Targeted therapy in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is an incurable malignancy. Recent insights into its biology has allowed the use of novel therapies targeting not only the deregulated intracellular signaling in MM cells but also its interaction with the bone marrow microenvironment that confers drug resistance, growth, and survival advantage to the malignant cells. METHODS: We review and summarize the recent advances in our knowledge of myeloma biology as well as the mechanism of action and clinical efficacy for novel therapeutic agents in clinical trials. RESULTS: Several novel therapeutic agents are currently in clinical trials. Thalidomide is already established for both initial and salvage treatment. Bortezomib is being tested alone and in combination with conventional chemotherapy in various settings. Other agents are less effective in producing response but have been able to stabilize disease in patients with relapsed and/or refractory disease, such as arsenic trioxide, farnesyltransferase inhibitors, 2-methoxyestradiol, and vascular endothelial growth factor receptor inhibitors. Insights into drug resistance mechanism have also led to the development of novel agents that sensitize myeloma cells to chemotherapy (Bcl-2 antisense). Gene expression studies have in many instances identified pathways other than the intended target of the drug and have provided insights into the therapeutic mechanisms. CONCLUSIONS: In the future, patients with MM will have more therapeutic options available than ever before. The challenge will be to identify patient subgroups that will benefit most from the different therapies and then determine how these biologically based therapies could be combined and incorporated into the overall management of patients.     

The location of the mental foramen in a selected Malay population

Knowledge of the position of the mental foramen is important both when administering regional anesthesia and performing periapical surgery in the mental region of the mandible. This study determines the position of the mental foramen in a selected Malay population. One hundred and sixty nine panoramic radiographs of Malay patients retrieved from a minor oral surgery waiting list were selected to identify the normal range for the position of the mental foramen. The foramen was not included in the study if there was any mandibular tooth missing between the lower left and right first molars (36-46). The findings indicated the most common position for the mental foramen was in line with the longitudinal axis of the second premolar (69.2%) followed by a location between the first and second premolar (19.6%). The right and left foramina were bilaterally symmetrical in three of six recorded positions in 67.7% patients. The mental foramen was most often in line with the second premolar.     

Persistence of lower birth weight in second generation South Asian babies born in the United Kingdom

OBJECTIVE: To assess differences in birth weight between all first and second generation South Asian babies born in Southampton, and trends since 1957. DESIGN: Retrospective, cohort study. SETTING: Birth records for babies born in Southampton from 1957 to 1996 were searched to identify all babies born of South Asian origin (including from the Indian subcontinent, East Africa, and elsewhere). MAIN OUTCOME MEASURES: All information recorded in the birth record about the mother and baby was extracted. RESULTS: 2395 full term (>37 weeks; mean birth weight 3110; 95%CI 3092 to 3129) singleton births were identified. Detailed analysis was restricted to mothers either born in the Indian subcontinent (India, Pakistan, or Bangladesh (1435)) or United Kingdom (283). Mean birth weight and % low birth weight (<2500 g) were 3133 g (95%CI 3108 to 3157) and 7.5%, for first generation babies and 3046 g (2992 to 3099) and 11.7% for second generation babies. There was no trend over time to increased average birth weight in either first or second generation babies. Adjusting for other factors that were statistically significantly related to birth weight (gender, gestational age, mother's age, maternal weight at 15 weeks, parity, and mother's ethnic group) did not alter the trends. CONCLUSIONS: For that group in the UK who derive from the Indian subcontinent, average birth weight is significantly less than the national average. There has not been any increase in the average birth weight over the past 40 years, and the birth weight of babies of women who were born in the UK are no greater. The persistence of lower than desirable birth weight may result long term in higher than average rates of diabetes and heart disease in these groups.     

N-acetyl-L-cysteine protects against delta-aminolevulinic acid-induced 8-hydroxydeoxyguanosine formation.

5-Aminolevulinic acid (ALA) is a heme precursor that accumulates in acute intermittent porphyria and lead poisoning. It has been shown that ALA induces free radical generation and may cause damage to proteins and DNA. In the present study, the effects of ALA on DNA damage and its prevention by N-acetyl-L-cysteine (NAC) and the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) are investigated. Oxidative damage to DNA was quantitated by measuring the increase in 8-hydroxy-2'-deoxyguanosine (oh8dG) formation. The time-course study demonstrated that ALA causes a linear increase in oh8dG levels in Chinese hamster ovary (CHO) cells. However, direct lead exposure did not cause any measurable increase in oh8dG levels. In the presence of either NAC (1 mM) or antioxidant enzymes (10 u/ml SOD and 10 u/ml CAT), oh8dG levels returned to the corresponding control levels. This suggests a protective role for NAC and the antioxidant enzymes. To determine the effect of ALA on cell proliferation, cell numbers were counted at the end of 24 h of incubation in the presence and absence of ALA at different concentrations. Results showed that levels of ALA up to 5 mM do not inhibit cell proliferation.     

