Interferon γ is a STAT1-dependent direct inducer of BCL6 expression in imatinib-treated chronic myeloid leukemia cells.

B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells. We proved that during combined treatment, inhibition of constitutive signal transducer and activator of transcription (STAT) 5 activation by IM allowed the specific enhancement of the STAT1 dependent, direct upregulation of BCL6 by IFNγ in CML cells. By using colony-forming assay, we found that IFNγ enhanced the ex vivo colony or cluster-forming capacity of human CML stem cells in the absence or presence of IM, respectively. Furthermore, inhibition of the transcriptional repressor function of BCL6 in the presence of IM and IFNγ almost completely blocked the cluster formation of human CML stem cells. On the other hand, by using small interfering RNA knockdown of BCL6, we demonstrated that in an IM-treated CML line the antiapoptotic effect of IFNγ was independent of BCL6 upregulation. We found that IFNγ also upregulated several antiapoptotic members of the BCL2 and BIRC gene families in CML cells, including the long isoform of MCL1, which proved to be essential for the antiapoptotic effect of IFNγ in an IM-treated CML line. Our results suggest that combination of TKIs with BCL6 and MCL1 inhibitors may potentially lead to the complete eradication of CML stem cells.

Ten-year myringoplasty series: does the cause of perforation affect the success rate?

OBJECTIVE: To present the results of primary myringoplasty procedures together with the perforation cause, perforation size and site, surgeon's experience, and surgical method, and to investigate how these factors relate to graft 'take' rates. STUDY DESIGN: Retrospective chart review of 243 consecutive patients undergoing primary myringoplasty with temporalis fascia underlay over a 10-year period from 1994 to 2004. RESULTS: The overall graft take rate was 95 per cent. The retroauricular approach resulted in a 97 per cent graft take rate, whereas a significantly lower rate (77 per cent) was seen for surgery conducted via the endaural approach, or via an ear speculum. There was no relationship between other factors and tympanic membrane healing. CONCLUSION: No association was found between perforation cause and graft take rate. The underlay technique is safe and reliable, and the retroauricular approach is preferable as it enables good surgical access and has better results.

Heavy-ion-induced electronic desorption of gas from metals.

During heavy-ion operation in several particle accelerators worldwide, dynamic pressure rises of orders of magnitude were triggered by lost beam ions that bombarded the vacuum chamber walls. This ion-induced molecular desorption, observed at CERN, GSI, and BNL, can seriously limit the ion beam lifetime and intensity of the accelerator. From dedicated test stand experiments we have discovered that heavy-ion-induced gas desorption scales with the electronic energy loss (dE_{e}/dx) of the ions slowing down in matter; but it varies only little with the ion impact angle, unlike electronic sputtering.

Chronology of particle emission from the E/A=61 MeV 36Ar+27Al reaction.

The emission time chronology of neutrons, protons, and deuterons from the E/A=61 MeV 36Ar+27Al reaction is deduced from two-particle correlation functions.

Regulation of adhesion and motility in B lymphocytes.

During the differentiation process of B lymphocytes, they go through changes in adhesion and motility. In order to investigate the molecular mechanism of such changes, in vitro culture systems are necessary. When B cells are activated by various stimuli, they form different types of homotypic aggregates. In addition, they might also spread and express microvilli and/or become polarized, the latter being a sign of motility. In this review, we summarize our own research in this area. We give evidence for involvement of different adhesion and signalling molecules, and by the end, we speculate on the in vivo significance of our findings.

Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes.

Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells are impaired in cytoskeletal-dependent processes. WAS is caused by a defective or a missing WAS protein (WASP). Signal mediators interleukin-4 (IL-4) and CD40 are important for actin-dependent morphology changes in B cells. A possible function of WASP and its interacting partners, Cdc42 and Rac1, was investigated for these changes. It was found that active Cdc42 and Rac1 induced filopodia and lamellipodia, respectively, in activated B cells. Evidence is given that IL-4 has a specific role in the regulated cycling of Cdc42 because IL-4 partially and transiently depleted active Cdc42 from detergent extract of activated B cells. WASP-deficient B lymphocytes were impaired in IL-4-- and CD40-dependent induction of polarized and spread cells. Microvilli were expressed on WASP-deficient B cells, but they appeared shorter and less dense in cell contacts than in wild-type cells. In conclusion, evidence is provided for the involvement of Cdc42, Rac1, and WASP in the cytoskeletal regulation of B lymphocytes. Aberrations in WASP-deficient B lymphocytes, described here, provide further evidence that WAS is a cytoskeletal disease of hematopoietic cells. (Blood. 2001;98:1086-1094)

Expression of alpha-synuclein in the human brain: relation to Lewy body disease.

