Human breast cancer in vivo: H-1 and P-31 MR spectroscopy at 1.5 T

To assess the potential of in vivo magnetic resonance (MR) spectroscopy for breast cancer, hydrogen-1 and phosphorus-31 MR spectra of five malignant human breast tumors were compared with those of unaffected breast tissue. The water-to-fat ratio was high in the tumors (average, 2.2) but low in the unaffected tissue (average, 0.3). The P-31 spectrum of normal breast tissue showed low levels of phosphomonoesters (PMEs), inorganic phosphate, phosphodiesters (PDEs), and ATP. In addition, an intense phosphocreatine (PCr) signal was observed in breast tissue of young women: The relative intensities of the PCr and ATP signals had a mean value of 1.9. The tumor spectrum showed elevated levels of PMEs, Pi, and PDEs, while no PCr was seen (PCr/ATP less than 0.2). In two breast cancers treated with radiation therapy, resulting in a decrease of tumor volume of more than 50%, a similar change in the tumor P-31 spectrum was observed: An intense PCr signal developed (PCr/ATP = 1.1). Control experiments indicated that the appearance of PCr after radiation therapy was the result of a radiation-induced metabolic change in the tumor itself.     

Platelet adhesion to collagen types I through VIII under conditions of stasis and flow is mediated by GPIa/IIa (alpha 2 beta 1-integrin)

Platelet adhesion to fibrillar collagens (types I, II, III, and V) and nonfibrillar collagens (types IV, VI, VII, and VIII) was investigated in the presence of physiologic concentrations of divalent cations under conditions of stasis and flow. Under static conditions, platelet adhesion was observed to collagen types I through VII but not to type VIII. Under flow conditions, platelet adhesion to collagen types I, II, III, and IV was almost independent of shear rates above 300/s. Collagen type V was nonadhesive. Platelet adhesion to collagen type VI was shear rate-dependent and optimal at a rate of 300/s. Collagen types VII and VIII showed minor reactivity and supported platelet adhesion only between shear rates 100 to 1,000/s. Monoclonal antibody (MoAb) 176D7, directed against platelet membrane glycoprotein Ia (GPIa; very late antigen [VLA]-alpha 2 subunit), completely inhibited platelet adhesion to all collagens tested, under conditions of both stasis and flow. Platelet adhesion to collagen type III at shear rate 1,600/s was only inhibited for 85%. The concentration of antibody required for complete inhibition of platelet adhesion was dependent on the shear rate and the reactivity of the collagen. An MoAb directed against GPIIa (VLA-beta subunit) partially inhibited platelet adhesion to collagen. These results show that GPIa-IIa is a major and universal platelet receptor for eight unique types of collagen.     

金翼黄芪甙A的化学结构和绵毛黄芪甙ⅩⅤ及7,2′-二羟基-3′,4′二甲氧基异黄烷-7-O-β-D-葡萄糖甙二维核磁共振谱的研究

从金翼黄芪中分离出金翼黄芪甙A(Ⅰ),绵毛黄芪甙XV (Ⅱ),7,2′-二羟基-3′,4′-二甲氧基异黄烷-7-O-β-D-葡萄糖甙(Ⅲ),大豆皂甙Ⅰ,胡萝卜甙及β-谷甾醇。Ⅰ为新化合物,确定其结构为3-O-[α[-L-鼠李吡喃糖基(1→2)-D-木吡喃糖基]-环黄芪醇。并应用二维核磁共振相关谱对Ⅱ和Ⅲ的~1H和~(13)C化学位移信号进行了全面归属。     

Bone marrow imaging: magnetic resonance studies related to age and sex

Measurements of T1 and T2 relaxation values and spin density of the lumbar vertebral bone marrow were performed in 212 patients, and the results were correlated with the patients' age and sex. T1 and T2 relaxation times for bone marrow in the lumbar vertebral bodies showed a progressive decrease with age for both sexes (except for the T2 relaxation values in female patients). The replacement of hematopoietic marrow by fatty marrow could explain the decrease in T1 and T2. The T1 and T2 values were in the same range for the first two age groups (age 1-10 years and age 21-40 years) and became slightly greater for the older female patients (age 51 years and older) than for the older males. This could be due to the loss of bone and mineral content, which is more rapid and significant for women. These normal T1 and T2 values may provide a baseline for future evaluation of diseases involving the lumbar spine.     

