The deleterious effects of sofosbuvir and ribavirin (antiviral drugs against hepatitis C virus) on different body systems in male albino rats regarding reproductive, hematological, biochemical, hepatic, and renal profiles and histopathological changes.

Sofosbuvir is one of the crucial drugs used in the treatment of chronic hepatitis C virus (HCV) in adults and children with compensated liver disease, including cirrhosis. It may be used alone or with other drugs. Ribavirin is an antiviral medication used to treat HCV infection. It is not effective when used alone and must be used in combination with other medications, such as sofosbuvir. This study pertains to a comprehensive assessment of the deleterious effects of sofosbuvir (an antiviral drug against chronic HCV) or sofosbuvir combined with ribavirin (an antiviral drug against RNA and DNA viruses) on several biological activities of the body, including hematological, hormonal, biochemical, histological, and immunohistochemical examinations during a long-standing period on male healthy rats. In addition, fertility assessments were performed, including sperm collections and semen parameter investigations. This study was conducted on 21 male rats divided into three equal groups. Group I (control group) received distilled water; group II (sofosbuvir group) received sofosbuvir (4 mg/kg); and group III (sofosbuvir + ribavirin) received sofosbuvir (4 mg/kg) plus ribavirin (30 ml/kg). All groups received the specific drug for six months. Blood and tissue samples were collected for hematological, hormonal, biochemical, histological, and immunohistochemical examinations. In addition, sperm collection and assessments of semen parameters were performed. Results revealed that sofosbuvir causes a highly significant decrease in the mean of most hematological, immunological, hormonal, and biochemical parameters, except for a few numbers of parameters such as neutrophils, monocytes, basophils, cortisol, GOT, and lipase, which exhibit a significant increase. The same occurred in the sofosbuvir + ribavirin group, but at much higher levels, as most hematological, immunological, hormonal, and biochemical parameters exhibit a highly significant decrease except for monocytes, triglyceride, and lipase, which exhibit a significant increase. When compared to the sofosbuvir group alone, the sofosbuvir + ribavirin group demonstrated a highly significant decline in the mean of most hematological, immunological, hormonal, and biochemical parameters except lymphocytes and triglycerides, which exhibit a substantial increase. For the reproductive parameters, both groups exhibit a significant decrease in the total sperm motility percentage. Finally, it can be concluded that sofosbuvir causes acute pancreatitis and combined immunodeficiency. Ribavirin is associated with hormonal deficiency, which indicates the occurrence of hypopituitarism. Moreover, sofosbuvir and ribavirin synergistically affect myelosuppression and cause iron-deficiency anemia. However, sofosbuvir, or its combination with ribavirin, is associated with a reduced risk of hepatocellular carcinoma. Besides, adding ribavirin to be combined with sofosbuvir improved the immunodeficiency caused by sofosbuvir; this confirms that using ribavirin with sofosbuvir reduces the side effects of both alone.

Treatment of Inactive Ovaries of Holstein Dairy Cows by Epidural Injection of GnRH Analogue (Receptal) and Its Impact on the Reproductive Hormones, Oxidant/Antioxidant Profile and Micro and Macro-Elements Profile.

This study was designed to evaluate a new therapeutic approach for inactive ovaries based on the epidural administration of a GnRH agonist (Receptal) and an investigation of the impact of this treatment on the hormonal, oxidant/antioxidant and micro- and macro-element profiles. Sixty cows with postpartum anestrus were divided into two groups: the first group (group Repid, n = 30) was administered an epidural injection of Receptal, while the second group (group Cepid, n = 30) received saline and was considered the control group. Evaluation of hormonal (progesterone, FSH, LH, testosterone, and cortisol), oxidant/antioxidant (MDA, SOD, GPx and TAC) as well as micro- and macroelement (calcium, phosphorus, manganese and magnesium) profiles was done in serum. The results showed that the epidural injection of Receptal has the potential to induce estrus response and conception incidence in treated cows. Compared to the control group, progesterone, FSH, and LH concentrations were significantly increased in the treated group, whereas testosterone and cortisol decreased (p < 0.05) following treatment. In addition, the treated group had greater TAC and GPx concentrations than the control group. Serum concentrations of magnesium increased (p < 0.05) following receptal treatment, but differences in other minerals were not detected. This research suggests a novel, effective method of treating inactive ovaries with epidural infusion of a GnRH agonist.

