The Emirates Mars Mission.

The Emirates Mars Mission (EMM) was launched to Mars in the summer of 2020, and is the first interplanetary spacecraft mission undertaken by the United Arab Emirates (UAE). The mission has multiple programmatic and scientific objectives, including the return of scientifically useful information about Mars. Three science instruments on the mission's Hope Probe will make global remote sensing measurements of the Martian atmosphere from a large low-inclination orbit that will advance our understanding of atmospheric variability on daily and seasonal timescales, as well as vertical atmospheric transport and escape. The mission was conceived and developed rapidly starting in 2014, and had aggressive schedule and cost constraints that drove the design and implementation of a new spacecraft bus. A team of Emirati and American engineers worked across two continents to complete a fully functional and tested spacecraft and bring it to the launchpad in the middle of a global pandemic. EMM is being operated from the UAE and the United States (U.S.), and will make its data freely available.

The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

An evaluation of the effects of high-dose fexofenadine on the central nervous system: a double-blind, placebo-controlled study in healthy volunteers.

BACKGROUND: As regards central nervous system (CNS) effects there are three types of antihistamines. Those that cross the blood-brain barrier and cause widespread impairment of cognitive and psychomotor function; those that cross into the brain and, although without much impairment at low clinical doses, have a dose-related relationship to impairment; and those that do not cross into the brain and therefore possess no intrinsic potential for impairing CNS function. OBJECTIVE: [corrected] To investigate the acute effects of fexofenadine (360 mg) on various aspects of cognitive and psychomotor function in comparison to placebo and promethazine (positive internal control), an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Fifteen healthy volunteers received fexofenadine 360 mg, promethazine 30 mg and placebo in a 3-way cross-over, double-blind study. For each treatment condition, subjects were required to perform a series of tests of cognitive function and psychomotor performance at baseline and 1, 3, 5 and 7 h post-dose. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking task (CTT) and a subjective assessment of sedation (LARS). RESULTS: Fexofenadine was not distinguishable from placebo in any of the objective and subjective tests for up to seven hours following drug administration. However, all measures were significantly impaired following the administration of promethazine, which confirms the sensitivity of the test battery for sedation. The effects of fexofenadine and placebo were not significantly different from one another, whereas promethazine caused an overall reduction in CFF thresholds when compared to placebo (P < 0.05). There was an overall significant increase (impairment) in recognition, motor and total reaction time (P < 0.05), and both the tracking accuracy and reaction time aspects of CTT were significantly impaired (P < 0.05) following the administration of promethazine. In contrast, the effects of fexofenadine could not be distinguished from the placebo condition. Subjective ratings of sedation were significantly higher with promethazine when compared to placebo (P < 0.05) and fexofenadine (P< 0.05). CONCLUSIONS: Fexofenadine at a dose of 360mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg. The identification of an antihistamine (fexofenadine) devoid of central effects even at supraclinical doses separates it from currently available first and second generation drugs with no objective evidence of CNS side-effects on cognition and psychomotor function, and highlights the need for the introduction of a third generation of non-sedative antihistamines.

An investigation into the effects of cetirizine on cognitive function and psychomotor performance in healthy volunteers.

OBJECTIVE: The cognitive and psychomotor effects of 2.5, 5 and 10 mg cetirizine, a second-generation H1 receptor antagonist, were compared with loratadine 10, 20 and 40 mg, promethazine 25 mg and placebo in 24 healthy volunteers in a double-blind, randomised cross-over study. METHODS: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3 and 6 h post-dose. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking task (CTT) and assessment of subjective sedation (LARS). RESULTS: Cetirizine and loratadine at all doses tested were not significantly different from placebo in any of the tests used. However, as expected for a verum, all measures with the exception of CTT were significantly disrupted by promethazine (P < 0.05). Promethazine caused a reduction in CFF threshold at all test points; these differences were significant at 3 h and 6 h post-dose (P < 0.05). There was also a significant increase in total reaction time at 3 h post-promethazine administration. Subjective reports of sedation were significantly greater following the administration of promethazine at all time points (P < 0.05). CONCLUSIONS: These results allow the conclusion that cetirizine at its recommended therapeutic dose of 10 mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the positive control, promethazine 25 mg.

The acute and sub-chronic effects of levocetirizine, cetirizine, loratadine, promethazine and placebo on cognitive function, psychomotor performance, and weal and flare.

