Real-life daily activity: the impact of misbeliefs on quality of life among cancer patients.

BACKGROUND: While side-effects and health-related quality of life (QoL) are routinely assessed in clinical trials, commonly used tools do not measure patients' ability to maintain normal daily activities. QoL can be severely affected directly by the disease, the treatment side-effects and by personal and societal misconceptions promoting avoidance from activities perceived as dangerous for cancer patients. We examined practices of actively treated patients with cancer. METHODS: A questionnaire was designed, assessing daily activities (11 items) and dietary limitations (7 items) distributed between October and December 2019 (before the coronavirus pandemic) among patients treated at the Oncology Division of Tel Aviv Sourasky Medical Center. RESULTS: The study population comprised 208 patients who participated in the survey. The majority reported at least one social-environmental avoidance or dietary limitation (136, 65% and 120, 57.7%, respectively), including abstaining from social contact, avoiding pets, public domains, traveling and maintaining dietary constraints. Adoption of these measures was not associated with clinical, demographic factors and treatment type. The major sources guiding restrictions came from advice of non-medical personnel (55.7%), the Internet (7.2%) and personal choice by the patients themselves (24%). CONCLUSIONS: Most cancer patients reported compromised daily activities, which are likely attributed to misbeliefs about disease and treatment, and have a deleterious impact on QoL, in its wider sense, namely, the ability to conduct a full and meaningful life. These findings call for the development and implementation of tools examining patients' real-life activity, beyond side-effects or health-related QoL (HRQoL). We propose this assessment as an integral part in the evaluation of new drugs and technologies and as an additional endpoint in pivotal clinical trials.

Enhancing clinician participation in quality improvement training: implementation and impact of an evidence-based initiative to maximise antenatal clinician participation in training regarding women's alcohol consumption during pregnancy.

BACKGROUND: There are significant challenges in ensuring sufficient clinician participation in quality improvement training. Clinician capability has been identified as a barrier to the delivery of evidence-based care. Clinician training is an effective strategy to address this barrier, however, there are significant challenges in ensuring adequate clinician participation in training. This study aimed to assess the extent of participation by antenatal clinicians in evidence-based training to address alcohol consumption during pregnancy, and to assess differences in participation by profession. METHODS: A 7-month training initiative based on six evidence-based principles was implemented in a maternity service in New South Wales, Australia. Descriptive statistics described participation in training (% attending: any training; six evidence-based principles of training; all principles). Regression analyses examined differences by profession. RESULTS: Almost all antenatal clinicians participated in some training (182/186; 98%); 69% participated in ≥1 h of training (µ = 88.2mins, SD:56.56). The proportion of clinicians participating in training that satisfied each of the six principles ranged from 35% (training from peers and experts) to 82% (training was educational and instructional). Only 7% participated in training that satisfied all principles. A significantly higher proportion of midwifery compared to medical clinicians participated in training satisfying five of the six training principles. CONCLUSIONS: A training initiative based on evidence-based principles resulted in almost all clinicians receiving some training and 69% participating in at least 1 h of training. Variability between professions suggests training needs to be tailored to such groups. Further research is required to determine possible associations with care delivery outcomes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, No. ACTRN12617000882325 (date registered: 16/06/2017).

Adjuvant endocrine therapy in HER2-positive breast cancer patients: systematic review and meta-analysis.

BACKGROUND: Approximately 50% of human epidermal growth factor receptor 2 (HER2)-positive breast cancer lesions express hormone receptors. These tumors present a unique therapeutic challenge, and the optimal endocrine therapeutic approach remains controversial. We aimed to study the optimal adjuvant endocrine therapy in this setting, to better establish the basis for clinical recommendations in HER2-positive disease. METHODS: We conducted a literature search up to May 2020, in which we identified randomized controlled trials (RCTs) that investigated the efficacy of various adjuvant hormonal therapies among premenopausal and postmenopausal patients with hormone receptor (HR)-positive, HER2-positive early breast cancer. Disease-free survival (DFS) was calculated with the random effect model and hazard ratios (HRs) with 95% confidence intervals (CI). RESULTS: Six RCTs (N = 5390 patients) were included in the final analysis. There was no significant difference in DFS between adjuvant treatment with aromatase inhibitors and tamoxifen (HR 0.99, 95% CI 0.68-1.44, P = 0.96). Furthermore, after omitting the ALTTO trial, as it did not randomize patients to hormonal therapy, no significant difference was observed between the two protocols (HR 1.06, 95% CI 0.65-1.73, P = 0.81). CONCLUSION: Our study demonstrates similar DFS with tamoxifen and aromatase inhibitors as adjuvant endocrine treatment in HER2-positive HR-positive early-stage breast cancer patients. Future larger prospective studies focusing on the various contemporary endocrine regimens are warranted to validate our findings.

