Clinical outcomes of COVID-19 in hemodialysis patients.

Background: The coronavirus disease 2019 (COVID-19) is known for its effects on the respiratory system. Three years after the pandemic morbid and mortal consequences, growing evidence is showing that the disease also has adverse outcomes and complications on additional organs including the kidneys. This study aims at investigating the effects of COVID-19 on hemodialysis patients receiving services at Palestine Medical Complex (PMC) kidney dialysis department, and to identify mortality related risk factors. Methods: In April 2022, data was collected using the electronic medical records system for the dialysis department at PMC. The study included all PMC hemodialysis patients that were infected with COVID-19 between January 2020-April 2022. The collected data included patient demographics, clinical features, laboratory tests, dialysis frequency and the disease outcome. Results: The results showed that the patients' outcomes and dialysis frequency were impacted by their blood urea nitrogen (BUN), serum creatinine (SCr) and calcium levels. About one third of the study population died after being infected with COVID-19. The frequency of dialysis was also affected by the presence of comorbidities like hypertension, diabetes mellitus (DM) and myocardial infarction (MI). Conclusion: This study found that there was a high mortality rate within the hemodialysis patients infected with COVID-19. Having comorbidities affected the frequency of dialysis following COVID-19 infection. Dialysis patients should be protected from infections such as COVID-19 and their comorbidities should be monitored and kept under control as much as possible.

Alarmingly high prevalence of high-risk drug use among palestinian males: a cross-sectional study.

BACKGROUND: The unique socioeconomic context in Palestine, characterized by political and economic tensions, creates conditions that facilitate the spread of illicit drug use among Palestinians. This paper presents findings from a 2017 survey of high-risk drug use (HRDU) among males in four regions in Palestine: the West Bank (north, middle, and south) and the Gaza Strip. These findings are essential for developing effective policies to respond to the increasing use of drugs among Palestinians. METHODS: Eligible participants were males aged 15 years and above who used at least one drug other than non-synthetic hashish or marijuana during the previous week. Participants underwent a face-to-face interview and had their drug use verified by urinalysis. Data were collected using respondent-driven sampling and data were analyzed using the successive sampling estimator. Multivariate regression analysis was conducted to examine factors associated with ever seeking rehabilitation services for illicit drug use in the West Bank and the Gaza Strip. RESULTS: A total of 400 males who use drugs were sampled in Gaza, plus 299 in the south, 300 in the north, and 299 in the middle region of the West Bank. It is estimated that there are 26,500 male HRDUs in Palestine comprising 1.8% of the male population aged 15 and above. Findings indicate that polydrug use is a serious issue in Palestine, especially in the West Bank, and that synthetic marijuana is prevalent among teenagers and young adults. CONCLUSIONS: Palestine must strengthen its national efforts to scale up harm reduction and treatment and care options for people suffering from drug use disorders, especially those involved in polydrug use. Additional measures are needed to prevent substance use among children and youth, support the families of people who use drugs, and ensure the continuity of HRDU services during emergencies.

Israel's spatial and a-spatial strategy of dispossessing the Jordan Valley's Palestinian Inhabitants.

The Jordan Valley's territorial extent is defined for this study as an elongated stretch of border area, located west of Jordan's boundary with the West Bank, Palestine. This region along with the West Bank was conquered by the Israeli Army during the June 1967 War and has been held by Israel since. Almost 88% of its 200,000 Palestinian population then living in the region were expelled and turned overnight into refugees in Jordan and elsewhere. In the subsequent 56 years since, the region, declared by Israel as a highly militarized zone, has often been discursively publicized as the front line of Israel's eastern defense. This paper seeks to refute such a notion that indirectly gave Israel justification to subject the remaining Palestinian inhabitants residing there (currently numbering ca. 60,000) to a harsh discriminatory regimen of surveillance and control under military occupation. At the same time, the Israeli government has over decades privileged the ca. 10,000 incoming Jewish settlers, now living in some 30 Israeli Jewish settlements in the Jordan Valley. Employing a grounded theory approach in our study provided an opportunity for the local Palestinians to have their voices heard, shedding needed analytical light on their difficult situation on the ground.