AIM: To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments. METHODS: Twenty healthy volunteers (18-50 years) received L-CTZ 5mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100 mg/ml histamine solution at baseline and at 1, 2, 3 ,4, 6, 8, 10 and 122 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit. RESULTS: The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). L-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, L-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4. CONCLUSIONS: In a study where the psychometric assessments were shown to be sensitive to impairment, L-CTZ 5 mg was found following both initial and repeated doses, but also to be demonstrably free from disruptive and sedative effects on objective measures of psychomotor and cognitive function. Similarly, CTZ showed evidence of pronounced antihistaminic activity and significantly reduced weal and flare scores after both acute and repeated doses, again without evidence of cognitive or psychomotor impairment. LOR also was non-sedative but the antihistaminic reaction was demonstrably weak.

The effects of single and repeated administration of ebastine on cognition and psychomotor performance in comparison to triprolidine and placebo in healthy volunteers.

OBJECTIVE: The cognitive and psychomotor effects of 10 mg, 20 mg and 30 mg ebastine, a second generation H1-receptor antagonist, were compared with sustained release triprolidine 10 mg (as a verum) and placebo in 10 healthy volunteers in a double-blind, randomised cross-over study. METHODS: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1 h, 2 h, 4 h and 8 h post-dose on days 1 and 5. The test battery consisted of critical flicker fusion, choice reaction time, simulated car tracking task, Sternberg memory scanning task, assessment of subjective sedation (LARS) and subjective evaluation of sleep (LSEQ). RESULTS: Ebastine at all doses investigated was not statistically significant from placebo in any of the objective tests used. However, as expected for a positive internal control, a number of objective measures were significantly disrupted by triprolidine (p < 0.05). Triprolidine produced an overall increase of the peripheral reaction time component of the simulated car tracking task (SCTT), the difference with placebo reaching statistical significance on day 1, 8 h post-dose (p < 0.05). The mean tracking accuracy scores were also significantly impaired following the administration of triprolidine after 8h on day 1 (p < 0.05). Triprolidine also produced a clear decrement on the SMST (Sternberg Memory Scanning Task), which was significantly different from placebo, at 4 h and 8 h post-dose on day 1. Subjective reports of sedation (LARS) were significantly greater at 2 h and 4 h following triprolidine administration on day 1 and ebastine (30 mg) was rated as sedative 4 h following administration on day 5. The perceived sedative activity of ebastine 30 mg was also reflected in the subjective reports on the LSEQ on day 1 (p < 0.05). CONCLUSIONS: These results allow the conclusion that ebastine, at its recommended therapeutic doses of 10-20 mg, is demonstrably free from impairment on objective aspects of psychomotor and cognitive function in a study where the psychometric assessments were shown to be sensitive to disruptive effects, as evidenced by the action of the positive control, triprolidine 10 mg.

Sedation and antihistamines: a review of inter-drug differences using proportional impairment ratios.

The use of antihistamines (AHs) has until recently been associated with a number of undesirable side effects, the most troublesome of which is sedation. There are two aspects to sedation. The first, an objectively determined measure based on the results of psychometric tests from controlled trials, and the second, the subject's response to the administration of a drug. Since AHs are largely used in ambulant patients, a complete evaluation of sedation should be performed through standardised objective and subjective tests, shown to be sensitive to the central effects of AHs.An extensive review of the literature identified 76 studies of H(1) receptor antagonists in healthy volunteers, in which assessment of sedation was the primary objective. Results from studies published in peer-reviewed journals which employed a placebo condition as well as a positive internal control using a crossover design were analysed to determine the extent to which a particular antihistamine produced impairments on a battery of psychometric tests. The impairment index for each antihistamine was calculated and subsequently compared with the impairment index obtained for all other AHs.The calculation of this proportional impairment ratio enabled the sedative potential of an individual antihistamine to be identified relative to all other AHs and thus allowed the ranking of AHs with respect to their ability to cause impairments of cognitive and psychomotor function.Findings from this review clearly demonstrate that there are distinct classes of AHs with respect to their ability to impair cognitive function and psychomotor performance. Copyright 2000 John Wiley & Sons, Ltd.

Antihistamines: models to assess sedative properties, assessment of sedation, safety and other side-effects.

Behavioural changes are produced by any drug that enters the central nervous system. These psychoactive effects include changes in alertness, concentration, attention, memory, cognition, psychomotor accuracy, skilled performance and affect. Changes in psychological performance may affect the safety of both the individuals taking the drug and of those people coming into contact with them. The aims of psychopharmacological performance tests are to describe the nature, extent and severity of these changes and identify drugs without deleterious effects upon performance. Use of traditional antihistamines has until recently been associated with a number of undesirable side-effects, the most troublesome of which is sedation. There are two aspects to sedation. Firstly, an objectively determined one based on the results of psychometric tests from controlled trials and secondly, the subjects response to the administration of a drug. Although the second generation of antihistamines have a much more favourable therapeutic index, use of these agents has also been reported to cause varying degrees of sedation. As antihistamines are largely used by ambulant patients, a complete evaluation of sedation should be performed through standardized objective tests, shown to be sensitive to the central effects of antihistamines as well as reliable ratings of subjective experiences. An extensive review of the literature has identified a number of tests which appear to be sensitive to the central effects of antihistamines. These include tests of psychomotor performance, sensori-motor co-ordination speed, information processing, sensory skills as well as physiological measures and subjective rating scales. Using this battery of cognitive and psychomotor tests, it is evident that only a very limited number of antihistamines can claim to be virtually free of both objective and subjective sedative effects, although the second generation of antihistamines are generally less impairing than the original ones; when prescribed at their recommended doses.

A double-blind, placebo-controlled investigation of the effects of fexofenadine, loratadine and promethazine on cognitive and psychomotor function.

AIMS: To assess whether fexofenadine in a range of doses from 80 to 180 mg has any disruptive effects on aspects of psychomotor and cognitive function in comparison with placebo, loratadine and promethazine, an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Twenty-four healthy volunteers received fexofenadine 80 mg, 120 mg and 180 mg, loratadine 10 mg, promethazine 30 mg (as a positive internal control) and placebo in a six-way crossover, double-blind study. Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3, 6, 9, 12 and 24 h post dose. The test battery included critical flicker fusion (CFF), choice reaction time (CRT) and assessment of subjective sedation (LARS). Overall levels of activity were monitored by means of wrist mounted actigraphs throughout each of the 24 h experimental periods. RESULTS: Fexofenadine at all doses tested was not statistically different from placebo in any of the tests used and loratadine did not cause any significant impairment of cognitive function. Significant impairments were found following promethazine. Promethazine caused a significant reduction in CFF threshold and this effect was evident up to 12 h post dose (P<0.05). There was a significant increase in recognition reaction time at 3 and 6 h post promethazine administration, and the drug caused a significant (P<0. 002) increase in the percentage of 'sleep-like' activity from actigraph records during the daytime. CONCLUSIONS: Fexofenadine at doses up to 180 mg appears free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg.

Immuno-histochemical analysis of estrogen receptors on the malignant gallbladder tissue.

Sex steroids play an important part in the functioning of normal gallbladder, formation of gallstones and possibly in the pathogenesis of gallbladder cancer. Steroids receptors have been previously demonstrated on normal and malignant gall bladder tissues. To study this phenomenon further, we correlated clinicopathological features and survival with estrogen receptor (ER) status of the tumour in 30 patients with histologically-proven adenocarcinoma of the gallbladder. Estrogen receptor assay was performed immuno-histochemically utilizing Universal Immunoperoxidase Staining Kit. Tumor tissue was obtained either surgically or with fine needle aspiration of the gallbladder mass. There were 27 females and 3 males. Eighteen patients had estrogen receptors expressed on the malignant tissue, 12 were negative. Comparison of clinicopathological characteristics and survival between the two groups demonstrated no significant difference in gender, mean age, marital status and parity. Similarly, presence of gallstones, histologic grade or survival did not correlate with the estrogen receptor status. There is, however, a trend in favour of poorly differentiated tumors being more often receptor negative. Further studies are necessary to elucidate the biologic significance of these receptors.

The effects of cigarette smoking on overnight performance.

Fifteen healthy smokers and 15 non-smokers were enrolled into this study investigating the effects of smoking on overnight performance. Subjects arrived at the test centre at 1930 hours and were assessed at baseline (2000 hours) and at 2200, 0000, 0200, 0400, 0600, and 0800 hours on a battery of tests (including Critical Flicker Fusion, CFF; Choice Reaction Time, CRT; Compensatory Tracking Task, CTT; Short Term Memory Task, STM; and the Line Analogue Rating Scale, LARS). Results showed that the performance of the smokers was more consistent with baseline measures than that of the non-smokers, which became more impaired throughout the night on a number of tasks [CFF (P < 0.005), Total Reaction Time (TRT, P < 0.05), CTT (P < 0.05) and the Reaction Time (RT) aspect of the CTT task (P < 0.0005)]. The Recognition Reaction Time (RRT) aspect of the CRT task showed that the performance of the non-smokers became more impaired from baseline (P < 0.005), while that of the smokers remained at baseline levels until 0400 hours, when it deteriorated to become comparable to that of the non-smoking controls. Subjective sedation ratings (LARS) resulted in comparable levels of impairment for both study groups (P < 0.00005). Findings from the STM task failed to reach significance. These data suggest that when performance is being measured overnight, smokers show little or no impairment, whilst the performance of non-smokers showed performance decrements.

Differing features of proteins in membranes may result in antioxidant or prooxidant action: opposite effects on lipid peroxidation of alcohol dehydrogenase and albumin in liposomal systems.

The influence of 3 thiol-containing compounds, bovine serum albumin (fatty acid free: BSA), glutathione (GSH) and yeast alcohol dehydrogenase (YADH) on lipid peroxidation in multilamellar liposomes, prepared from ox-brain phospholipid, was investigated. Thiol-compounds were added either before liposome formation, or after liposome formation; and their effects compared to a positive control. Bovine serum albumin (BSA), an acidic hydrophilic protein, displays a small, concentration dependent, antioxidant effect when added to preformed liposomes. A much larger antioxidant effect was observed when the BSA was entrapped inside the liposome, by adding BSA just prior to liposome preparation. In contrast, a Zn(2+) containing redox enzyme, YADH, a basic hydrophobic membrane-associating protein, displays a large pro-oxidant effect at much lower concentrations especially when entrapped inside the liposome. This was observed also with GSH; but per mole of -SH, YADH was about 18 times as powerful a pro-oxidant perhaps because of structural changes to the membrane. Oxidized glutathione and N-acetylcysteine were also pro-oxidant (cysteine and cystine showed little effect). Formation of thiyl radicals may occur in the presence of iron ions with these pro-oxidant sulphur-containing compounds. Partial protection against lipid peroxidation was observed with EDTA, desferrioxamine and protoporphyrin (IX), potent iron-chelating agents.

Clinicopathological features and management of immunoproliferative small intestinal disease and primary small intestinal lymphoma in Pakistan.

This study was performed to confirm the existence of immunoproliferative small intestinal disease (IPSID) in Pakistan. Clinicopathological features of 12 patients with histologically confirmed disease were analysed. Patients were mostly young males with median age of 24.6 years. Two thirds belonged to poor socioeconomic class. Main presenting features were chronic diarrhoea and weight loss. Eleven patients had radiologic evidence of malabsorption syndrome. Endoscopic findings of mucosal thickening, edema, and flattened villi were present in the majority. Patients had both secretory and non-secretory types of disease. Six patients presented with stage A disease. Four responded to antibiotics or steroids, although mucosal abnormalities persisted in three. Two stage A patients evolved into stage C disease, one was lost to follow-up, the other is alive with disease. Three patients presented with stage B disease. Two responded completely to chemotherapy, the third refused treatment and expired after 16 months. Three patients had stage C disease at diagnosis. They received aggressive combination chemotherapy and remain in complete remission with a median follow-up of 2.2 years. This is the first series of patients with IPSID reported from Pakistan. Clinicopathological features and therapeutic results are consistent with the experience elsewhere. Increased awareness may result in early diagnosis and better management.

Correlation of endoscopic and histological diagnosis in upper gastrointestinal lesions.

A correlation between endoscopic and histological diagnosis was studied in 240 patients undergoing upper gastrointestinal endoscopy for dyspeptic symptoms. The biopsies from one or all the three sites were taken from oesophagus (158), stomach (193) and duodenum (146) according to the presenting symptoms of the patients. There was a better correlation between endoscopic and histological diagnosis when a positive finding was seen by the endoscopists as compared to when the endoscopy revealed no abnormality. One out of six benign looking ulcers in oesophagus and 1 out of 9 benign looking gastric ulcers turned out on endoscopy, to be malignant on subsequent histology. Inflammation of oesophagus, stomach and duodenum were the most commonly missed lesions on endoscopy.

Ulcerative colitis in Karachi.

Experience of 189 patients with non-specific ulcerative colitis has been reviewed. The majority of patients was in the 21-30 year age group, and neither sex predominated. Seventy-two percent had mild to moderate disease. The disease was mainly confined to the left colon (60%) and 13% had total colitis.