Potential of Aucklandia Lappa Decne Ethanolic Extract to Trigger Apoptosis of Human T47D and Hela Cells

Breast and cervical cancers are global health concerns and major cause of deaths among women. Current treatments such as chemotherapy are associated with several drawbacks that limit their effectiveness. Several anticancer remedies have been found with natural products in the past and the search continues for more examples. Cytotoxic natural compounds may have considerable benefits for cancer therapy either in potentiating the impact of chemotherapy or curtailment of harmful effects. Therefore, discovery and identification of new drugs for breast and cervical cancer treatment are of high priority. The present study addressed the potential role of the ALD (Aucklandia lappa Decne) in suppressing proliferation of T-47D, HeLa and HEp-2 cells in comparison with the non-cancer HCC1937 BL cell line. Treatment with an ALD extract of T-47D, HeLa, and HEp-2 cells resulted in reduction in cell viability in MMT assays. Furthermore, lyophilized ALD principally suppressed cancer cell line growth and proliferation through induction of either intrinsic or extrinsic apoptotic pathways as demonstrated by significantly suppressed release of LDH, and NO production in a dose-dependent manner, and activation of death receptors in T-47D and HeLa cells but not the HEp-2 cell line. Interestingly, lyophilized ALD significantly (p<0.005) repressed the growth of HEp-2 and T-47D cells after treatment for 48hrs while 24hrs treatment significantly suppressed T-47D and HeLa cells. We report for the first time that lyophilized ALD selectively influences apoptosis through alternative apoptotic pathways in both breast and cervical human cancer cells.

Frequency of TLR4 (1063A/G and 1363C/T) polymorphisms in healthy and HIV-infected Omani individuals and their relationship to viral load and T cell count.

Toll-like receptors (TLRs) are essential elements of the innate immune response to different infections including the infection with human immunodeficiency virus (HIV). Single nucleotide polymorphisms (SNPs) in TLRs such as TLR4 1063A/G and 1363C/T have been found to be associated with changes in CD4 count, viral load (VL), and disease progression during HIV infection. However, the association of these SNPs with the pathogenesis during HIV infection is controversial. We investigated the frequency of TLR4 1063A/G and 1363C/T SNPs in 168 Omani donors [68 HIV-infected patients (>3% of Omani HIV-infected patients) and 100 healthy controls] and the association of these SNPs with the VL, CD8 and CD4 counts, and the immune recovery after cART as observed by CD4 T cell increase. SNPs were analyzed after the amplification of the regions that contain them by polymerase chain reaction (PCR) and sequencing of the PCR products. The TLR4 1063GG genotype was detected in the HIV-infected group only. No association was found between the studied SNPs and the average VL during 1 year of infection, the average CD4 and CD8 count during 1 year of viremia, the nadir CD4 count, the CD4 count when the patient reached VL < 50 copies/mL due to cART, and the ratio of the CD4 count 3 and 6 months after reaching VL < 50 copies/mL after cART to the last CD4 count before reaching VL < 50 copies/mL. Our study suggests that TLR4 (1063A/G and 1363C/T) SNPs have no association with the VL or the CD4 and CD8 counts during HIV infection.

Knowledge, attitudes and intended behaviours towards HIV testing and self-protection: a survey of Omani pregnant women.

Routine HIV testing of all pregnant women in Oman has been introduced without prior knowledge of women's attitudes towards testing or their behaviour in the event of a positive test. This study recruited 1000 Omani pregnant women from antenatal clinics to explore their knowledge of HIV/AIDS, attitudes towards HIV testing and intended behaviours in the event of a positive test. Mother-to-child transmission was recognized by 86.6% of the women but only 21.0% knew that it was preventable and a few acknowledged the important role of antiviral drugs. Half of the women (51.9%) reported having been tested for HIV and 75.8% agreed about routine HIV testing for all pregnant women. A higher level of knowledge was significantly associated with a favourable intended behaviour related to voluntary testing, disclosure and seeking professional assistance in the event of a positive HIV test. The results are discussed in relation to opt-in and opt-out approaches to voluntary testing during pregnancy.