Screening of Antioxidant and Antimicrobial Activity of Micromeria fruticosa serpyllifolia Volatile Oils: A Comparative Study of Plants Collected from Different Regions of West Bank, Palestine.

BACKGROUND: The investigation of volatile oils used in traditional medicine is vital to enhance the quality of healthcare. This study is aimed at screening the antioxidant and antimicrobial properties of Micromeria fruticosa serpyllifolia volatile oils from three different regions in Palestine (north, middle, and south). METHODS: Volatile oils of three samples of M. fruticosa serpyllifolia were extracted using the microwave-ultrasonic apparatus. The antioxidant activity of the volatile oils was assessed by inhibition of DPPH free radical. The antimicrobial activity was examined using the broth microdilution method. Assessment of antifungal activity was achieved using the agar dilution method. RESULTS: Screening the biological activity of plant extracts revealed that the sample from Ramallah (middle region) possessed the most potent antioxidant activity with an IC50 value of 0.45 µg/mL. The three samples exhibited broad antimicrobial activity and showed potential antifungal activity. The sample from the southern region showed the highest potency against Shigella sonnei with the lowest reported MIC; the sample from the northern region demonstrated the least potency against clinical isolate of Staphylococcus aureus and "methicillin"-resistant Staphylococcus aureus. CONCLUSIONS: The study showed that Micromeria fruticosa serpyllifolia volatile oil samples from different regions in Palestine possess different potential antioxidant and antimicrobial activities that were in line with traditional uses of the plant extracts.

Variability of Chemical Compositions and Antimicrobial and Antioxidant Activities of Ruta chalepensis Leaf Essential Oils from Three Palestinian Regions.

INTRODUCTION: Interest in essential oils was recently revived with their popularity increasing in medicine, pharmacy, and aromatherapy. This study was performed to identify the chemical compositions of the essential oil of Ruta chalepensis growing wildly in three regions in Palestine and to assess and compare their antimicrobial and antioxidant activities. METHODS: Identification of the essential oil was performed by gas chromatography coupled with mass spectrometry (GC-MS). Antimicrobial activity was tested against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Methicillin-Resistant Staphylococcus aureus, and Candida albicans by using minimum inhibitory concentration (MIC) assay, while antioxidant activity was analyzed by using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. RESULTS: The essential oils of R. chalepensis from Jerusalem and Hebron regions have almost identical components; the major compounds identified were linalyl acetate and ß-linalool; these essential oils exerted potential antioxidant and antibacterial activities. On the other hand, the major components of the plant essential oil from Jenin region were 2-undecanone and 2-nonanone, which exhibited potential antifungal activity. CONCLUSIONS: The phytoconstituents and antioxidant and antimicrobial properties of the essential oil of R. chalepensis from different regions in Palestine were established in this study. The obtained results indicate possible applications for R. chalepensis in the treatment of various infectious and noninfectious diseases.

Chemical composition, anthelmintic, antibacterial and antioxidant effects of Thymus bovei essential oil.

BACKGROUND: It has been recently recognized that oxidative stress, helminth and microbial infections are the cause of much illness found in the underdeveloped, developing and developed countries. The present study was undertaken to identify the chemical composition, and to assess anthelmintic, antimicrobial and antioxidant effects of Thymus bovei essential oil. METHODS: The chemical composition of the essential oil was analyzed using gas chromatography mass spectrometry (GC-MS). Antimicrobial activity was tested against the selected strains from American Type Culture Collection (ATCC) and clinical isolates such as Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Methicillin Resistant Staphylococcus aureus, Candida albicans using MIC assay. The anthelmintic assay was carried out on adult earthworm (Pheretima posthuma), while antioxidant activity was analyzed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. RESULTS: Trans-geraniol (35.38 %), α-citral (20.37 %) and ß-citral (14.76 %) were the major compounds comprising 70.51 % of the essential oil. Our results showed that T. bovei essential oil exhibited strong anthelmintic activity, even higher than piperazine citrate, the used reference standard, with potential antioxidant activity almost equal to the Trolox standard. Furthermore, T. bovei essential oil had powerful antibacterial and antifungal activities against the studied pathogens. CONCLUSION: Essential oil of T. bovei exerted excellent antioxidant, antimicrobial, and anthelmintic activities. Moreover, this study found that T. bovei volatile oil contains active substances that could potentially be used as natural preservatives in food and pharmaceutical industries, these substances could also be employed for developing new anthelmintic, antimicrobial and antioxidant agents.

