Activation of tyrosine kinases by mutation of the gatekeeper threonine.

Protein kinases targeted by small-molecule inhibitors develop resistance through mutation of the gatekeeper threonine residue of the active site. Here we show that the gatekeeper mutation in the cellular forms of c-ABL, c-SRC, platelet-derived growth factor receptor-alpha and -beta, and epidermal growth factor receptor activates the kinase and promotes malignant transformation of BaF3 cells. Structural analysis reveals that a network of hydrophobic interactions-the hydrophobic spine-characteristic of the active kinase conformation is stabilized by the gatekeeper substitution. Substitution of glycine for the residues constituting the spine disrupts the hydrophobic connectivity and inactivates the kinase. Furthermore, a small-molecule inhibitor that maximizes complementarity with the dismantled spine (compound 14) inhibits the gatekeeper mutation of BCR-ABL-T315I. These results demonstrate that mutation of the gatekeeper threonine is a common mechanism of activation for tyrosine kinases and provide structural insights to guide the development of next-generation inhibitors

The impact of patients' chronic disease on family quality of life : an experience from 26 specialties

BACKGROUND: Previous studies have assessed family quality of life in individual disease areas and specialties. The aim of this study was to investigate the impact of disease on family members of patients over a wide range of specialties and identify key impact areas. This information is essential in order to reveal the extent of this impact and to allow strategies to be developed to support the family members of patients with chronic disease. METHODS: Semi-structured interviews were carried out with 133 family members of mostly chronically ill patients from 26 medical specialties. Family members were invited to discuss all areas of their lives that had been affected by having an unwell relative. Thematic analysis was carried out using NVivo9® software. RESULTS: Most family members were female (61%), the partner or spouse of the patient (56%), or the parent (22%). Their mean age was 56.1 years (range: 21-85 years) and the mean duration of the patient's disease was 8.9 years (range: 1 month to 60 years). Ten key themes of family quality of life were identified from interviews. The median number of themes reported by family members was six (range: 1-10). The key themes included: emotional impact (mentioned by 92% of subjects), daily activities (91%), family relationships (69%), sleep and health (67%), holidays (62%), involvement in medical care and support given to family members (61%), work and study (52%), financial impact (51%), social life (37%), and time planning (14%). Relationships between the themes were identified. CONCLUSION: This large scale multi-specialty study has demonstrated the significant, yet similar, impact that illness can have on the quality of life of patients' family members. Family quality of life is a previously neglected area of health care which needs to be addressed in order to provide appropriate support for the patient and the family unit.Peer reviewedFinal Published versio

Enzyme replacement therapies: What is the best option?

Despite many beneficial outcomes of the conventional enzyme replacement therapy (ERT), several limitations such as the high-cost of the treatment and various inadvertent side effects including the occurrence of an immunological response against the infused enzyme and development of resistance to enzymes persist. These issues may limit the desired therapeutic outcomes of a majority of the lysosomal storage diseases (LSDs). Furthermore, the biodistribution of the recombinant enzymes into the target cells within the central nervous system (CNS), bone, cartilage, cornea, and heart still remain unresolved. All these shortcomings necessitate the development of more effective diagnosis and treatment modalities against LSDs. Taken all, maximizing the therapeutic response with minimal undesired side effects might be attainable by the development of targeted enzyme delivery systems (EDSs) as a promising alternative to the LSDs treatments, including different types of mucopolysaccharidoses (MPSs ) as well as Fabry, Krabbe, Gaucher and Pompe diseases

An empirical study based on BSC-DEA to measure the relative efficiencies of different health care centers in province of Semnan, Iran

In this paper, we present an empirical investigation to measure the relative efficiency of seven health care centers in province of Semnan, Iran, which were under the coverage of social security organization of Iran. The proposed model of this paper uses a hybrid of balanced score card and data envelopment analysis for performance measurement. The proposed sudy uses four perspectives of balanced score card including learning and growth, internal process, customer and financial perspectives and within each perspective, data envelopment analysis is adopted so that the outputs of each perspective are used as inputs of the other perspective. The preliminary results indicate that all seven units perform relatively well and the overall efficiency of all units in this province is 0.769

