Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer

Insulin-like growth factor 1 (IGF-1) is a potent mitogen for human breast-cancer cells in vitro. In circulation, most of IGF-1 is bound to IGF-binding protein 3 (IGFBP-3). This high-affinity binding is thought to have an important limiting effect on the availability of IGF-1 for biological activity. To assess the availability of IGF-1 for receptor binding, we determined serum levels of IGF-1 and IGFBP-3 and IGF-1/IGFBP-3 ratios. In a case-control study, 150 women aged 38 to 75 years presenting with stage-l or-II breast cancer were investigated just prior to surgery (n = 76), or to irradiation one month after surgery (n = 74). The population-based control group consisted of 441 women of the same age having no breast cancer. Women reporting diabetes mellitus or other hormonal abnormalities were excluded. Premenopausal cases showed elevated IGF-1 serum concentrations, decreased IGFBP-3 levels and increased IGF-1/IGFBP-3 ratios. The IGF-1/IGFBP-3 ratio was a significant breast-cancer risk factor, also after adjustment for age, family history, height, body-mass index, body-fat distribution, and serum levels of C-peptide. The relative risk was 7.34 for the highest compared with the lowest quintile of IGF-1/IGFBP-3. The presence or absence of tumor had no influence on these results. Increased levels of available IGF-1 in the circulation of pre-menopausal women may contribute to the development of breast cancer. © 1995 Wiley-Liss Inc.     

Ivermectin for the chemotherapy of bancroftian filariasis: a meta-analysis of the effect of single treatment

Summary The efficacy and safety of ivermectin in the treatment of filariasis due to Wuchereria bancrofti was assessed by a meta-analysis of the results from 15 published clinical trials. Seven hundred and forty-eight microfilaraemic patients were enrolled in 7 dose-finding and 8 comparative studies. Administered as a single dose, ivermectin induced nearly complete clearance of microfilariae from the blood from the first day to 30 days post-treatment, followed by gradual recurrence of microfilaraemia and increase in its intensity. Higher doses of ivermectin showed greater clearance effects and maintained lower microfilaraemia levels for a longer time. The adverse reactions caused by the drug were flu-like, transient, generally mild and well tolerated by patients. The frequency and intensity of adverse reactions were strongly associated with pretreatment microfilaria counts in the blood, but independent of dose. The findings of the meta-analysis suggest that ivermectin given at a single annual dose of 200 μg/kg body weight or higher, whether or not in combination with DEC, has great potential for therapeutic strategies to control bancroftian filariasis.     

Cytogenetic and comparative genomic hybridization findings in four cases of breast cancer after neoadjuvant chemotherapy

To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer.     

Effect of gaze direction on neck muscle activity during cervical rotation

Control of the neck muscles is coordinated with the sensory organs of vision, hearing and balance. For instance, activity of splenius capitis (SC) is modified with gaze shift. This interaction between eye movement and neck muscle activity is likely to influence the control of neck movement. The aim of this study was to investigate the effect of eye position on neck muscle activity during cervical rotation. In eleven subjects we recorded electromyographic activity (EMG) of muscles that rotate the neck to the right [right obliquus capitis inferior (OI), multifides (MF), and SC, and left sternocleidomastoid (SCM)] with intramuscular or surface electrodes. In sitting, subjects rotated the neck in each direction to specific points in range that were held statically with gaze either fixed to a guide (at three different positions) that moved with the head to maintain a constant intra-orbit eye position or to a panel in front of the subject. Although right SC and left SCM EMG increased with rotation to the right, contrary to anatomical texts, OI EMG increased with both directions and MF EMG did not change from the activity recorded at rest. During neck rotation SCM and MF EMG was less when the eyes were maintained with a constant intra-orbit position that was opposite to the direction of rotation compared to trials in which the eyes were maintained in the same direction as the head movement. The inter-relationship between eye position and neck muscle activity may affect the control of neck posture and movement.     

Polymorphic nucleotide within the promoter of nitrate reductase (NarGHJI) is specific for Mycobacterium tuberculosis