Abortion associated with postpartum opportunistic bacterial invasion reduces fertility and induces disturbances of reproductive hormones, hematological profile, and oxidant/antioxidant profiles in dairy cows.

Objective: The following study examines for the first time the changes that occur in the post-partum period following abortion in the first trimester of dairy cows using hormonal, hematological, and oxidant/antioxidant profiles. In addition, a bacteriological examination was also performed to explore the role of infections in the complications that occur during this period. Materials and Methods: One hundred cows were split into two equal groups: The first group enrolled cows that suffered from abortion in the first trimester. The second group enrolled cows that did not experience abortion problems (the control group). Uterine swabs were collected from cows. Blood samples were collected for hormonal, hematological, and oxidative profiles. Results: Results reveal that Escherichia coli, Staphylococcus spp., and Streptococcus spp. are the opportunistic bacteria that were isolated from abortive cows with multidrug-resistant (MDR) characteristics. Red blood cell (RBC) count, hemoglobin, mean corpuscular hemoglobin (MCH), and MCH concentration (MCHC) were significantly higher in the abortive group than in controls in the first 3 days after calving. Conversely, total leukocyte count, platelet count, neutrophils, eosinophils, and immunoglobulin G and M were significantly lower in the abortion group than in controls. The concentrations of estradiol, prostaglandin F2α, oxytocin, and cortisol are significantly increased in the abortive cows, while progesterone is significantly decreased. The levels of malondialdehyde (MDA) were higher in the abortive group, while the levels of superoxide dismutase (SOD), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) were lower. Conclusion: Abortion during the first trimester of pregnancy increases the risk of postpartum opportunistic bacterial invasion of the uterus. Oxidative stress (OS) and neutropenia are the most important findings that may occur in the postpartum period after abortion and may be due to the abortion itself or its predisposition to opportunistic bacterial invasion of the uterus, which finally causes a fertility reduction.

Protective effects of Folic acid against reproductive, hematological, hepatic, and renal toxicity induced by Acetamiprid in male Albino rats.

Acetamiprid (ACP) is a widespread used insecticide belonging to neonicotinoids (NNs) that are introduced for controlling pests, and for domestic use to control fleas on cats and dogs. The current experiment pertains to a comprehensive overview of the toxic effects of acetamiprid and the protective role of folic acid against reproductive, hematological, histopathological and biochemical toxicity induced by ACP during 5 weeks. Male Albino rats were divided into four groups of seven each: First group served as control rats (CL group); Second group received acetamiprid (ACP group) (10 mg/Kg body weight) by oral gavage. Third group received both acetamiprid and folic acid (ACP + FA group) (2 mg/Kg body weight); Fourth group received folic acid (FA group) (2 mg/Kg body weight). Exposure of rats to acetamiprid caused significant changes in the reproductive indices as it cause a significant decrease in the sperm count, viability and motility. Furthermore, reproductive hormones such as testosterone and gonadotropin-releasing hormones (GnRH) were found significantly decreased in acetamiprid treated group. In addition, acetamiprid administration causes significant changes of some hematological and immunological parameters (red blood cells (RBC), hemoglobin (Hb), platelet (Plt), white blood cells (WBCs), lymphocyte, monocyte, neutrophil, eosinophil, IgG, IgM and IgA) in treated rats compared to controls. Significant increases in the levels of hepatic markers enzymes (aspartate transaminase (AST), Alanine transaminase (ALT), alkaline phosphatase (ALP) in acetamiprid treated group, as well as severe toxic effect was found on the liver and kidney after acetamiprid delivery according to the histopathological examinations which were confirmed after applying histological, histochemical, and Immunohistochemistry tests. The most conspicuous histopathological changes occurred on the liver and kidney of the acetamiprid treated group represented in the liver by fatty liver cells, leukocytic infiltration, and hemorrhage while in kidney tissues revealed tubular atrophy, dense eosinophilic cytoplasm and dilated congested blood vessels. Both liver and kidney tissues showed an increase in the amount of collagenous fibers and immune reactivity of fatty acid synthase. Moreover, other markers such as uric acid and total antioxidant capacity (TAC) were significantly decreased in acetamiprid treated rats. Co-administration of folic acid to the third group restored all the parameters cited above to near-normal values. Therefore, our investigation revealed that acetamiprid induce severe toxicity on different body systems and parameters and folic acid appeared to be a promising agent for protection against acetamiprid-induced toxicity.