Tolfenamic acid reduces tau and CDK5 levels: implications for dementia and tauopathies.

Tau and its aggregates are linked to the pathology of Alzheimer's disease (AD) and other tauopathies and, therefore, are explored as therapeutic targets for such disorders. Tau belongs to a family of microtubule-associated proteins that promote microtubule assembly. When hyperphosphorylated, tau becomes prone to forming aggregates. Increased brain levels of hyperphosphorylated tau correlate with dementia. Specificity protein 1 (Sp1), a transcription factor elevated in AD, is responsible for the transcription of AD-related proteins including the amyloid precursor protein, tau, and its cyclin-dependent kinase-5 (CDK5) activators. Tolfenamic acid promotes the degradation of Sp1, our previous studies demonstrated its ability to down-regulate transcriptional targets of Sp1 like amyloid precursor protein and reduce amyloid beta (Aß), the main component of AD plaques. In this study, we administered tolfenamic acid daily to hemizygous R1.40 transgenic mice for 34 days, and examined tau and CDK5 gene and protein expression within the brain. Our results demonstrate that tolfenamic acid lowers tau mRNA and protein, as well as the levels of its phosphorylated form and CDK5. Thus, we present a drug candidate that inhibits the transcription of multiple major intermediates in AD pathology, thereby helping uncover a new mechanism-based approach for targeting AD. A new approach for targeting Alzheimer's disease through a transcriptional based mechanism is presented. Tolfenamic acid lowers the levels of tau, which forms pathological aggregates in Alzheimer's disease and other tauopathies, by promoting the degradation of the transcription factor specificity protein 1 which regulates tau transcription.

Reduction of amyloid-ß deposition and attenuation of memory deficits by tolfenamic acid.

We have previously reported that tolfenamic acid treatment decreases the amyloidogenic proteins in C57BL/6 and in old hemizygous R1.40 transgenic mice via the degradation of the transcription factor specificity 1 protein (Sp1). The lowering of amyloid-ß protein precursor (AßPP) and amyloid-ß (Aß) in hemizygous R1.40 transgenic mice was accompanied by reversal of the identified spatial reference and working memory deficits observed in the mouse model. In this study, we examined the ability of tolfenamic acid to reduce the amyloid plaque burden, as well as to ameliorate spatial learning and memory deficits in homozygous R1.40 mice. Results from immunohistochemical analysis indicated that tolfenamic acid treatment resulted in a profound decrease in cerebral Aß plaque burden that was accompanied by improvements in spatial working memory assessed by spontaneous alternation ratio in the Y-maze. These results provide further evidence that tolfenamic acid could be utilized as a repurposed drug to modify Alzheimer's disease pathogenesis.

Tolfenamic acid downregulates BACE1 and protects against lead-induced upregulation of Alzheimer's disease related biomarkers.

Environmental exposure to lead (Pb) early in life results in a latent upregulation of genes and products associated with Alzheimer's disease (AD), particularly the plaque forming protein amyloid beta (Aß). Furthermore, animals exposed to Pb as infants develop cognitive decline and memory impairments in old age. Studies from our lab demonstrated that tolfenamic acid lowers the levels of the amyloid ß precursor protein (APP) and its aggregative cleavage product Aß by inducing the degradation of the transcription factor specificity protein 1 (Sp1). These changes were accompanied by cognitive improvement in transgenic APP knock-in mice. In this study, we examined the effects of tolfenamic acid on beta site APP cleaving enzyme 1 (BACE1) which is responsible for Aß production and tested its ability to reverse Pb-induced upregulation in the amyloidogenic pathway. Mice were administered tolfenamic acid for one month and BACE1 gene expression as well as its enzymatic activity were analyzed in the cerebral cortex. Tolfenamic acid was also tested for its ability to reverse changes in Sp1, APP and Aß that were upregulated by Pb in vitro. Differentiated SH-SY5Y neuroblastoma cells were either left unexposed, or sequentially exposed to Pb followed by tolfenamic acid. Our results show that tolfenamic acid reduced BACE1 gene expression and enzyme activity in mice. In neuroblastoma cells, Pb upregulated Sp1, APP and Aß, while tolfenamic acid lowered their expression. These results along with previous data from our lab provide evidence that tolfenamic acid, a drug that has been used for decades for migraine, represents a candidate which can reduce the pathology of AD and may mitigate the damage of environmental risk factors associated with this disease.

