COVID-19 and Cell Stress.

The present century will undoubtedly be marked with the COVID-19 global health crisis. It is not time yet to talk about the total number of deaths and hospitalizations, as they are enormously growing daily. Understanding the nature of COVID-19-induced pneumonia is vital in order to deal with the associated health complications. Cell stress is an established mechanism known to be associated with infection and cancer. Different proteins crucial for cellular response to stress are reported to be a possible target to stop the infection and to reduce the chemo-resistance in cancer. Heat shock protein (HSP) families of chaperones play an essential role in cells both in normal state and under stress. The upregulation of HSP5A, also termed GRP78 or Bip, is reported in different viral infections. This chapter introduces the current knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused the COVID-19 pandemic, and cell stress aimed at defining possible strategies to combat the COVID-19 pandemic.

Recognition of gluconeogenic enzymes; Icl1, Fbp1, and Mdh2 by Gid4 ligase: A molecular docking study.

The pro/N-degron pathway is an evolved protein degradation pathway through the ubiquitin-proteasome system. It is a vital pathway to attain protein homeostasis inside the liver cells with varying glucose levels. N-terminal proline exists in more than 300 proteins in Saccharomyces cerevisiae, but only three of them are the gluconeogenic enzymes; isocitrate lyase (Icl1), fructose-1,6-bisphosphatase (Fbp1), and malate dehydrogenase (Mdh2). The present in silico study aims to structurally illustrate the binding of Icl1 enzyme to Gid4 ligase concerning its peers; Fbp1 and Mdh2. Based on the molecular docking scores and interactions, one can attribute the binding stability of Gid4 with degrons, to peptides of length six up to eight from the N-terminal. Moreover, the percent change in the docking score provides a rationale for the unique Gid4-Icl11-4 interaction. The present study provides insights on the binding attitude of Gid4 ligase to degrons of different lengths, so one will consider in designing peptidomimetics to target Gid4 ligase.

Recognition of the gluconeogenic enzyme, Pck1, via the Gid4 E3 ligase: An in silico perspective.

Gluconeogenesis, the reverse process of glycolysis, is a favorable mechanism at conditions of glucose deprivation. Pck1 is a rate-limiting gluconeogenic enzyme, where its deficiency or mutation contributes to serious clinical situations as neonatal hypoglycemia and liver failure. A recent report confirms that Pck1 is a target for proteasomal degradation through its proline residue at the penultimate position, recognized by Gid4 E3 ligase, but with a lack of informative structural details. In this study, we delineate the localized sequence motif, degron, that specifically interact with Gid4 ligase and unravel the binding mode of Pck1 to the Gid4 ligase by using molecular docking and molecular dynamics. The peptide/protein docking HPEPDOCK web server along with molecular dynamic simulations are applied to demonstrate the binding mode and interactions of a Pck1 wild type (SPSK) and mutant (K4V) with the recently solved structure of Gid4 ligase. Results unveil a distinct binding mode of the mutated peptide compared with the wild type despite having comparable binding affinities to Gid4. Moreover, the four-residue peptide is found insufficient for Gid4 binding, while the seven-residue peptide suffices for binding to Gid4. The amino acids S134, K135, and N137 in the loop L1 (between ß1 and ß2) of the Gid4 are essential for the stabilization of the seven-residue peptide in the binding site of the ligase. The presence of Val4 instead of Lys4 smashes the H-bonds that are formed between Lys4 and Gid4 in the wild type peptide, making the peptide prone to bind with the other side of the binding pocket (L4 loop of Gid4). The dynamics of Gid4 L3 loop is affected dramatically once K4V mutant Pck1 peptide is introduced. This opens the door to explore the mutation effects on the binding mode and smooth the path to target protein degradation by design competitive and non-competitive inhibitors.

Prevalence and risk factors of obstetric violence in the Gaza strip: A retrospective study from a conflict setting.

OBJECTIVES: To assess the prevalence and risk factors of obstetric violence (OV) among laboring women in the past 5 years in the Gaza Strip (GS). METHODS: Women who delivered between January 2017 and December 2021 were invited to complete an anonymous online survey between November 2021 and February 2022 to explore their experiences of labor. RESULTS: Seven hundred twenty-two women completed the online questionnaire. Two-thirds (484; 67.2%) were in their 20s, and half (362; 50.1%) were from low socioeconomic households. A vast majority (508; 70.4%) delivered in a government hospital. Four out of ten (300; 41.6%) reported experiencing at least one form of OV. Among these women, the types of OV reported were physical (143; 47.8%), psychological (122; 40.8%), verbal (109; 36.4%), and sexual (13; 4.4%). Delivery in private facilities (adjusted odds ratio [AOR] 0.45, 95% confidence interval [CI] 0.32-0.74) and prior knowledge of the care provider (AOR 0.37, 95% CI 0.23-0.59) were both independently protective for OV. In contrast, women's awareness of OV increased their likelihood of reporting it (AOR 3.45, 95% CI 2.37-5.01). CONCLUSION: GS has an alarming prevalence of reported OV. Increasing awareness of OV, identifying its causes, and developing locally led initiatives to eliminate it are urgently needed.