Association of single-nucleotide polymorphisms in TLR7 (Gln11Leu) and TLR9 (1635A/G) with a higher CD4T cell count during HIV infection.

BACKGROUND: Toll-like receptors (TLRs) are essential elements of the innate immune response to different infections including HIV-1 infection. The single-nucleotide polymorphisms (SNPs) in TLRs have been associated with CD4T cell count and HIV disease progression. The TLR7 (Gln11Leu) SNP was shown to be associated with a rapid decline of CD4T cell count. A relation between TLR9 (1635A/G) SNP and CD4T cells count in HIV-infected patients is suggested, although the outcome associated with this SNP is still controversial. OBJECTIVES: To determine the relation of the TLR7 (Gln11Leu) and TLR9 (1635A/G) SNPs with the damage to the immune system during HIV infection as reflected by the average CD4T cell count. METHODS: A total of 63 HIV-infected patients and 100 healthy individuals (controls) were enrolled in this study. The above named SNPs were analyzed after amplification of the regions that potentially contain the SNPs by polymerase chain reaction (PCR) and sequencing of the PCR products. The frequency of these SNPs and their relation with the CD4T cell count were investigated. RESULTS: The TLR7 (AA) genotype 'Gln' had a trend toward being associated with a CD4T cell count >400cells/µl after controlling viremia via HAART. Additionally, the TLR9 1635 (GG) genotype was associated with a low average CD4T cell count and the TLR9 1635 (AG) genotype was significantly related to a higher average CD4T cell count during the viremic period in HIV-infected patients. CONCLUSION: The results of this longitudinal study supports the presence of an association between the TLR9 (1635A/G) genotype and the CD4T cell count, which helps clarifying the controversial results regarding this association. It also suggests that the CD4T cell count during the viremic period might be linked to the combination of both TLR7 (Gln11Leu) and TLR9 (1635A/G) genotypes. These results may help predicting the damage to the immune system, and thus impacting the planning for novel anti-HIV strategies.

New genetic variants in the CCR5 gene and the distribution of known polymorphisms in Omani population.

C-C motif chemokine receptor-5 (CCR5) is a pro-inflammatory receptor that binds to chemokines and facilitates the entry of the R5 strain of HIV-1. A number of polymorphisms were identified within the promoter and coding regions of the CCR5 gene, some of which have been found to affect the protein expression and thus receptor function. Although several CCR5 polymorphisms were shown to vary widely in their distribution among different ethnic populations, there has been no study addressing the potential variants of the CCR5 gene in the Omani population. The aim of this study was to identify the polymorphic sites that exist within the CCR5 gene in Omanis. Blood samples were collected from 89 Omani adult individuals, and genomic DNA was amplified by polymerase chain reaction and sequenced to identify the polymorphic sites. The distribution of the detected variants was examined and compared with the previously published data. Four new indels were detected of 32 variable positions, -2973A/-, -2894A/-, -2827TA/- and -2769T/-, and all were located in the 5'UTR. Furthermore, two new mutations, -2248G/A and +658A/G, were observed for the first time; the -2248G/A was detected in the intron 1 region in one subject and +658A/G in the coding region of the CCR5 in another subject. In silico analysis showed that the novel variations in the 5'UTR may have effects on the transcription factor binding sites. Therefore, this study demonstrates the presence of two new SNPs and four novel indels in the CCR5 gene in the Omani population. Our findings support the wide spectrum of genetic diversity reported within the CCR5 gene region among different ethnic groups.

Neutralisation of Local Haemorrhage Induced by the Saw-Scaled Viper Echis carinatus sochureki Venom Using Ethanolic Extract of Hibiscus aethiopicus L.