Technical efficiency of peripheral health units in Pujehun district of Sierra Leone: a DEA application

Background  

The Data Envelopment Analysis (DEA) method has been fruitfully used in many countries in Asia, Europe and North America to shed light on the efficiency of health facilities and programmes. There is, however, a dearth of such studies in countries in sub-Saharan Africa. Since hospitals and health centres are important instruments in the efforts to scale up pro-poor cost-effective interventions aimed at achieving the United Nations Millennium Development Goals, decision-makers need to ensure that these health facilities provide efficient services. The objective of this study was to measure the technical efficiency (TE) and scale efficiency (SE) of a sample of public peripheral health units (PHUs) in Sierra Leone.     

Heart rate variability is related to training load variables in interval running exercises

Overload principle of training states that training load (TL) must be sufficient to threaten the homeostasis of cells, tissues, organs and/or body. However, there is no “golden standard” for TL measurement. The aim of the present study was to investigate if post-exercise heart rate variability (HRV) could be used to evaluate TL of interval running exercises with different intensities and durations. Thirteen endurance-trained men (35 ± 5 years) performed MO₂₅₀ [moderate intensity, 2 × 6 × 250 m/rec 30 s/5 min at 85% of the maximal velocity of the graded maximal test (V _max)], MO₅₀₀ (2 × 3 × 500 m/rec 1 min/5 min at 85% V _max) and HI₂₅₀ (high intensity, 2 × 6 × 250 m/rec 30 s/5 min at 105% V _max) interval exercises on a treadmill. HRV was analyzed during rest, exercise and immediate 15 min recovery. Fast recovery of LFP (P < 0.001), HFP (P < 0.01) and TP (P < 0.01) occurred during the first two recovery minutes after each exercise. Strong negative correlations (P < 0.01) were found between post-exercise HRV and perceived exertion as well as excess post-exercise oxygen consumption. Post-exercise HRV differentiated interval exercises of equal work, but varying intensity or distance of running bout. The results of the present study suggest that immediate post-exercise HRV may offer objective information on TL of interval exercises with different bout durations and intensities.     

Effects of exercise intensity and duration on nocturnal heart rate variability and sleep quality

Acute physical exercise may affect cardiac autonomic modulation hours or even days during the recovery phase. Although sleep is an essential recovery period, the information on nocturnal autonomic modulation indicated by heart rate variability (HRV) after different exercises is mostly lacking. Therefore, this study investigated the effects of exercise intensity and duration on nocturnal HR, HRV, HR, and HRV-based relaxation, as well as on actigraphic and subjective sleep quality. Fourteen healthy male subjects (age 36 ± 4 years, maximal oxygen uptake 49 ± 4 ml/kg/min) performed five different running exercises on separate occasions starting at 6 p.m. with HR guidance at home. The effect of intensity was studied with 30 min of exercises at intensities corresponding to HR level at 45% (easy), 60% (moderate) and 75% (vigorous) of their maximal oxygen uptake. The effect of duration was studied with 30, 60, and 90 min of moderate exercises. Increased exercise intensity elevated nocturnal HR compared to control day (p < 0.001), but it did not affect nocturnal HRV. Nocturnal HR was greater after the day with 90- than 30- or 60-min exercises (p < 0.01) or control day (p < 0.001). Nocturnal HRV was lower after the 90-min exercise day compared to control day (p < 0.01). Neither exercise intensity nor duration had any impact on actigraphic or subjective sleep quality. The results suggest that increased exercise intensity and/or duration cause delayed recovery of nocturnal cardiac autonomic modulation, although long exercise duration was needed to induce changes in nocturnal HRV. Increased exercise intensity or duration does not seem to disrupt sleep quality.     