Mycobacterium tuberculosis rapidly reduces nitrate, leading to the accumulation of nitrite. This characteristic served for the past 40 years to differentiate M. tuberculosis from other members of the Mycobacterium tuberculosis complex (MTBC), such as Mycobacterium bovis (non-BCG [referred to here as simply "M. bovis"]), Mycobacterium bovis BCG, Mycobacterium africanum, or Mycobacterium microti. Here, a narG deletion in M. tuberculosis showed that rapid nitrite accumulation of M. tuberculosis is mediated by narGHJI. Analysis of narG mutants of M. bovis and M. bovis BCG showed that, as in M. tuberculosis, nitrite accumulation was mediated by narGHJI, and no other nitrate reductase was involved. However, in contrast to M. tuberculosis, accumulation was delayed for several days. Comparison of the narGHJI promoter revealed that, at nucleotide -215 prior to the start codon of narG, M. tuberculosis carried a thymine residue, whereas the bovine mycobacteria carried a cytosine residue. Using LightCycler technology we examined 62 strains of M. tuberculosis, M. bovis, M. bovis BCG, M. microti, and M. africanum and demonstrated that this single nucleotide polymorphism was specific for M. tuberculosis. For further differentiation within the MTBC, we included, by using LightCycler technology, the previously described analysis of oxyR polymorphism, which is specific for the bovine mycobacteria, and the RD1 polymorphism, which is specific for M. bovis BCG. Based on these results, we suggest a LightCycler format for rapid and unambiguous diagnosis of M. tuberculosis, M. bovis, and M. bovis BCG.     

In Vitro and In Vivo Interactions of Haemophilus ducreyi with Host Phagocytes

We investigated the phagocytosis of Haemophilus ducreyi both in vitro and in vivo. Human granulocyte and monocyte phagocytosis of opsonized and nonopsonized, fluorescence-labeled H. ducreyi was assessed by flow cytometry. Both Escherichia coli and noncapsulated H. influenzae were included as controls. The maximal percentage of granulocytes taken up by H. ducreyi was 35% after 90 min. In contrast, 95% of H. influenzae bacteria were phagocytosed by granulocytes after 30 min. These results indicated that H. ducreyi phagocytosis was slow and inefficient. Bacterial opsonization by using specific antibodies increased the percentage of granulocytes phagocytosing H. ducreyi from 24 to 49%. The nonphagocytosed bacteria were completely resistant to phagocytosis even when reexposed to granulocytes, indicating that the H. ducreyi culture comprised a mixture of phenotypes. The intracellular survival of H. ducreyi in granulocytes, in monocytes/macrophages, and in a monocyte cell line (THP-1) was quantified after application of gentamicin treatment to kill extracellular bacteria. H. ducreyi survival within phagocytes was poor; approximately 11 and <0.1% of the added bacteria survived intracellularly after 2 and 20 h of incubation, respectively, while no intracellular H. influenzae bacteria were recovered after 2 h of incubation with phagocytes. The role of phagocytes in the development of skin lesions due to H. ducreyi was also studied in vivo. Mice that were depleted of granulocytes and/or monocytes and SCID mice, which lacked T and B cells, were injected intradermally with approximately 10⁶ CFU of H. ducreyi. Within 4 days of inoculation, the granulocyte-depleted mice developed lesions that persisted throughout the experimental period. This result reinforces the importance of granulocytes in the early innate defense against H. ducreyi infection. In conclusion, H. ducreyi is insufficiently phagocytosed to achieve complete eradication of the bacteria. Indeed, H. ducreyi has the ability to survive intracellularly for short periods within phagocytic cells in vitro. Since granulocytes play a major role in the innate defense against H. ducreyi infection in vivo, bacterial resistance to phagocytosis probably plays a crucial role in the pathogenesis of chancroid.     

Left heart function in chronic obstructive lung disease

Summary In patients with varying degrees of chronic obstructive pulmonary disease (COPD), simultaneous measurements of central hemodynamics and left ventricular radionuclide ventriculograms at rest and during exercise were made. In 21 of these patients, satisfactory echocardiograms could be performed. In seven of the patients, arterial blood pressure at rest was increased. Decreased compliance of the left ventricle was thought to be present in patients with COPD and additional arterial hypertension. The left ventricular ejection fraction (LVEF) at rest was in the high normal range in all patients. During exercise, no further increase was observed. This pattern of LVEF response seems to be typical in patients with COPD. Because the highest values were observed in the more severe COPD and right ventricular hypertrophy, it is unlikely that an impairment of left ventricular function is caused by COPD. In five of 27 patients, an abnormal decrease of LVEF and regional hypokinesis occurred during exercise, thus suggesting additional coronary heart disease. The fact that at least 30% of the patients with COPD suffered from arterial hypertension and 20% of the patients exhibited unexpected ischemia detected by regional hypokinesis in RNV during exercise, but not in the ECG, may be of practical relevance. Coronary angiography was not indicated because most of these patients were over 65 and the factor limiting the working capacity was ventilatory impairment and not angina pectoris, in all patients. For this reason, a diagnostic uncertainty remains with regard to additional coronary heart disease in the older patients with advanced chronic obstructive pulmonary disease.Lung Function Parameters VC (1) inspiratory vital capacity - FEV1 (1) forced exspiratory volume in 1 sec - Raw (cmH20/l/s) airways resistance - RV/TLC (%) residual volume/total lung capacity - paO₂ (mm Hg) O₂ partial pressure Hemodynamic Parameters CI (1/min/sqm) cardiac index - SVI (ml/sqm) stroke volume index - PAP (mm Hg) pulmonary artery mean pressure - PwP (mm Hg) pulmonary capillary wedge pressure - RRs (mm Hg) systolic arterial pressure - RRd (mm Hg) diastolic arterial pressure (at the time of catheterization) - RR(WHO) (mm Hg) mean values measured at different days (at least 3 values). Parameters Derived from Combined Radionuclide Ventriculography and Central Hemodynamics LVEF (%) left ventricular ejection fraction - LVESVI (ml/sqm) left ventricular endsystolic volume index - P/V (mm Hg/ml/sqm) peak systolic pressure/endsystolic volume index - PFR (1/sec) peak filling rate: endsystolic volume/sec Echocardiographic Parameters RV d wth (mm) right ventricular enddiastolic wall thickness - LV d wth (mm) left ventricular enddiastolic wall thickness In honor to Prof. W.E. Adam's 60th birthday     

Elevated levels of IgG and IgG4 to Malassezia allergens in atopic eczema patients with IgE reactivity to Malassezia

BACKGROUND: The opportunistic yeast Malassezia is considered to be one of the factors that can contribute to atopic eczema (AE). Elevated serum IgE levels, T-cell proliferation and positive skin prick test (SPT) and atopy patch test (APT) reactions to Malassezia are found among AE patients. METHODS: Sera from 127 AE patients, 14 patients with seborrheic dermatitis (SD) and 33 healthy controls were investigated for IgE and IgG4 to M. sympodialis extract and four recombinant Malassezia allergens; rMala s 1, rMala s 5, rMala s 6, and rMala s 9. In addition, IgG to the recombinant allergens was analyzed. The IgG and IgG4 levels were compared to IgE levels and in vivo reactions (SPT and APT) to Malassezia. RESULTS: AE patients with serum IgE levels >0.35 kU/l to M. sympodialis extract had significantly higher IgG4 levels to M. sympodialis extract than AE patients without detectable serum IgE to M. sympodialis extract, SD patients and healthy controls. Among the AE patients with and without detectable serum IgE to M. sympodialis extract, respectively, there were no differences in IgG4 levels between patients with positive or negative in vivo reactions to M. sympodialis extract. IgG4 to the rMala s allergens was almost exclusively found among patients with IgE to the same allergen. Within the four tested rMala s allergens, most IgG4 reactions were found to rMala s 6, an allergen with homology to cyclophilin. CONCLUSIONS: Elevated serum IgG4 to M. sympodialis extract accompanies elevated serum IgE to the extract. This is further confirmed by the association between IgG/IgG4 and IgE to recombinant Malassezia allergens.     

Mucosal FOXP3-expressing CD4+ CD25high regulatory T cells in Helicobacter pylori-infected patients

Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4(+) CD25(high) T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express FOXP3, a key gene for the development and function of regulatory T cells, as well as high levels of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) protein. In contrast, mucosal CD4(+) CD25(low) and CD4(+) CD25(-) cells express little FOXP3 mRNA and low levels of the CTLA-4 protein. Mucosal CD4(+) CD25(high) T cells are present in individuals with asymptomatic H. pylori infections as well as in duodenal ulcer patients. The frequencies of CD4(+) CD25(high) cells are also increased in the stomachs of H. pylori-infected patients with gastric adenocarcinoma, particularly in cancer-affected tissues. These findings suggest that regulatory T cells may suppress mucosal immune responses and thereby contribute to the persistence of H. pylori infections.     

Changes in the surface electromyogram during increasing isometric shoulder forward flexions

Summary When using electromyographic techniques in the evaluation of muscular load it is necessary to determine the mathematical relationship between the torque and the amplitude of the electromyographic signal. Isometric gradually increasing contractions up to 100% MVC can then be used. Often more than linear increases for the amplitude (RMS) — force regression have been reported. The present study was designed to test whether changes in power spectral density function take place during a gradually increasing isometric contraction (duration 10 s). Twenty-two clinically healthy females performed an increasing isometric shoulder forward flexion for 10 s using an isokinetic dynamometer. Electromyographic activity was measured in trapezius, deltoid, infraspinatus and biceps brachii using surface electrodes. Mean torque values were determined together with mean power frequency (MPF) and root mean square values (RMS) from the EMG signals for each 256 ms period. The RMS-torque regressions showed higher regression coefficients during the 6th to 9th sec than during the first 5 s. No significant correlation existed between MPF for the four muscles and the torque. A gradual decrease in MPF was generally found from the 6th s. It is concluded that this decrease in power spectral density function might have contributed to the significantly higher regression coefficient for the RMS torque regression at the high output part of the gradually increasing isometric contraction.