The objective of the study is to investigate the anti-snake venom activities of a local plant, Hibiscus aethiopicus L. The H. aethiopicus was dried and extracted with ethanol. Different assays were performed according to standard techniques, to evaluate the plant's acute toxicity and its antivenom activities. The results of evaluating the systemic acute toxicity of the H. aethiopicus extract using "oral and intra-peritoneal" route were normal even at the highest dose (24 g/kg) tested. All guinea pigs (n = 3) when treated with venoms E. c. sochureki (75 µg) alone induced acute skin haemorrhage. In contrast, all guinea pigs (n = 18) treated with both venom and the plant extract at a concentration between 500 and 1000 mg/kg showed no signs of haemorrhage. Moreover, all guinea pigs (n = 18) treated with venom and the plant extract below 400 mg/kg showed acute skin haemorrhage. All guinea pigs treated with venom E. c. sochureki (75 µg) alone induced acute skin haemorrhage after both 24 and 32 hours. In contrast, all guinea pigs treated with both venom and the plant extract (administered independently) at concentrations between 500 and 1000 mg/kg showed no signs of haemorrhage after 32 hours. However, after 24 hours all tested guinea pigs showed less inhibition (<60%) compared to that obtained after 32 hours. The outcome of this study reflects that the extract of H. aethiopicus plant may contain an endogenous inhibitor of venom induced local haemorrhage.

Antibacterial activity of Lawsonia inermis Linn (Henna) against Pseudomonas aeruginosa.

OBJECTIVE: To investigate the antibacterial activity of henna (Lawsonia inermis Linn) obtained from different regions of Oman against a wide array of micro-organisms. METHODS: Fresh henna samples were obtained from different regions of Oman as leaves and seeds. 100 g fresh and dry leaves and 50 g of fresh and dry seeds were separately soaked in 500 mL of ethanol for three days, respectively, with frequent agitation. The mixture was filtered, and the crude extract was collected. The crude extract was then heated, at 48 °C in a water bath to evaporate its liquid content. The dry crude henna extract was then tested for its antibacterial activity using well-diffusion antibiotic susceptibility technique. Henna extracts were investigated for their antibacterial activity at different concentrations against a wide array of different micro-organisms including a laboratory standard bacterial strain of Pseudomonas aeruginosa (NCTC 10662) (P. aeruginosa) and eleven fresh clinical isolates of P. aeruginosa obtained from patients attending the Sultan Qaboos University Hospital (SQUH). 2-Hydroxy-p-Nathoqinone-Tech (2-HPNT, MW=174.16, C10H6O3) was included as control (at 50% concentration) along with the henna samples tested. RESULTS: Henna samples demonstrated antibacterial activity against all isolates but the highest susceptibility was against P. aeruginosa with henna samples obtained from Al-sharqyia region. CONCLUSIONS: Omani henna from Al-sharqyia region demonstrates high in vitro anti-P. aeruginosa activity compared with many henna samples from different regions of Oman.

Serine protease variants encoded by Echis ocellatus venom gland cDNA: cloning and sequencing analysis.

Envenoming by Echis saw-scaled viper is the leading cause of death and morbidity in Africa due to snake bite. Despite its medical importance, there have been few investigations into the toxin composition of the venom of this viper. Here, we report the cloning of cDNA sequences encoding four groups or isoforms of the haemostasis-disruptive Serine protease proteins (SPs) from the venom glands of Echis ocellatus. All these SP sequences encoded the cysteine residues scaffold that form the 6-disulphide bonds responsible for the characteristic tertiary structure of venom serine proteases. All the Echis ocellatus EoSP groups showed varying degrees of sequence similarity to published viper venom SPs. However, these groups also showed marked intercluster sequence conservation across them which were significantly different from that of previously published viper SPs. Because viper venom SPs exhibit a high degree of sequence similarity and yet exert profoundly different effects on the mammalian haemostatic system, no attempt was made to assign functionality to the new Echis ocellatus EoSPs on the basis of sequence alone. The extraordinary level of interspecific and intergeneric sequence conservation exhibited by the Echis ocellatus EoSPs and analogous serine proteases from other viper species leads us to speculate that antibodies to representative molecules should neutralise (that we will exploit, by epidermal DNA immunization) the biological function of this important group of venom toxins in vipers that are distributed throughout Africa, the Middle East, and the Indian subcontinent.

Antisnake Venom Activity of Hibiscus aethiopicus L. against Echis ocellatus and Naja n. nigricollis.

The objective of the study is to investigate whether the Hibiscus aethiopicus L. plant has neutralization activity against venoms of two clinically important snakes. The H. aethiopicus was dried and extracted with water. Different assays were performed to evaluate the plant's acute toxicity and its anti-snake venom activities. The results showed that H. aethiopicus extract alone had no effect on the viability of C(2)C(12) muscle cells, but significantly (P < .05) protected muscle cells against the toxic effects of E. ocellatus venom at 55, 150, and 300 mug/mL. The maximum protective effect of the extract was exhibited at 75 mug/mL. The extract significantly (P < .001) inhibited the cytotoxic effects of E. ocellatus venom at 300 mug/mL. All rabbits (n = 10) and guinea pigs (n = 10) were alive after the two weeks of given the lethal dosage 16 g/Kg of the H. aethiopicus extract herbal solution. No abnormal behaviour was observed of both groups of animals. All guinea pigs (n = 3) treated with venoms alone (5 mg/kg) died. However, all guinea pigs (n = 21) treated with venom (5 mg/kg) and the extract (400 to 1000 mg/kg) survived. Guinea pigs (n = 3) treated with Naja n. nigricollis venom alone (2.5 mg/kg) and guinea pigs (n = 21) venom with the extract (400 to 1000 mg/kg) died. The H. aethiopicus completely (100%) blocked the haemorrhagic activity of E. ocellatus in the egg embryo at 3.3 mg/mL of extract. These findings suggest that H. aethiopicus may contain an endogenous inhibitor of venom-induced haemorrhage.

Neutralisation of venom-induced haemorrhage by IgG from camels and llamas immunised with viper venom and also by endogenous, non-IgG components in camelid sera.

Envenoming by snakes results in severe systemic and local pathology. Intravenous administration of antivenom, prepared from IgG of venom immunised horses or sheep, is the only effective treatment of systemic envenoming. Conventional antivenoms, formulated as intact IgG, papain-cleaved (Fab) or pepsin-cleaved F(ab')2 fragments, are however ineffective against the local venom effects because of their inability to penetrate the blood/tissue barrier. We have embarked on a new research program to examine (i) whether the unusually small (15 kDa) antigen-binding fragment of camelid heavy chain IgG (V(H)H) can be exploited to neutralise the local effects of envenoming and (ii) whether a novel antivenom to treat both the systemic and local effects of envenoming can be formulated by combining anti-snake venom V(H)H and conventional F(ab')2. In this preliminary study, we demonstrate that camels and llamas respond to immunisation with Echis ocellatus venom with high antibody titres and broad antigen specificity. These encouraging immunological results were matched by the successful elimination of venom-induced haemorrhage by IgG from the venom-immunised camels and llamas. Unexpectedly, we report for the first time that camelid serum contains a non-IgG, highly potent inhibitor of venom-induced haemorrhage.

Antibody zymography: a novel adaptation of zymography to determine the protease-neutralising potential of specific antibodies and snake antivenoms.

A common problem in the development of antibody-based therapeutics is the selection, usually from a large population, of specific antibodies with the desired function. One of our research objectives is to identify antibodies capable of neutralising the most important haemorrhagic and haemostasis-disruptive proteases from viper venom. Here, we describe a modification of conventional gelatin-zymography that permits the identification of antibodies capable of neutralising gelatinolytic proteases. We demonstrate that the gelatinolytic activity of viper venom proteases is neutralised by addition of viper antivenom to the matrix of conventional gelatin-zymograms. Venom protein gelatinolytic activity was unaffected by inclusion of antibody from control, non-immunised animals or immunoglobulin-depleted serum. The application of this antibody zymogram technique for future research on snake venoms is evaluated in the context of identified limitations.

Cloning of a prothrombin activator-like metalloproteinase from the West African saw-scaled viper, Echis ocellatus.

Systemic envenoming by the saw-scaled viper, Echis ocellatus, is responsible for more deaths than any other snake in West Africa. Despite its medical importance, there have been few investigations into the toxin composition of the venom of this viper. Here we describe the isolation of E. ocellatus venom gland cDNAs encoding a protein of 514 amino acids that showed 91% sequence similarity to Ecarin, a prothrombin-activating metalloproteinase from the venom of the East African viper, E. pyramidum leakeyi, that induces severe consumption coagulopathy. Structural similarities between the E. ocellatus metalloproteinase and analogues in venoms of related vipers suggest that antibodies raised to phylogenetically conserved E. ocellatus metalloproteinase domains may have potential for cross-specific and cross-generic neutralisation of analogous venom toxins.

Novel sequences encoding venom C-type lectins are conserved in phylogenetically and geographically distinct Echis and Bitis viper species.

Envenoming by Echis saw scaled vipers and Bitis arietans puff adders is the leading cause of death and morbidity in Africa due to snake bite. Despite their medical importance, the composition and constituent functionality of venoms from these vipers remains poorly understood. Here, we report the cloning of cDNA sequences encoding seven clusters or isoforms of the haemostasis-disruptive C-type lectin (CTL) proteins from the venom glands of Echis ocellatus, E. pyramidum leakeyi, E. carinatus sochureki and B. arietans. All these CTL sequences encoded the cysteine scaffold that defines the carbohydrate-recognition domain of mammalian CTLs. All but one of the Echis and Bitis CTL sequences showed greater sequence similarity to the beta than alpha CTL subunits in venoms of related Asian and American vipers. Four of the new CTL clusters showed marked inter-cluster sequence conservation across all four viper species which were significantly different from that of previously published viper CTLs. The other three Echis and Bitis CTL clusters showed varying degrees of sequence similarity to published viper venom CTLs. Because viper venom CTLs exhibit a high degree of sequence similarity and yet exert profoundly different effects on the mammalian haemostatic system, no attempt was made to assign functionality to the new Echis and Bitis CTLs on the basis of sequence alone. The extraordinary level of inter-specific and inter-generic sequence conservation exhibited by the Echis and Bitis CTLs leads us to speculate that antibodies to representative molecules should neutralise the biological function of this important group of venom toxins in vipers that are distributed throughout Africa, the Middle East and the Indian subcontinent.

Molecular cloning of phospholipases A(2) from venom glands of Echis carpet vipers.

Venom toxin-specific antibodies offer a more rational treatment of snake envenoming than conventional antivenom. Here, we describe novel cDNAs encoding phospholipase A(2) (PLA(2)) isoforms from venom gland RNA of Echis pyramidum leakeyi (Epl), Echis sochureki (Es) and Echis ocellatus (Eo). The deduced amino acid sequences of these cDNAs encoded proteins with high overall sequence identity to the viper group II PLA(2) protein family, including the 14 cysteine residues capable of forming seven disulphide bonds that characterize this group of PLA(2) enzymes. Comparison of the PLA(2) sequences from Echis with those from related vipers failed to make significant geographic, taxonomic or PLA(2)-function distinctions between these Echis PLA(2) isoforms. However, their deduced hydrophilicity profiles revealed a conserved tertiary structure that we will exploit, by epidermal DNA immunization, to generate PLA(2)-neutralizing antibodies with polyspecific potential.

Methods of H-reflex evaluation in the early stages of Parkinson's disease.

Differentiating the early stages of Parkinson's disease from the normal consequences of aging or from other common neurologic conditions can be diagnostically problematic. The purpose of this study was to compare methodologies for measuring motor neuron excitability of Parkinson's disease patients with a control group. H-reflexes were monitored in 16 patients diagnosed in the early stages of Parkinson's disease (Hoehn & Yahr stages I and II) compared with 30 subjects who were disease free. Methods of measurement included H-reflex latencies, the relative values of maximum H-reflexes to maximum direct motor responses (H-to-M ratio), the relative values of H-reflex amplitudes during vibration compared with control H-reflex amplitudes (Hv-to-Hc ratio), and double-stimulation H-reflex recovery curves using different interstimulus interval parameters. No significant differences were observed for the H-to-M or Hv-to-Hc ratios, or for the H-reflex latencies. The H-reflex recovery curves for the patients with Parkinson's disease demonstrated significantly greater ratio amplitudes than the control group during the double-stimulus responses between the 150-msec and 700-msec interstimulus intervals. Although comparisons of simple H-reflexes and H-reflexes during vibration did not differentiate the patients in the early stages of Parkinson's disease from the control group, the double-stimulation paradigm was a sensitive method for detecting early diagnoses of this disease.