Functionally intact in vitro preparation generating respiratory activity in neonatal and mature mammals

The present report describes a novel rhythmically active brainstem slice preparation that generates respiratory activity spontaneously in both mice and rats of varying maturational states. The brainstems of neonatal (0–4 days) and mature (3–8 weeks) mice and rats were isolated and a 600- to 750-m thick slice cut to include the dorsomedial and the ventrolateral regions of the complete rostro-caudal extent of the medulla. This plane of section we have termed tilted-sagittal. Rhythmically discharging neurones were recorded extracellularly from both the dorsal and ventral regions of the slice. The recording sites of these neurones were found in the hypoglossal motonucleus (XII) and in areas of the ventrolateral medulla that includes the ventral respiratory group (VRG) region. Histological examination revealed the preservation of neuronal structures important for cardiorespiratory regulation and reflex control including the nucleus of the solitary tract as well as the nucleus ambiguus. In addition, pontine structures including the A5 region were also preserved. Rhythmic activity was found only in slices where the ambiguual column was preserved in its entirety. The mean frequency of discharge of XII neurones was 20 and 10 bursts per minute in neonates and mature rodents respectively. In preparations of mature animals we demonstrate that this frequency increased significantly (P<0.05) by either raising temperature from 29°C to 38°C (54%), elevating extracellular potassium concentration from 4 to 7.5 mM (52%), blocking potassium channels (20%) or decreasing pH from 7.4 to 7.0 (18%). The burst duration to frequency ratio of XII and VRG rhythmic neurones was similar and therefore indicative of a common brainstem oscillator. Consistent with this finding was that rhythmic activity in the VRG persisted despite removal of the dorsomedial region of the slice. In contrast, rhythmic XII neurones became tonic following mechanical disconnection of the VRG.     

A comparison of sampling and analytical methods for assessing occupational exposure to diesel exhaust in a railroad work environment

Methods of assessing occupational exposure to diesel exhaust were evaluated in a railroad work environment. The American Conference of Governmental Industrial Hygienists (ACGIH)-recommended elemental carbon and respirable combustible dust methods of sampling and analysis for assessing diesel exhaust were included in the study. A total of 215 personal and area samples were collected using both size-selective (nylon cyclone and Marple) and non-size-selective samplers. The results demonstrate that the elemental carbon method is suitable for the railroad environment and the respirable combustible dust method is not. All elemental carbon concentrations measured were below the proposed ACGIH Threshold Limit Value (TLV) of 0.15 mg/m3. The concentrations of oxides of nitrogen (nitric oxide and nitrogen dioxide) were also found to be below their respective TLVs. There is no correlation between elemental carbon or respirable combustible dust and the oxides of nitrogen. The elemental carbon as fraction of total carbon is about 13 percent, except for onboard locomotives where it is about 24 percent. Comparison of elemental carbon and respirable combustible dust measurements showed consistent relationships for most sampling locations, with respirable combustible dust concentrations 12 to 53 times higher than the elemental carbon levels.     

Technetium-99m sestamibi imaging in paediatric neuroblastoma and ganglioneuroma and its relation to P-glycoprotein

Imaging with technetium-99m sestamibi offers a non-invasive approach to detect the presence of functional P-glycoprotein (Pgp), one of the major causes of multidrug resistance, in human malignancies. A clinical role for Pgp has been suggested in the subpopulation of primary neuroblastoma without amplification of the proto-oncogene MYCN. We wanted to evaluate the usefulness of 99mTc-sestamibi scintigraphy in the screening of neural crest tumours for the presence of Pgp. In ten children suffering from MYCN-negative neuroblastoma, ganglioneuroblastoma or ganglioneuroma, 99mTc-sestamibi imaging was performed at initial diagnosis. All patients underwent planar imaging 20-30 min and 3.5-4 h after intravenous injection of 740 MBq/1.73 m2 99mTc-sestamibi. Tumour to normal tissue ratios, as well as washout rates, were determined and compared with in vitro flow cytometric analysis of Pgp expression and function. Pgp expression was analysed flow cytometrically with the monoclonal antibodies 4E3 and MRK16, and Pgp function was evaluated by means of rhodamine 123 uptake and efflux either in the absence or in the presence of the Pgp inhibitor verapamil. In nine of ten patients, we found that the intratumoral 99mTc-sestamibi activity was comparable to the background activity, which might be suggestive of Pgp presence. This was confirmed flow cytometrically in all but one patient. 99mTc-sestamibi enhancement was seen in the primary tumour and the bone marrow metastases of one of the ten patients, and this result was concordant with a negative Pgp status. The findings presented suggest that 99mTc-sestamibi imaging results might correlate with the presence of functional Pgp in neural crest tumours without MYCN amplification.     

Breast Carcinoma in Childhood and Adolescence: Case Report and Review of the Literature

Secretory breast carcinoma is a rare tumor originally described in children and adolescent women with a characteristic morphology and a controversial choice of treatment. We report an additional case of a 4-year-old girl with a breast tumor diagnosed as a secretory carcinoma without involvement of the axillary lymph nodes. The therapy consisted of simple mastectomy and low axillary dissection. She presented with a local recurrence near the surgical scar 8 months later, and a wide elliptical excision of the scar and underlying tissue was performed with subsequent radiotherapy of the surgical bed. This tumor has a relatively benign behavior and rarely metastasizes. A literature review revealed only 22 cases of breast carcinoma in childhood and adolescence. ▪     

Quality of life following transplantation. The impact ofa new immunosuppressive substance

The improvement of quality of life is one of the major goals in the treatment of patients after renal transplantation. While immunosuppressive therapy is present in almost all of these patients, little is known about the effects of newer immunosuppressive agents. We therefore investigated the impact of tacrolimus on life quality. From November 1997 to January 1998, a questionnaire was handed out which focussed on physical and mental problems as well as sexual capacity and the attitudes towards graft, donor and transplant related side effects. 50 kidney graft recipients treated with tacrolimus were matched to 50 patients with a cyclosporine-based immunosuppression (= controls). Values are given as mean +/- standard deviation. Tacrolimus treated patients had a mean creatinine of 1.8 +/- 0.8 mg/dl, as compared to 1.6 +/- 0.7 mg/dl in controls. The overall status of health was assessed to be good in 82% of the tacrolimus group (controls: 80%). 38% were working full-time (controls: 20%). Only 14% of patients described their physical condition as poor (16% in controls). Sexual function was good in 66% (controls: 74%) and poor in 10% (controls: 12%). Mental function was assessed to be good in 92% (controls: 82%). The majority of patients felt comfortable with their physical, sexual and mental capabilities. This was independent from the immunosuppressive regimen.     

Sex hormones and gender-related differences: their influence on chronic renal allograft rejection

BACKGROUND: Renal hemodynamics and immune responses differ between males and females. Thus, sex hormones and genetically determined gender differences may determine the process of chronic rejection to some extent. METHODS: Female (F) or male (M) F344 kidneys were orthotopically transplanted into ovariectomized female Lewis recipients and were treated for 16 weeks with either estradiol, testosterone, or vehicle. RESULTS: Testosterone treatment resulted in increased urinary protein excretion independently of the donor gender, as well as extended glomerular sclerosis, interstitial fibrosis, and severe vascular lesions. Additionally, mononuclear cell infiltration was most pronounced in these animals, in parallel to an increased expression of intercellular adhesion molecule-1 (ICAM-1), fibronectin, laminin, and transforming growth factor-beta (TGF-beta) in the grafts. Estradiol treatment resulted in an improved graft function, reduced glomerular sclerosis, and a diminished cellular infiltration, in parallel to a reduced ICAM-1, fibronectin, laminin, and TGF-beta expression. In animals treated with vehicle, the gender of the donor influenced the outcome. Grafts of male origin had good graft function and histology, whereas grafts from female donors developed severe proteinuria and glomerular, interstitial, and vascular damage. CONCLUSIONS: These results suggest that a protective effect of estradiol on the progression of chronic rejection exists that is independent of donor gender. Additionally, a male kidney may benefit from the absence of testosterone, whereas the function of a female kidney deteriorates in the absence of estradiol.     

Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group

BACKGROUND: The novel agent sirolimus (SRL; Rapamune; rapamycin) inhibits the immune response by a mechanism distinct from those of calcineurin antagonists or antimetabolites. This randomized, controlled, multicenter, single blind, phase II trial examined the combination of SRL, steroids, and full versus reduced doses of cyclosporine (CsA) for prophylaxis of acute renal allograft rejection. METHODS: A total of 149 recipients of mismatched cadaveric- or living-donor primary renal allografts were randomized into six groups. Three groups received placebo or 1 or 3 mg/m2/day SRL, as well as steroids and full-dose CsA (Sandimmune). Three groups received steroids, reduced-dose CsA (target trough level 50% of full-dose range), and 1, 3, or 5 mg/m2/day SRL. RESULTS: The incidence of biopsy-proven acute rejection episodes within the first 6 months after transplant was reduced from 32.0% in the control group to 8.5% in patients receiving SRL (1 or 3 mg/m2/day) and full-dose Sandimmune CsA (P=0.018). Similar low rates of acute rejection episodes were observed among non-African-Americans, but not African-Americans, treated with SRL and reduced-dose Sandimmune CsA. Despite the augmented immunosuppression, 1-year patient and graft survival rates did not differ significantly across groups. Adverse effects attributable to CsA, including hypertension and new-onset diabetes mellitus, were not exacerbated by SRL. Except for an increased incidence of pneumonia among patients receiving full-dose CsA and 3 mg/m2/day SRL, the incidences of opportunistic infections were similar in all treatment groups. Although SRL produced more frequent, but reversible, hematological and lipid abnormalities, it had no apparent nephrotoxic effects to exacerbate CsA-induced renal dysfunction. CONCLUSIONS: SRL in combination with CsA and steroids not only lowers the incidence of biopsy-proven acute renal allograft rejection episodes, but also may permit CsA sparing, at least among Caucasian patients, without an increased risk of rejection.     

维生素D_3对报告载体荧光素酶表达的作用

目的：　研究１,２５－二羟维生素Ｄ３ 对结肠癌细胞系Ｃａｃｏ－２ 细胞中报告基因表达的作用,并探讨在报告载体ｐＧＬ２ 序列中存在潜在的抑制性维生素Ｄ应答元件（ＶＤＲＥ）的可能性。方法：　采用磷酸钙沉淀法将报告载体转染入Ｃａｃｏ－２ 细胞。Ｃａｃｏ－２细胞经不同浓度１,２５－二羟维生素Ｄ３ 处理后测定细胞裂解液中表达的荧光素酶活性。结果：　应用ｐＧＬ２ 报告载体时,当用ｐＳＧ５－ＶＤＲ表达载体共转染后,１,２５－二羟维生素Ｄ３显著地抑制Ｃａｃｏ－２ 细胞荧光素酶的表达（Ｐ＜ ０．０５）;而未使用该表达载体共转染则无抑制作用（Ｐ＞ ０．０５）。应用ｐＧＬ３ 报告载体时,不同浓度的１,２５－二羟维生素Ｄ３ 对ｐＬＧ３转染后Ｃａｃｏ－２ 细胞表达的荧光素酶活性均无显著抑制作用（Ｐ＞ ０．０５）,该作用不依赖是否存在有ｐＳＧ５－ＶＤＲ表达载体共转染。结论：１,２５－二羟维生素Ｄ３ 对报告载体ＰＧＬ２ 荧光素酶表达具有抑制作用,而对ｐＧＬ３ 则否;类似人类ＰＴＨ基因中的潜在抑制性ＶＤＲＥ存在于报告载体ｐＧＬ２,在ｐＧＬ３ 中该ＶＤＲＥ业已改变。     

Malignant Melanoma Incidence and Association with Arsenic

The aetiology of malignant melanoma is not wholly explained by exposure to sunshine. The present of arsenic in the soil has been suggested as a possible causative factor. Geographical clustering of malignant melanoma cases in the South Western Region is demonstrated for males and this clustering is associated with the distribution of arsenic in the soil. No evidence of geographical clustering is however found for females. This suggests possible sex-specific differences in the aetiology of malignant melanoma and indicates the need for further study of the association with arsenic.

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