychological ones, was less pessimistic about the long-term outcome if the person did not have treatment, and was more likely to see depression as due to weakness and to be under the individual's control. LIMITATIONS: The survey did not directly ask about reasons for believing that antidepressants would be harmful. CONCLUSIONS: Belief in the harmfulness of antidepressants is associated with a general lack of exposure to depression, leading to an underestimation of its seriousness and of the necessity for intervention.     

Genetic linkage analysis identifies new proximal and distal flanking markers for the X-linked agammaglobulinemia gene locus, refining its localization in Xq22

Genetic linkage analysis has been instrumental in mapping thegene for X-linked agammaglobulinemia (XLA) to the proximal longarm of the human X chromosome, to Xq22. Due to the relativerarity of this disease the localization of the gene within Xq22has remained imprecise. We have investigated twenty-nine familiesaffected by XLA and have found no recombinants with the DXS178locus in over 30 informative meioses. DXS178 is now the mostreliable and informative locus for use in pre-natal diagnosisand carrier detection of XLA. In addition, we have identifiednew closely linked proximal and distal flanking markers forXLA, DXS442 and DXS101, respectively. These loci are separatedby 2cM, considerably reducing the extent of DNA within whichthe XLA locus can be contained. This will open up the way formore directed positional cloning efforts for the isolation ofthe XLA gene.     

Development of glomerular filtration rate and electrolyte and osmolal clearance in the late-embryonic and newly hatched chicken

Summary Techniques have been developed for collection of urine in embryonic and newly hatched chickens for the purpose of studying the development of renal function.The reliability of EDTA-⁵¹Cr as a substitute for inulin-¹⁴C in the determination of GFR was studied. Since inulin and EDTA-⁵¹Cr clearances in the hatched chicken averaged 1.61±0.23 (S.E.) ml/min per kg body weight and 1.58±0.27 ml/min per kg body weight, respectively, EDTA-⁵¹Cr clearance was considered a suitable measure of GFR.GFR increased significantly in the first few days after hatching. Filtration rate was 0.068±0.008 (S.E.) ml/min per g kidney weight in the embryo and increased to 0.148±0.008 ml/min per g shortly after hatching. By nine days after hatching GFR had risen to 0.290±0.015 ml/min per g, a value comparable to that reported for the adult.Clearances of sodium, potassium, chloride and total osmolyte also increased with age. When these clearances were corrected for changing glomerular filtration rates the embryonic chicks were found to excrete a greater percentage of the filtered load. These results show that adult levels of glomerulo-tubular balance are not attained until after hatching.A preliminary report of this work has already been published [3].     

Baseline levels of chromosome instability in the human lymphoblastoid cell TK6

Induced genomic instability in the human B lymphoblastoid cell line TK6 manifests itself as increases in end-to-end chromosome fusions and non-reciprocal chromosome translocations. It is not associated with elevated frequencies of specific locus mutations or other cytogenetic alterations. Previous studies on a limited number of cells and end-points suggested that induced instability in TK6 mirrors spontaneous instability in terms of the types of alterations observed. In the present study we expanded on our previous analysis to include more cells and more end-points in order to derive a more precise measure of spontaneous instability in TK6 cells. The frequency of normal growth rate thymidine kinase mutants (TK(-/-)), measured in 44 independently isolated clones, was 2.73 +/- 0.78 x 10(-6)/cell, while that for slow growth mutants was 2.39 +/- 0.52 x 10(-6)/cell. These are similar to the frequencies observed for HPRT mutants in primary human cells. There was wide variation in chromatid break frequencies, but the average break frequency, at 0.04+/-0.01 breaks/cell, was only slightly higher than that reported for primary human cells. In contrast, the dicentric frequency of 0.006/cell was more than 10-fold higher for TK6 cells than that reported for normal primary human cells. Furthermore, the dicentrics in TK6 cells are unusual in that they are the result of end-to-end chromosome fusions. TK6 cells also show much higher levels of non-reciprocal chromosome translocations than are usually observed in primary human cells. The results suggest an inherent instability in TK6 cells that differs from what is observed in primary cells in that it affects the frequency of end-to-end chromosome fusions and non-reciprocal chromosome translocations, but not TK gene mutations or other cytogenetic alterations.     

The aniridia-Wilms tumor association: The critical role of chromosome band 11p13

The role of del (11)(p13) as a cause of aniridia, with and without Wilms tumor, is strengthened by demonstration of this chromosome aberration in 3 patients: monozygous twin girls, both of whom have aniridia and mental retardation and one of whom has a Wilms tumor; and an unrelated boy with aniridia and ambiguous genitalia. The break points defining the interstitial deletion for the twins are 11p13 and 11p15.1, while for the boy they are 11p1302 and 11p14.1. These patients and their karyotypes substantiate the critical importance of chromosome band 11p13 (or its hemizygous representation) in the development of aniridia and an associated Wilms tumor diathesis, as had been suggested previously (Riccardi VM, Sujansky E, Smith AC, Francke U, (1978): Pediatrics 61, 604-610).