Alpha-synuclein is mutated in some hereditary cases of Parkinson's disease and the protein precipitates in Lewy bodies, the pathological hallmark of both Parkinson's disease and Lewy body disease. Transgenic mice overexpressing human wild-type alpha-synuclein develop alpha-synuclein-immunoreactive inclusions in brain regions typically affected with Lewy body disease. We used in situ hybridization to characterize alpha-synuclein expression and examine mRNA levels in patients affected with Lewy body disease and controls. Substantia nigra was avoided because of the extensive neuronal loss and cingulate gyrus was chosen as it is one of the diagnostic regions in Lewy body disease where Lewy bodies most frequently are demonstrated. beta-tubulin was used to control for neuronal degeneration. The alpha-synuclein probe showed intense labeling of pyramidal cells in lamina III and V in both patients and controls. We found no difference in alpha-synuclein mRNA levels and beta-tubulin mRNA was not significantly altered (P=0.06) in patient brains. There was no difference in the ratio of alpha-synuclein and beta-tubulin mRNA levels between patients and controls. Further, we found no relationship between alpha-synuclein mRNA levels and Lewy bodies. Great variability in alpha-synuclein mRNA levels among patients indicates that Lewy body disease may be a heterogeneous disorder with regard to alpha-synuclein involvement.

Working conditions and family situation in relation to functional gastrointestinal disorders. The Swedish Dyspepsia Project.

OBJECTIVE: To examine whether improvement and/or deterioration of functional gastrointestinal symptoms relate to psychosocial factors, and whether patients with such symptoms have special characteristics with regard to working environment in comparison to a referent population. DESIGN: Multicentre, prospective study of consecutive patients seeking medical advice at health centres for gastrointestinal symptoms. SETTING: Several municipalities in Sweden: Vänersborg, Trollhättan, Tibro, Alfta, Borensberg, Malmö, Kungälv, Hudiksvall, Vadstena, and Sandviken. PARTICIPANTS: 615 patients, aged 18-81 years, who after medical examination, upper endoscopy and laboratory test were defined as having functional gastrointestinal disorders. MAIN OUTCOME MEASURES: Initial characteristics and response to treatment according to a 5-graded symptom score as obtained from a psychosocial questionnaire collected during and at the end of a four-week treatment period. RESULTS: Patients with functional gastrointestinal disorders differed from a referent population of actively employed women and men in the county of Stockholm. They felt less possibility to influence their working conditions. Shift workers were also overrepresented. Psychosocial background factors had an effect on improvement of symptoms during four weeks of treatment. There were some differences between men and women. For women, working hours and home circumstances were important. After four weeks women who worked part-time felt better than those who worked full-time. Married women made a better recovery than single women. For men, working conditions had a greater effect on recovery. Those who felt that they received support from their colleagues at work improved to a greater extent than the other men.

The circulation in the nipple-areola complex following subcutaneous mastectomy in breast cancer.

To evaluate the decrease in circulation in the nipple-areola complex after subcutaneous mastectomy and immediate implantation of a submuscular prosthesis, the blood flow was studied by both fluorescein flowmetry and laser Doppler flowmetry in 24 patients with invasive breast cancer. In 14 patients a lazy-S-shaped horizontal lateral incision was used, and 10 underwent a subcutaneous reduction mammaplasty. After subcutaneous mastectomy with a lazy-S incision there was no significant decrease in blood flow in the nipple-areola complex compared with that in the untreated contralateral breast. In the breasts in which reduction mammaplasty had been done, the blood flow was reduced by 74% as measured by fluorescein (p less than 0.01), and 70% by laser Doppler flowmetry (p less than 0.05), compared with the contralateral breast. Five patients had partial or complete epidermal, and one patient had total dermal, necrosis of the complex, but there was no deep necrosis. No fluorescence was seen within the areas in which necrosis later developed in any of these six cases. The laser Doppler signal in the corresponding areas, however, was not reduced. The results show that the circulation in the nipple-areola complex is reduced more after subcutaneous reduction mammaplasty than after subcutaneous mastectomy with a lazy-S incision.

Prostaglandin-induced parturition in swine -- a field study on its accuracy after treatment with different amounts of PGF.

This trial was performed within one large piglet producing herd in Sweden during June-August 1976. One hundred and sixty sows were randomly assigned to one of the following treatments: (1) 15 mg PGF2alpha i.m., (2) 20 mg PGF2alpha i.m., (3) two injections of 10 mg PGF2alpha i.m. at c. 8 h interval, (4) untreated countrol sows. PGF2alpha was administered in the morning of days 111, 112 or 113 of pregnancy. Of the PGF2alpha-treated sows, 83--85% farrowed within 48 h after treatment. No effect of day of treatment was found. Nor was any difference between groups observed. Neither of the treatments had a significantly negative influence of the viability of the piglets born. A numerically lower incidence of agalactia post partum was demonstrated in sows treated once with 15 mg or 20 mg PGF2alpha. A possible effect of PGF2alpha for prevention of agalactia post partum is discussed.