Anti-inflammatory activity of Crinum asiaticum plant and its effect on bradykinin-induced contractions on isolated uterus

Crinum asiaticum Linn plant is used in Malaysia as a rheumatic remedy and to relieve local pain. In the present study, we examined the anti-inflammatory effects of this plant extract on carrageenan-induced hind paw oedema in mice. C. asiaticum was serially extracted with petroleum ether, followed by chloroform and lastly, methanol. The chloroform and methanol extracts of the plant given orally (50 mg kg-1) caused significant (p < 0.05; n = 7) reduction in paw oedema but the petroleum ether extract did not induce significant effect (p > 0.05) on paw oedema. The methanol extract was then dissolved in water and extracted consecutively with chloroform, ethyl acetate and butanol. The chloroform fraction of methanol extract (CFME) treatment (50 mg kg(-1)) significantly reduced (p < 0.05; n = 7) the acute paw oedema. This may indicate that active anti-inflammatory compounds are present in the CFME. In an attempt to study the mechanism of action of its anti-inflammatory activity, the effects of CFME on BK- and histamine-induced contractions were investigated in isolated rat uterus and guinea-pig ileum preparations, respectively. It was found that CFME caused dose-dependent reduction (p < 0.05; n = 6) of the contractile response induced by BK and shifted the log dose-response curve of histamine to the right. The present findings suggest that C. asiaticum possessed an anti-inflammatory activity as suggested by its use in traditional medicine. The anti-inflammatory activity of this plant could not have been due to its anti-bradykinin activities as CFME non-specifically inhibited BK-induced contraction. It also suggest that CFME may contain compound(s) with anti-histaminic properties. The significance of these findings is discussed.     

Role of schools of public health on maternal and child health programmes in the Asia-Pacific region

This paper assessed the role of public health schools on maternal and child health programmes in the Asia Pacific region. Economic development and its associated effects, particularly in the ASEAN countries, for example, migrant labour, ageing, environmental health, turbulence and social climate, has a tremendous impact on maternal and child health. Based on these current issues, it is evident that public health schools can play a major role in maternal and child health in terms of policy formulation and programme development. Several areas were proposed as to what schools of public health can do, namely, through networking, communication, research and training.     

The Implementation of Industrial Byproduct in Malaysian Peat Improvement: A Sustainable Soil Stabilization Approach

Peat is a well-known problematic soil associated with poor engineering properties. Its replacement with an expensive competent foundation material is practiced for road embankment construction which is costly and causes greenhouse gas emissions. Therefore, this paper investigated the effectiveness of a byproduct from a metal industry (silica fume) to stabilize peat along with ordinary Portland cement (OPC) through a series of experimental tests. After peat-indexed characterization, a number of standard compaction and mechanical tests were performed on the stabilized and parent peat. For this purpose, nine designated mixes were prepared possessing various combinations of silica fume (SF) and 10–20% OPC. Unconfined compressive strength (UCS) and California Bearing Ratio (CBR) tests were carried out after 7, 14, and 28 days of curing to assess strength enhancement and binder effectiveness, and the microstructural evolution induced by the binders was examined with scanning electron microscopy (SEM). The analysis revealed a substantial improvement in mechanical properties with the incorporation of SF and OPC, ultimately meeting the minimum strength requirement for highway construction (i.e., 345 kPa). A peak UCS of 1063.94 kPa was recorded at 20% SF, and an unsoaked CBR value of 42.95 was observed using 15% SF and 15% OPC after 28 days of curing. Furthermore, the increasing percentage of hydraulic binders exhibited brittle, collapsible failure, while the microstructural study revealed the formation of a dense matrix with a refined pore structure in the treated peat. Finally, a significant statistical analysis was carried out by correlating the test parameters. In this way, rather than stockpiling and dumping, an industrial byproduct was implemented in peat stabilization in an eco-friendly manner.     

Strategies for the preparation of non-amplified and amplified genomic dengue gene samples for electrochemical DNA biosensing applications

The application of electrochemical DNA biosensors in real genomic sample detection is challenging due to the existence of complex structures and low genomic concentrations, resulting in inconsistent and low current signals. This work highlights strategies for the treatment of non-amplified and amplified genomic dengue virus gene samples based on real samples before they can be used directly in our DNA electrochemical sensing system, using methylene blue (MB) as a redox indicator. The main steps in this study for preparing non-amplified cDNA were cDNA conversion, heat denaturation, and sonication. To prepare amplified cDNA dengue virus genomic samples using an RT-PCR approach, we optimized a few parameters, such as the annealing temperature, sonication time, and reverse to forward (R/F) primer concentration ratio. We discovered that the generated methylene blue (MB) signals during the electrochemical sensing of non-amplified and amplified samples differ due to the different MB binding affinities based on the sequence length and base composition. The findings show that our developed electrochemical DNA biosensor successfully discriminates MB current signals in the presence and absence of the target genomic dengue virus, indicating that both samples were successfully treated. This work also provides interesting information about the critical factors in the preparation of genomic gene samples for developing miniaturized PCR-based electrochemical sensing applications in the future. We also discuss the limitations and provide suggestions related to using redox-indicator-based electrochemical biosensors to detect real genomic nucleic acid genes.

The application of electrochemical DNA biosensors in real genomic sample detection is challenging due to the existence of complex structures and low genomic concentrations, resulting in inconsistent and low current signals.