Cellular and organismal toxicity of the anti-cancer small molecule, tolfenamic acid: a pre-clinical evaluation.

BACKGROUND/AIMS: The small molecule, Tolfenamic acid (TA) has shown anti-cancer activity in pre-clinical models and is currently in Phase I clinical trials at MD Anderson Cancer Center Orlando. Since specificity and toxicity are major concerns for investigational agents, we tested the effect of TA on specific targets, and assessed the cellular and organismal toxicity representing pre-clinical studies in cancer. METHODS: Panc1, L3.6pl, and MiaPaCa-2 (pancreatic cancer), hTERT-HPNE(normal), and differentiated/un-differentiated SH-SY5Y (neuroblastoma) cells were treated with increasing concentrations of TA. Cell viability and effect on specific molecular targets, Sp1 and survivin were determined. Athymic nude mice were treated with vehicle or TA (50mg/kg, 3times/week for 6 weeks) and alterations in the growth pattern, hematocrit, and histopathology of gut, liver, and stomach were monitored. RESULTS: TA treatment decreased cell proliferation and inhibited the expression of Sp1 and survivin in cancer cells while only subtle response was observed in normal (hTERT-HPNE) and differentiated SH-SY5Y cells. Mice studies revealed no effect on body weight and hematocrit. Furthermore, TA regimen did not cause signs of internal-bleeding or damage to vital tissues in mice. CONCLUSION: These results demonstrate that TA selectively inhibits malignant cell growth acting on specific targets and its chronic treatment did not cause apparent toxicity in nude mice.

Short-term treatment with tolfenamic acid improves cognitive functions in Alzheimer's disease mice.

Tolfenamic acid lowers the levels of the amyloid precursor protein (APP) and amyloid beta (Aß) when administered to C57BL/6 mice by lowering their transcriptional regulator specificity protein 1 (SP1). To determine whether changes upstream in the amyloidogenic pathway that forms Aß plaques would improve cognitive outcomes, we administered tolfenamic acid for 34 days to hemizygous R1.40 transgenic mice. After the characterization of cognitive deficits in these mice, assessment of spatial learning and memory functions revealed that treatment with tolfenamic acid attenuated long-term memory and working memory deficits, determined using Morris water maze and the Y-maze. These improvements occurred within a shorter period of exposure than that seen with clinically approved drugs. Cognitive enhancement was accompanied by reduction in the levels of the SP1 protein (but not messenger RNA [mRNA]), followed by lowering both the mRNA and the protein levels of APP and subsequent Aß levels. These findings provide evidence that tolfenamic acid can disrupt the pathologic processes associated with Alzheimer's disease (AD) and are relevant to its scheduled biomarker study in AD patients.

Epigenetics: a novel therapeutic approach for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid ß plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to the lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and memory and have been recently highlighted for holding promise as potential targets for AD therapeutics. Dynamic and latent epigenetic alterations are incorporated in AD pathological pathways and present valuable reversible targets for AD and other neurological disorders. The approval of epigenetic drugs for cancer treatment has opened the door for the development of epigenetic drugs for other disorders including neurodegenerative diseases. In particular, methyl donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders. This review explores the area of epigenetics for potential AD interventions and presents the most recent findings in this field.

Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice.

Alzheimer's disease (AD) is characterized by plaques of amyloid-beta (Abeta) peptide, cleaved from amyloid-beta protein precursor (AbetaPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 (SP1), and the beta amyloid precursor cleaving enzyme (BACE1). In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases.