Vitamin A and Daucus carota root extract mitigate STZ-induced diabetic retinal degeneration in Wistar albino rats by modulating neurotransmission and downregulation of apoptotic pathways.

The objective of our study was to explore the deleterious effects of diabetes on the visual functions of the retina and to address whether the administration of vitamin A and carrot root extract (CE) confer retinal protection in hyperglycemic rats via modulation of oxidative stress, biochemical alternations, and retinal neurotransmission. Fifty male Wistar albino rats weighing 180 ± 12.41 g were randomized into five groups (n = 10): controls, diabetic group (injected with 40 mg/kg dissolved in 0.1 sodium citrate buffer), diabetic group treated with vitamin A (2,500 IU/kg, low dose), diabetic group treated with vitamin (5,000 IU/kg, high dose), and diabetic groups administered CE (200 mg/kg/every other day). Our findings showed that, compared to controls, diabetic rats showed a significant decrease in their retinal thickness, increased apoptotic ganglion cells, and a noticeable degeneration of their synaptic layers. The inner retina displayed increased activity of neovascularization; however, the outer retina exhibited vacuolar degeneration of the photoreceptor cell layer. Our biochemical assessments showed reduced levels of CAT, SOD, and GST along with increased lipid peroxidation. Concurrently, cellular angiogenic and stress markers were significantly elevated associated with increased apoptotic activities as evidenced by increased expressions of annexin-V and PARP. Furthermore, the neurotransmitter content of the retina was altered in diabetic rats compared to controls and diabetic-treated groups. Paradoxically, vitamin A and CE supplementation attenuate these retinal insults in diabetic animals and normalized aforementioned assayed parameters; evidencing that both treatments exerted ameliorative impacts and restored visual functions by diminishing oxidative stress and neuronal degeneration. PRACTICAL APPLICATIONS: Diabetes is a complex disease that involves various physiological perturbations especially visual functions. In our study, we showed that vitamin A and carrot root extract (CE) confer remarkable protection against retinal degeneration in STZ-induced diabetic rats. Our findings showed that the chemical and phytochemical ingredients of the vitamin A and CE substantially attenuated the histopathological changes, oxidative stress, inflammatory reactions, and cellular death in diabetic rats. These favorable changes are attributable to the high content of retinoic acid, carotenoids, and phenolic compounds that effectively regulates the production of visual pigments, increases the antioxidant defense system, and diminishes the pro-inflammatory and apoptotic pathways. Thus, the nutritional values of vitamin A and CE represent promising therapeutic choices to mitigate the retinal-induced diabetic insults.

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Mitigation of 5-fluorouracil-induced liver damage in rats by vitamin C via targeting redox-sensitive transcription factors.

Adverse complications associated with antineoplastic drug-based cancer therapy are the major clinical drawbacks. Oxidative stress and inflammation play a major role in the damage due to cancer therapy. In the current study, we investigated the modulatory effect of vitamin C (Vit. C) on liver toxicity induced by 5-fluorouracil (5-FU) in rats. Animals were divided into four groups. Animals in group I received vehicle. Oral gavage of Vit. C (500 mg kg-1 body weight (b.wt.)) was given to the animals in group III and group IV. 5-FU (150 mg kg-1 b.wt.) was injected intraperitoneally to the animals in group II and group III. Findings of the present study revealed that oral administration of Vit. C significantly ameliorated the level of lipid peroxidation and the activity of myeloperoxidase. Vit. C administration markedly reduced the activation of nuclear factor κB and expression of cyclooxygenase 2, whereas nuclear translocation of nuclear factor erythroid 2-related factor 2 was increased. Hepatic histopathological analyses further supported the protective effect of Vit. C. Findings of the current study demonstrate that the toxic free radicals and inflammatory mediators generated due to chemotherapy play a critical role in 5-FU-induced hepatic damage. Attenuating action of Vit. C may be due to the modulation of redox-sensitive transcription factors and associated target molecules.

Taurine ameliorates 5-flourouracil-induced intestinal mucositis, hepatorenal and reproductive organ damage in Wistar rats: A biochemical and histological study.

5-Fluorouracil is one of the most commonly used anticancer drugs for the treatment of various types of cancer but has potential adverse effects such as intestinal mucositis, renal, hepatic, and reproductive organ toxicity. Attention has been given to approaches to reduce the side effects and improve the therapeutic effectiveness of chemotherapeutic drugs. In this study, we have investigated the protective effect of taurine (Tau) on 5-fluorouracil (5-FU) induced adverse effects in Wistar rats. Animals were divided into four groups with six animals (n = 6) in each group. Group I received vehicle only and served as control group. Groups II, III, and IV animals were given oral gavage of 5-FU at 50 mg/kg body weight for 4 days. Tau was given to the animals of groups III and IV 30 min prior to 5-FU administration. We observed marked elevation in the myeloperoxidase (MPO) activity after 5-FU administration, which was reversed by Tau pretreatment. Histological observation of liver, kidney, intestine, testis, and prostate revealed that 5-FU administration resulted in anomalies like distortion of normal cellular architecture, infiltration of inflammatory cells, and loss of cellular integrity. These histopathological changes were markedly suppressed by Tau treatment. In conclusion, biochemical and histological findings of this study suggest that Tau has strong preventive potential against complications of anticancer drug 5-FU and hence Tau may play an important role in combinational chemotherapy to enhance the therapeutic efficacy of anticancer drugs.

Effect of Androctonus bicolor scorpion venom on serum electrolytes in rats: A 24-h time-course study.

Black fat-tailed scorpion (Androctonus bicolor) belongs to the family Buthidae and is one of the most venomous scorpions in the world. The effects of A. bicolor venom on serum electrolytes were not known and therefore investigated in this study. Adult male Wistar rats were randomly divided into seven groups with five animals in each group. One of the groups served as control and received vehicle only. The animals in the remaining groups received a single subcutaneous injection of crude A. bicolor venom (200 µg/kg bodyweight) and were killed at different time intervals including 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after venom injection. The results showed that scorpion venom caused significant increase in serum sodium levels within 30 min after injection which slightly subsided after 1 h and then persisted over 24 h. Serum potassium levels continued to significantly increase until 4 h and then slightly subsided. There were significant decreases in serum magnesium (Mg(+)) levels following scorpion venom injection, at all the time points during the course of study. Serum calcium levels were significantly increased during the entire course of study, whereas serum chloride was significantly decreased. In conclusion, A. bicolor envenomation in rats caused severe and persistent hypomagnesemia with accompanied hypernatremia, hyperkalemia, and hypercalcemia. It is important to measure serum Mg(+) levels in victims of scorpion envenomation, and patients with severe Mg(+) deficiency should be treated accordingly.

Genetic association of catechol-O-methyltransferase val(158)met polymorphism in Saudi schizophrenia patients.

Schizophrenia is a complex neuropsychiatric disorder strongly associated with dopamine dysregulation. Catechol-O-methyl-transferase (COMT) is a candidate gene for schizophrenia that encodes an enzyme involved in the metabolic inactivation of dopamine. The COMT Val(158)Met polymorphism has been associated with schizophrenia and has significant inter- and intra-ethnic variations. We examined a possible association between the COMT Val(158)Met polymorphism and schizophrenia in Saudis, taking into account gender and functional symptoms. Saudi subjects including 172 unrelated schizophrenia patients and 177 matched controls were analyzed for allele and genotype distribution of the COMT Val(158)Met polymorphism. We found significant differences in allele and genotype frequencies between patients and controls. The frequencies of Met(158) allele (A) and genotype Val(158)Met (GA) were significantly higher in patients compared to those in controls. On the other hand, the frequencies of Val(158) allele (G) and genotype Val(158)Val (GG) were significantly higher in controls than those in patients. We found a significant association of the COMT Val(158)Met polymorphism with schizophrenia. Moreover, male patients with the COMT Val(158)Met polymorphism had increased risk for schizophrenia compared to female subjects. However, no association was noticed with the COMT Val(158)Met polymorphism and negative or positive symptoms of schizophrenia. These results provide evidence for a role of the COMT Val(158)Met polymorphism in the etiopathophysiology of schizophrenia in Saudi population. It appears that the association of the COMT Val(158)Met polymorphism with schizophrenia is mediated by gender.

Inflammation and schizophrenia: alterations in cytokine levels and perturbation in antioxidative defense systems.

OBJECTIVE: Although several theories have been proposed including developmental/neurodegenerative processes, neurotransmitter abnormalities, viral infection, and immune dysfunction, the exact causative factor of schizophrenia is unclear. A relationship between inflammation and schizophrenia has been supported by abnormal cytokine production and altered antioxidant status. This study was aimed to examine the alterations in serum oxidative-antioxidative status and cytokine levels of schizophrenic patients. METHODS: A total of 91 schizophrenic patients from Saudi Arabia and 50 age- and sex-matched healthy controls were enrolled in the present study. Fresh blood samples were collected to measure the levels of cytokines and markers of oxidative stress by spectrophotometric assays simultaneously. RESULTS: We observed that there was a significant increase in the levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 and a decrease in the levels of interferon-γ. Lipid peroxides are elevated in serum, while total-sulfhydryl levels were decreased. Also, the activities of superoxide dismutase and glutathione peroxidase were decreased, while the activities of catalase, glutathione reductase, and myeloperoxidase were found to be elevated in serum. CONCLUSION: We conclude that inflammation resulting from dysregulation of cytokines and altered antioxidant systems may play a critical role in the etiology of schizophrenia.

Tumor necrosis factor-α and -ß genetic polymorphisms as a risk factor in Saudi patients with vitiligo.

Vitiligo is an acquired depigmentary disorder of the skin, characterized by multiple susceptibility loci and genetic heterogeneity. The etiology of vitiligo is unknown but several hypotheses, including an autoimmune origin, have been proposed. Tumor necrosis factor (TNF)-α, a pleiotropic proinflammatory cytokine, has been shown to play a critical role in several autoimmune diseases including vitiligo. The aim of present study was to determine the association of TNF-α and -ß gene polymorphisms with vitiligo in Saudi patients. TNF-α and -ß genes were amplified in 123 Saudi patients and 200 matched controls using polymerase chain reaction to search for polymorphisms involved at positions -308, and intron 1 +252. The frequency of the TNF-α (-308) GA genotype was higher and the frequencies of the GG and AA genotypes were significantly lower in vitiligo patients compared to controls. These findings suggested that genotype GA-positive individuals at position -308 of TNF-α are susceptible to vitiligo, whereas the GG and AA genotypes might exert a protective effect. The frequency of allele A (TNF-α 2-allele) was significantly higher and that of allele G (TNF-α 1-allele) was lower in vitiligo patients compared to controls, indicating an association of allele A with susceptibility to vitiligo in Saudi patients. The results of our examination of TNF-ß (intron 1 +252) polymorphisms showed a significant increase in the frequency of the GG genotype and allele G (TNF-ß 1-allele) in vitiligo patients, suggesting a susceptibility of the GG genotype and allele G for vitiligo. By contrast, the high frequency of the GA genotype in controls might indicate a protective effect. The results of the present study strongly support a link between TNF-α (-308) and -ß (intron 1 +252) polymorphisms and vitiligo in Saudi patients.

The role of dihydrocodeine (DHC) metabolites in dihydrocodeine-related deaths.

The focus of this study was to report the blood and urine concentrations of dihydrocodeine (DHC) and its metabolites, dihydrocodeine-6-glucuronide (DHC6G), dihydromorphine (DHM), dihydromorphine-3-glucuronide (DHM3G), and dihydromorphine-6-glucuronide (DHM6G) in deaths involving DHC, and to report the range of concentrations detected in real cases in order to understand their contribution to DHC intoxication. Twenty-six positive postmortem cases were involved in the current study. Five cases were attributed solely to DHC intoxication, 13 cases to polydrug intoxication, and the remainder of the cases were unrelated to DHC (DHC has been detected but is unrelated to the cause of death). DHC and its glucuronide were detected in all cases investigated in blood and urine matrices. Unchanged parent drug is the most abundant analyte detected in blood samples mean and median of DHC/total DHC (DHC plus DHC6G) percentages were 63% and 72%, and DHC6G is the most abundant DHC metabolite in urine with a mean and median DHC6G/TDHC of 69% and 70%, respectively. Blood DHC concentrations ranged from 40 to 166,000 ng/mL and 200 to 159,000 ng/mL in urine. DHC6G concentrations in these cases ranged from 20 to 62,180 ng/mL in blood and 40 to 500,000 ng/mL in urine. However, DHM and its glucuronide were present at lower concentrations than DHC and its glucuronide. In the current study, it can be concluded that concentrations of DHC that cause death may be lower in polydrug intoxication. Concentrations found at autopsy overlapped between toxic and therapeutic concentrations because of the presence of other harmful substances, and death can occur with concentrations below lethal concentrations as reported in Case 1 (500 ng/mL). It has been suggested that DHM and DHM6G may play a major role in assessing the cause of death in cases where DHC is not detected and when it is detected in low concentrations. The current study does not support this hypothesis, and it can be seen clearly from the data reported here that DHM and its glucuronide were not detected where DHC was not detected. Toxic concentrations of DHM and DHM6G were identified in some of these cases; however, the concentration of DHC was enough to cause death on its own. It seems that DHM and DHM6G have less influence in causing death than the parent drug itself.

New additions to the scorpion fauna of Riyadh region, Saudi Arabia

In this work, we present additional morphological data about the scorpion fauna of Saudi Arabia. This investigation was carried out in the central region (Riyadh) of the country and identified existing and newly discovered scorpion species for taxonomic documentation while determining the medically important ones. The survey covered the entire Riyadh region, including all major districts, and collected a total of 4,164 specimens. Morphological identification of collected animals was based on identification keys. There were two species (one with a subspecies) that belonged to the family Scorpionidae, namely Scorpio maurus kruglovi (0.02 percent) and Hemiscorpius arabicus (0.05 percent). The latter, currently, is part of the Hemiscorpiidae family that had been upgraded from a subfamily. Eight more species from the Buthidae family were found: Leiurus quinquestriatus (7.20 percent), Androctonus crassicauda (17.24 percent), Androctonus bicolor (64.60 percent), Compsobuthus arabicus (3.84 percent), Compsobuthus werneri (0.94 percent), Buthacusyotvatensis nigroaculeatus (2.31 percent), Buthacusleptochelys (3.24 percent) and Orthochirus innesi (0.55 percent). The major locations of collection were the outskirts of Riyadh city and the airport vicinity. The specimens were transported from all central region areas in 124 short trips.(AU)

Morphological identification of scorpion species from Jazan and Al-Medina Al-Munawara regions, Saudi Arabia

The present work is a complementary contribution to the comprehensive study of the scorpion sting syndrome in Saudi Arabia. It deals with the identification and determination of medically important scorpions and the other ones, which were collected from two regions (Jazan and Al-Medina Al-Munawara), based on their morphology (the molecular phylogeny and venom characteristics will appear in subsequent publications). The specimens collected from those two regions were brought to the Research Center laboratories in several batches. Morphological identification of the collected specimens was done employing identification keys. There were 646 specimens collected from Jazan Region. A single species, Nebo hierichonticus (Family Diplocentridae), and five genera with four identified species, Parabuthus liosoma, Hottentotta jayakari (salei?), Compsobuthus werneri, Leiurus quinquestriatus (Vachoniolus globimanus?), Vachoniolus spp. (other species) and Orthochirus innesi (Family Buthidae), were classified as extant scorpions in the region. Three hundred and ninety-six specimens from Al-Medina Al-Munawara Region were categorized into eight groups; four of them were identified. Three buthids, Leiurus quinquestriatus, Androctonus crassicauda, Orthochirus innesi and one scorpion specimen, Scorpio maurus, were identified and classified as extant scorpions in this region. The other four species are still not completely identified. They are Vachoniolus (Buthacus minipectinibus?) globimanus? (Unidentified-1), Compsobuthus spp (arabicus?) (Unidentified-2), Compsobuthus spp (werneri?) (Unidentified-3) and a single specimen of Androctonus spp (australis?) (Unidentified-4), all of which belong to the family Buthidae.(AU)

Cerebral palsy: incidence and clinical features in Saudi Arabia.

The purpose of this work is to analyse the cerebral palsy (CP) incidence, aetiology, birthweight, types and/or subdiagnosis and associated impairments, individually or in combination, in children at Riyadh Military Hospital (RMH). The study covered the birth year period 1984 - 2003, during which 99,788 live births were recorded at Riyadh Military Hospital (RMH). Incidence ratio and clinical features of 412 positive cases of cerebral palsied children between 1 - 10 years old were investigated. Medical information was collected from patient files at the medical records department. The incidence of CP was 0.41%. The five intervals of the study period gave a pattern of decreasing percentage incidence. The case distribution according to birth weight, aetiology, duration and subdiagnoses was studied. It could be concluded that livebirth incidence of cerebral palsied patients in Saudi Arabia was relatively high as compared to most other studies. Severe disability due to cerebral palsy was associated with impairments such as mental retardation, epilepsy and visual impairments, often found in combinations.

Pharmacological characterization of rat paw edema induced by Cerastes gasperettii (cerastes) venom

Inflammatory response induced by the venom of the Arabian sand viper Cerastes gasperettii was studied by measuring rat hind-paw edema. Cerastes gasperettii venom (CgV, 3.75-240 µg/paw), heated for 30s at 97°C, caused a marked dose and time-dependent edema in rat paw. Response was maximal 2h after venom administration and ceased within 24h. Heated CgV was routinely used in our experiments at the dose of 120 µg/paw. Among all the drugs and antivenoms tested, cyproheptadine and 5-nitroindazole were the most effective in inhibiting edema formation. Aprotinin, mepyramine, dexamethasone, diclofenac, dipyridamole, Nomega-nitro-L-arginine, quinacrine, and nordihydroguaiaretic acid showed statistically (p 0.001) significant inhibitory effect, but with variations in their inhibition degree. Equine polyspecific and rabbit monospecific antivenoms significantly (p 0.001) reduced edema when locally administered (subplantar) but were ineffective when intravenously injected. We can conclude that the principal inflammatory mediators were serotonin, histamine, adenosine transport factors, phosphodiesterase (PDE), cyclooxygenase, lipoxygenase and phospholipase A2 (PLA2), in addition to other prostaglandins and cytokines.

Pharmacological characterization of rat paw edema induced by Naja haje arabica venom

This investigation was performed in order to assess the inflammatory response induced by Naja haje arabica venom (NhaV) in rat hind paw. The inflammatory response was estimated by measuring the edema with a Plethysmometer. The venom (0.625-10mug/paw) produced a dose and time-dependent increase in non-hemorrhagic paw edema. The response to NhaV was maximal within 15 min and disappeared in 24 h. Five mug/paw of NhaV was chosen to test the effect of various drugs on the edema induced by this venom. Quinacrine (QNC), a phospholipase A2 (PLA2) inhibitor, and dipyridamole (DPM), an adenosine transport inhibitor, attenuated venom-induced edema in rat paw (P<0.001). Commercially available antivenom was ineffective when administered intravenously, whereas its local administration with NhaV attenuated the edema formation (P<0.001). In conclusion, NhaV-induced edema in rat paw involves PLA2 and adenosine mechanisms. Additionally, the use of polyspecific antivenom, intravenously, was ineffective in preventing NhaV-induced edema.(AU)

Assessment of an ovine antivenom raised against venom from the desert black cobra (Walterinnesia aegyptia).

The desert black cobra (Walterinnesia aegyptia) is an elapid widely distributed throughout the deserts of Saudi Arabia and currently available antivenoms are ineffective in the treatment of its envenoming. Walterinnesia aegyptia venom was assessed for several of its physicochemical, enzymatic and biological characteristics. An antivenom was raised in sheep using a low-dose immunization schedule and digested with papain to provide Fab fragments. The antivenom neutralized all of the above enzymatic and biological activities and provided good protection in mice (ED50 0.25 g/kg), whereas the commercial polyspecific products showed only partial neutralization and did not protect mice.