Study on genotoxicity, oxidative stress biomarkers and clinical symptoms in workers of an asbestos-cement factory

The purpose of the present study was to investigate whether the markers of oxidative stress could be altered in workers exposed to asbestos. A comparative cross-sectional research was conducted in a group of 50 subjects exposed to asbestos and another group of 50 with the same age and sex unexposed to asbestos. Malondialdehyde (MDA), total thiol molecule (TTM), total antioxidant capacity (TAC), and DNA damage, were measured in the blood samples of workers and controls. Compared to the control group, the workers showed higher blood levels of DNA damage (P=0.0001) and MDA (P=0.0001). The workers showed lower TTM (P=0.02) as compared with the control group. There was no considerable difference on the level of TAC (P=0.1) between the groups. The workers indicated clinical symptoms such as breathlessness, phlegm, coughing and wheezing. There was a positive correlation between levels of 8-OHdG and MDA of asbestos workers and the smoking status suggesting the negative role of smoking

The Effect of black cumin (Nigella Sativa L.) alcoholic extract on body weight and the harms created in the spitial memory and learning caused by stress

Background and aims: Nigella sativa L. grain has a rich medical and religious history. Also, due to the importance of learning and memory, human being is always looking for ways to increase the ability of them. The aim of this study was to investigate the effect of alcoholic extract of Nigella Sativa L. on memory and learning. Methods: The present study was carried out on 28 adult female Wistar rats (weighing 160-200 g) in 4 groups (7 mice per group). The first group (control group) received no treatment, the second and third groups were treated orally with alcoholic extract of Nigella sativa, at a dose of 400 mg/kg of body weight by gavage for 21 days. In addition to oral gavage treatment, the third group was also treated with immobilization stress, and the 4th group was only given immobilization stress to animals. Animals were trained for 3 days and on day 21, (without the extract intake) were conducted memory tests using radial arm 8 branches. On the 1st day and the 21th day of the experiment, all mice by digital scales were weighed. The data were analyzed by One-way ANOVA and Tukey’s post hoc test. The level of significance was considered at P<0.05. Results: According to the results of Nigella sativa group and "Nigella sativa + Stress" group significantly enhanced spatial learning and memory compared to the control group and stress group, respectively (P<0.05). The results showed that Nigella sativa causes weight increases in animals receiving the Nigella sativa (P<0.05). Conclusion: The obtained results showed alcoholic extract of Nigella Sativa enhances learning and reduces the negative effects of stress on learning and spatial memory and also causes proportionable increase of bodyweigh

Efektivitas Sholat Tahajud Dalam Mengurangi Tingkat Stres Santri Pondok Islam Nurul Amal Bekasi Jawa Barat

Stres dapat menyebabkan kerusakan fungsi biologis dan psikologis. Penelitian ini bertujuan untuk mengetahui efektivitas sholat tahajud dalam menurunkan stres Santri Pondok Islam Nurul Amal Bekasi Jawa Barat. Penelitian ini merupakan penelitian eksperimen non randomized pretest posttest control group design. Hipotesis penelitian ada 2, yang pertama ada perbedaan tingkat stres individu kelompok pengamal sholat tahajud dan kelompok bukan pengamal sholat tahajud, dan hipotesis kedua adalah ada perbedaan tingkat stres individu pengamal sholat tahajud antara sebelum dan sesudah mengamalkan sholat tahajud, tingkat stres setelah sholat tahajud lebih rendah dibandingkan sebelum sholat tahajud. Sampel penelitian ini sebanyak 30 santri, yang terdiri dari 15 santri pada kelompok eksperimen dan 15 santri pada kelompok kontrol. Metode penggalian data dengan menggunakan satu skala psikologi yang terdiri dari 2 aspek yaitu biologis dan psikologis. Hasil uji validitas pada skala stres terdapat 44 aitem valid (α = 0,953), dan analisis data menggunakan paired t test dan independent sample test. Hasil posttest antara kelompok eskperimen dan kelompok kontrol menunjukkan bahwa tingkat stres santri kelompok pengamal sholat tahajud lebih rendah dibandingkan dengan kelompok bukan pengamal sholat tahajud (t = -5,042; p &lt; 0,001). Hasil pretest dan posttest kelompok eksperimen menunjukkan adanya penurunan tingkat stres individu setelah melakukan sholat tahajud dibandingkan dengan sebelum melakukan sholat tahajud (t = 10,821; p &lt; 0,001). Jadi sholat tahajud terbukti efektif mengurangi tingkat stres santri di Pondok Islam Nurul Amal Bekasi Jawa Barat

An epidemiological survey of drug poisoning and a comparison with other poisonings cases admitted to a university hospital in Gorgan, Iran, 2008-2015

Background and aims: Acute drug poisoning is a major public health problem in the world.The aim of this study was to investigate the trends and characteristics of acute drug poisoning and to compare that with other poisonings in Gorgan, Iran. Methods: This descriptive cross-sectional study was done from March 2008 to march 2015. Data were obtained from medical records. Stata software and Pearson's chi-squared test were used for data analysis. Results: A total of 800 poisoning cases, 573 cases were due to drug poisoning. The majority of the 573 patients (50.8 male) were in the age range of 20-29 years (47.8) and 78 of them were living in urban areas. The maximum number of poisoning occurred during summer season (27). The most common agents involved in acute drug poisoning were sedatives-hypnotics drugs, especially BZDs (37.2), followed by Tramadol (17.3) and Cardiac drugs (13.1). Poisoning most commonly occurred as ingestion of single drug (55). More than half (77.1) of the cases were intentional poisoning (suicide), followed by overdose (63.1), drug abuse (51.9) and accidental poisoning (17.3). Moreover, the most common drug involved in intentional poisoning was BZDs (44).9 patients (1.6) died, of which 3(33.3) were due to Narcotic drugs. Conclusion: Drugs were the most common cause of poisonings and the majority of acute drug poisoning in Gorgan was associated with suicide attempts. So, easy access to the most prominent methods of suicide i.e. consumption of drugs particularly BZDs should be restricted

Helicobacter Pylori Gastritis and risk of Ischaemic Stroke

OBJECTIVE: To identify the association between H. Pylori gastritis and stroke. METHOD: Patients with biopsy proven H. Pylori gastritis and non H. Pylori gastritis were enrolled. Patients were followed for a period of two years. RESULTS: A total of 326 patients were included in the study. 162 patients were with H. Pylori gastritis. There was no significance difference in age, sex and duration of symptoms in the two groups. Three patients in H. Pylori group had stroke or TIA as compared to one in non H. Pylori group. Patients with H. Pylori gastritis were more likely to die or have cardiac and or neurological event as compared to Non H. pylori gastritis (OR 1.23, 95% CI 0.89-1.67). This relationship was not significant after adjusting for cardiovascular risk factors (AOR 0.85, 95% CI 0.45-1.31). CONCLUSION: H. Pylori gastritis is not independently associated with increased risk for stroke. Larger, randomized studies are needed to confirm our findings

Fenugreek seed extract treats peripheral neuropathy in pyridoxine induced neuropathic mice

Trigonella foenum graecum commonly known as Fenugreek exerts normoglycemic and insulinotropic effects in humans by compounds from its seed and leaf extracts. Some studies reported that treating pregnant mice with fenugreek seed could cause toxic effects on the nervous system of its pubs during developmental growth, while in some other studies neuroprotective properties were considered for it. Safety of anti-diabetic drugs for nervous system is very important because peripheral neuropathy is a common complication of diabetes and hazardous drugs could worsen it. In this study, the effect of treatment with fenugreek seed extract on the function of sciatic nerves of neuropathic mice was evaluated. Neuropathy was induced in male mice by pyridoxine intoxication. After that, animals were treated with 0.2, 2 and 20 mg/kg of hydro-alcoholic extract of fenugreek seeds for 10 days, tail flick, electrophysiological and histological assays were performed to evaluate the effect of fenugreek seed extract on function of the peripheral nerves. Our data showed that fenugreek has anti neuropathic effect and restores the function of nerve fibers. Results of electrophysiological recordings stated that the highest rate of healing was occurred in 20 mg/kg fenugreek extract treated animals. In conclusion, findings of the present study demonstrate that treatment with fenugreek seed extract can potentially facilitate healing from pyridoxine induced peripheral neuropathy in mice