The deleterious effect of postpartum pyometra on the reproductive indices, the metabolic profile, and oxidant/antioxidant parameters of dairy cows.

BACKGROUND AND AIM: Postpartum uterine infectious diseases, such as pyometra, have discrepancy with both health and, subsequently, productivity of dairy cows due to its high prevalence and the high cost of treatment. Therefore, this study investigates the influence of pyometra on the reproductive indices, the metabolic profile, and oxidant/antioxidant parameters of the pyometric animal compared to those of healthy ones. MATERIALS AND METHODS: The study included 30 cows. The animals were differentiated into two groups of 15 cows each: A group of pyometra and a control group. All pyometric cows were subjected to breeding soundness examination after the end of pyometra and were compared to the control group. Blood samples were obtained to assess the levels of glucose, non-esterified fatty acids (NEFA), triglycerides (TGs), cholesterol, albumin, total protein, alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, calcium (Ca), phosphorus, sodium, potassium, progesterone hormone (P4), malondialdehyde (MDA), total antioxidant capacity (TAC), glutathione peroxidase (GPx), and superoxide dismutase. RESULTS: Results revealed significant prolonged duration of first estrus, the days open, and the required number of services due to pyometra. The pyometra group yielded increased levels of NEFA, TGs, ALP, BUN, creatinine, MDA, and progesterone hormone. In addition, significant decrease in the levels of glucose, cholesterol, albumin, Ca, phosphorus, sodium, TAC, GPx, and superoxide dismutase was observed in the pyometra group. Finally, no difference in the concentrations of total protein, ALT, AST, and potassium was observed in the pyometra group. CONCLUSION: The reproductive indices was adversely influenced in cows with postpartum pyometra, and metabolic profile, involving energy balance signals and liver function indicators, revealed differences between the two groups. Increased levels of oxidative stress parameters and decrease levels of antioxidant levels were also found, suggesting that pyometra is an incentive for oxidative stress. Overall, checking the energy balance, metabolic imbalances, and oxidant/antioxidant profile, accompanied with pre-emptive procedures during the postpartum period, is essential and can reduce the chances of such diseases and possible noxious results in highly productive cows.

Changes of reproductive indices of the testis due to Trypanosoma evansi infection in dromedary bulls (Camelus dromedarius): Semen picture, hormonal profile, histopathology, oxidative parameters, and hematobiochemical profile.