Ciprofloxacin inhibits advanced glycation end products-induced adhesion molecule expression on human monocytes

BACKGROUND AND PURPOSE

Advanced glycation end products (AGEs) subtypes, proteins or lipids that become glycated after exposure to sugars, can induce complications in diabetes. Among the various AGE subtypes, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) are involved in inflammation in diabetic patients; monocytes are activated by these AGEs. Ciprofloxacin (CIP), a fluorinated 4-quinolone, is often used clinically to treat infections associated with diabetis due to its antibacterial properties. It also modulates immune responses in human peripheral blood mononuclear cells (PBMC) therefore we investigated the involvement of AGEs in these effects.

EXPERIMENTAL APPROACH

Expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 was examined by flow cytometry. The production of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, prostaglandin E₂ (PGE₂) and cAMP were determined by enzyme-linked immunosorbent assay. Cyclooxygenase (COX)-2 expression was determined by Western blot analysis. Lymphocyte proliferation was determined by [³H]-thymidine uptake.

KEY RESULTS

CIP induced PGE₂ production in monocytes, irrespective of the presence of AGE-2 and AGE-3, by enhancing COX-2 expression; this led to an elevation of intracellular cAMP in monocytes. Non-selective and selective COX-2 inhibitors, indomethacin and NS398, inhibited CIP-induced PGE₂ and cAMP production. In addition, CIP inhibited AGE-2- and AGE-3-induced expressions of ICAM-1, B7.1, B7.2 and CD40 in monocytes, the production of TNF-α and IFN-γ and lymphocyte proliferation in PBMC. Indomethacin, NS398 and a protein kinase A inhibitor, H89, inhibited the actions of CIP.

CONCLUSIONS AND IMPLICATIONS

CIP exerts immunomodulatory activity via PGE₂, implying therapeutic potential of CIP for the treatment of AGE-2- and AGE-3-induced inflammatory responses.     

16α-Hydroxycleroda-3,13 (14)Z-dien-15,16-olide from Polyalthia longifolia: a safe and orally active antileishmanial agent

Background and purpose:

New antileishmanials from natural products are urgently needed due to the emergence of drug resistance complicated by severe cytotoxic effects. 16α-Hydroxycleroda-3,13 (14)Z-dien-15,16-olide (Compound 1) from Polyalthia longifolia was found to be a potential antileishmanial and non-cytotoxic, as evidenced by long-term survival (>6 months) of treated animals. This prompted us to determine its target and, using molecular modelling, identify the interactions responsible for its specific antileishmanial activity.

Experimental approach:

In vitro activity of compound was assessed using intracellular transgenic green fluorescent protein-stably expressed Leishmania donovani parasites. In vivo activity and survival of animals post-treatment were evaluated in L. donovani-infected hamsters. Known property of clerodane diterpenes as potent human DNA topoisomerase inhibitors led us to evaluate the inhibition of recombinant L. donovani topoisomerase I using relaxation assay. Mode of cell death induced by Compound 1 was assessed by phosphotidylserine exposure post-treatment. Molecular modelling studies were conducted with DNA topoisomerase I to identify the binding interactions responsible for its activity.

Key results:

Bioassay-guided fractionation led to isolation of Compound 1 as a non-cytotoxic, orally active antileishmanial. Compound 1 inhibited recombinant DNA topoisomerase I which, ultimately, induced apoptosis. Molecular docking studies indicated that five strong hydrogen-bonding interactions and hydrophobic interactions of Compound 1 with L. donovani DNA-topoisomerase are responsible for its antileishmanial activity.

Conclusions and implications:

The data reveal Compound 1 is a potent and safe antileishmanial. The study further exploited the structural determinants responsible for its non-cytotoxic and potent activity, to raise the feasibility of specifically targeting the target enzyme responsible for its activity through rational drug design.