OBJECTIVE: IThis study was designed for the investigation of the effect of infection by Trypanosoma evansi on the changes of reproductive indices of the testis, causing reproductive failure in dromedary bulls (Camelus dromedarius). MATERIALS AND METHODS: Seventy-five bulls were used for monitoring of the changes in the semen characteristics, reproductive hormones, hematobiochemical profiles, histopathological characters in the testis, and oxidative biomarkers. The animals were divided into two groups. Group A represented the uninfected or control group, while group B represented the infected group. Group B was again divided into two subgroups, such as acute and chronic infected animals. RESULTS: Results showed that the semen analysis of infected camels revealed the presence of alterations in the morphology of sperms, especially the heads and tails, as compared to control animals. The hormonal profile indicated a significant decrease in the luteinizing hormone, follicle- stimulating hormone, and testosterone levels, accompanied by the rise in the cortisol level in infected camels compared with the negative control. The histopathology and testicular degeneration were found to be associated with other disorders in infected camels. The oxidative profile and protein oxidation were promoted in infected testicles, indicating the occurrence of harmful effects in the cell. CONCLUSION: It is concluded that T. evansi infection in dromedary bulls causes severe damage to the testicular tissue and decreases the reproductive hormone levels associated with severe morphological disorders in sperms due to oxidative stress resulting from the infection. All these findings indicate that T. evansi can cause reproductive failure and fertility damage.

Synchronization with controlled internal drug release (CIDR) and prostaglandin F2α (PGF2α) influences oxidant/antioxidant biomarkers and mineral profile in summer-stressed anoestrous buffalo (Bubalus bubalis).

During the summer season, high ambient temperature in tropical and subtropical countries exposes buffaloes to oxidative stress that have antigonadotropic and antisteroidogenic effects. Uses of hormonal therapy can improve the state of ovarian inactivity caused by heat stress and cause anoestrous buffaloes to come into oestrus and successfully achieve pregnancy. Therefore, this study was designed to detect the role of oxidative stress in production of the anoestrous state in summer heat stressed buffaloes and the effects of treatment by Controlled internal drug release (CIDR) in solving of this problem. Also it monitored the changes in Oxidant/antioxidant biomarkers and mineral profile before and after the treatment. Forty buffaloes with no signs of oestrus for more than 120 days after calving were selected. The animals were divided into two groups: the first group (group I, n = 25) was subjected to treatment with CIDR, while the second group (group II) received no treatment and was considered the control group (n = 25). Blood samples were collected before treatment, after treatment and after 45 days of oestrus. The serum level of TAC, MDA, NO, ascorbic acid (vitamin C), P, Cu and Zn were measured. The results showed that 80% of treated buffaloes came into oestrus. The conception rate was 75%. TAC concentrations were significantly higher in group I than in group II. There were significant decreases in the mean values of MDA, NO and ascorbic acid in the buffaloes in oestrus, but these values increased when the buffaloes became pregnant. In contrast there were no significant differences in the mean values of MDA, NO or ascorbic acid in the buffaloes that came into oestrus but failed to conceive. The mean serum P, Cu and Zn values were significantly increased (P < 0.05) in the buffaloes that came into oestrus compared to the control animals. The levels of P and Zn significantly increased when the buffaloes became pregnant and remained unchanged when they failed to conceive. In conclusion, known physiological and pathological variations in the oxidant/antioxidant parameters and mineral profile of summer anoestrous buffaloes may help to understand this problem of infertility.

Mutations in TBC1D24, a gene associated with epilepsy, also cause nonsyndromic deafness DFNB86.

Inherited deafness is clinically and genetically heterogeneous. We recently mapped DFNB86, a locus associated with nonsyndromic deafness, to chromosome 16p. In this study, whole-exome sequencing was performed with genomic DNA from affected individuals from three large consanguineous families in which markers linked to DFNB86 segregate with profound deafness. Analyses of these data revealed homozygous mutation c.208G>T (p.Asp70Tyr) or c.878G>C (p.Arg293Pro) in TBC1D24 as the underlying cause of deafness in the three families. Sanger sequence analysis of TBC1D24 in an additional large family in which deafness segregates with DFNB86 identified the c.208G>T (p.Asp70Tyr) substitution. These mutations affect TBC1D24 amino acid residues that are conserved in orthologs ranging from fruit fly to human. Neither variant was observed in databases of single-nucleotide variants or in 634 chromosomes from ethnically matched control subjects. TBC1D24 in the mouse inner ear was immunolocalized predominantly to spiral ganglion neurons, indicating that DFNB86 deafness might be an auditory neuropathy spectrum disorder. Previously, six recessive mutations in TBC1D24 were reported to cause seizures (hearing loss was not reported) ranging in severity from epilepsy with otherwise normal development to epileptic encephalopathy resulting in childhood death. Two of our four families in which deafness segregates with mutant alleles of TBC1D24 were available for neurological examination. Cosegregation of epilepsy and deafness was not observed in these two families. Although the causal relationship between genotype and phenotype is not presently understood, our findings, combined with published data, indicate that recessive alleles of TBC1D24 can cause either epilepsy or nonsyndromic deafness.

Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48.

Sensorineural hearing loss is genetically heterogeneous. Here, we report that mutations in CIB2, which encodes a calcium- and integrin-binding protein, are associated with nonsyndromic deafness (DFNB48) and Usher syndrome type 1J (USH1J). One mutation in CIB2 is a prevalent cause of deafness DFNB48 in Pakistan; other CIB2 mutations contribute to deafness elsewhere in the world. In mice, CIB2 is localized to the mechanosensory stereocilia of inner ear hair cells and to retinal photoreceptor and pigmented epithelium cells. Consistent with molecular modeling predictions of calcium binding, CIB2 significantly decreased the ATP-induced calcium responses in heterologous cells, whereas mutations in deafness DFNB48 altered CIB2 effects on calcium responses. Furthermore, in zebrafish and Drosophila melanogaster, CIB2 is essential for the function and proper development of hair cells and retinal photoreceptor cells. We also show that CIB2 is a new member of the vertebrate Usher interactome.

Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p.

A missense mutation of Gipc3 was previously reported to cause age-related hearing loss in mice. Point mutations of human GIPC3 were found in two small families, but association with hearing loss was not statistically significant. Here, we describe one frameshift and six missense mutations in GIPC3 cosegregating with DFNB72 hearing loss in six large families that support statistically significant evidence for genetic linkage. However, GIPC3 is not the only nonsyndromic hearing impairment gene in this region; no GIPC3 mutations were found in a family cosegregating hearing loss with markers of chromosome 19p. Haplotype analysis excluded GIPC3 from the obligate linkage interval in this family and defined a novel locus spanning 4.08 Mb and 104 genes. This closely linked but distinct nonsyndromic hearing loss locus was designated DFNB81.

Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42.

By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31-q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment.

Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome.

Mutations of PCDH15, encoding protocadherin 15, can cause either combined hearing and vision impairment (type 1 Usher syndrome; USH1F) or nonsyndromic deafness (DFNB23). Human PCDH15 is reported to be composed of 35 exons and encodes a variety of isoforms with 3-11 ectodomains (ECs), a transmembrane domain and a carboxy-terminal cytoplasmic domain (CD). Building on these observations, we describe an updated gene structure that has four additional exons of PCDH15 and isoforms that can be subdivided into four classes. Human PCDH15 encodes three alternative, evolutionarily conserved unique cytoplasmic domains (CD1, CD2 or CD3). Families ascertained on the basis of prelingual hearing loss were screened for linkage of this phenotype to markers for PCDH15 on chromosome 10q21.1. In seven of twelve families segregating USH1, we identified homozygous mutant alleles (one missense, one splice site, three nonsense and two deletion mutations) of which six are novel. One family was segregating nonsyndromic deafness DFNB23 due to a homozygous missense mutation. To date, in our cohort of 557 Pakistani families, we have found 11 different PCDH15 mutations that account for deafness in 13 families. Molecular modeling provided mechanistic insight into the phenotypic variation in severity of the PCDH15 missense mutations. We did not find pathogenic mutations in five of the twelve USH1 families linked to markers for USH1F, which suggest either the presence of mutations of yet additional undiscovered exons of PCDH15, mutations in the introns or regulatory elements of PCDH15, or an additional locus for type I USH at chromosome 10q21.1.