Supplementation of clomiphene citrate cycles with Cimicifuga racemosa or ethinyl oestradiol--a randomized trial.

The anti-oestrogenic activity of clomiphene citrate (CC) on the cervical mucous and endometrium may be the reason for the relatively low pregnancy rates in CC induction cycles. Various follicular-phase supplements have been tried to improve cycle outcome in these patients. This study compared follicular-phase supplementation with either phytoestrogen (PE) or ethinyl oestradiol (EE) in CC induction cycles for the treatment of unexplained infertility. A total of 134 patients were randomly allocated to each treatment group (67 each). The PE group needed significantly fewer days for adequate follicular maturation, had a thicker endometrium and higher oestradiol concentration at the time of human chorionic gonadotrophin injection (all P < 0.001). The PE group had higher luteal-phase serum progesterone compared with the EE group. No significant difference was found regarding clinical pregnancy rates (14.0% versus 21.1%, respectively). In conclusion, the cycle characteristics in unexplained infertility women treated with clomiphene citrate induction and timed intercourse improved after follicular-phase supplementation with PE compared with EE supplementation. Further studies are needed to confirm the mechanism beyond these effects.

Effect of oral N-acetyl cysteine on recurrent preterm labor following treatment for bacterial vaginosis.

OBJECTIVE: To evaluate the effect of N-acetyl cysteine (NAC) on gestational age at delivery in women with previous preterm labor and bacterial vaginosis. METHODS: A randomized, double-blind, placebo-controlled trial with 280 women between 16 and 18 weeks of pregnancy who had 1 previous preterm birth and had just been successfully treated for bacterial vaginosis with metronidazole for 1 week. The women were randomized to receive 0.6 g of NAC per day plus 17-hydroxyprogesterone caproate (17-OHPC) or placebo plus 17-OHPC until 36 completed weeks of pregnancy or active labor. A vaginal swab was taken during labor. RESULTS: Reaching 36 weeks of pregnancy was more frequent (P<0.05) and gestational age at delivery was significantly higher in the NAC than in the placebo group (37.4 weeks+/-0.4 weeks vs 34.1 weeks+/-1.2 weeks, P<0.05). The discontinuation rate was 11.4% in the NAC group. CONCLUSIONS: Oral NAC was found to reduce the recurrence of preterm birth in patients with bacterial vaginosis.

Plasma membrane proteins: A new probe for the characterization of breast cancer.

This work aimed to characterize normal, benign and malignant excised breast tissues through the analysis of the FTIR spectra of their plasma membrane proteins. Tissue characterization parameters such as peak position, peak intensity, area under the peak, relative peak intensity and relative area under peak were evaluated mainly for protein spectral peaks; 1150 cm-1, Amide I, Amide II, Amide III, and Amide A. The sensitivity, specificity and diagnostic accuracy for each parameter were obtained and Receiver Operating Characteristic (ROC) Curves were plotted. Results showed significant spectral differences between normal and benign tissues compared to malignant tissues at 1536 and 1645 cm-1. The three tissues could be distinguished at 2900 cm-1, where the malignant peak uniquely split into two separate peaks. ROC curves showed that the Amide A peak position yielded a higher accuracy compared to all other investigated characterization parameters. The deconvolution of Amide I revealed the conformational changes in plasma proteins characterizing the transformation to malignancy (a decrease in the percentage of alpha helix accompanied by an increase in the percentage of beta sheets). The use of the present structure-based analysis in conjunction with histopathological examination of excised breast tissues would offer an enhanced characterization that might reduce possible personal diagnostic mistakes.

Topical lidocaine-prilocaine cream versus lidocaine infiltration for pain relief during repair of perineal tears after vaginal delivery: randomized clinical trial.

OBJECTIVE: The current study aims to compare the analgesic effect of lidocaine-prilocaine (LP) cream with lidocaine infiltration during repair of perineal tears after vaginal delivery. MATERIALS AND METHODS: A single center open-labeled randomized clinical trial was carried out in a tertiary University Hospital between October 2016 and May 2017 (Clinical Trials.Gov: NCT02883179). We included parous women, who delivered at gestational age >37 weeks with first- or second-degree perineal tears. The participants were randomized in a 1:1 ratio to either lidocaine infiltration (Group I); or application of LP cream (Group II) for pain relief during perineal repair. The primary outcome was the difference in mean pain score during perineal repair. Secondary outcomes included the participants' satisfaction, the need for additional anesthesia, the duration of perineal repair, and the rate of adverse effects of both medications. RESULTS: The study included 144 participants randomized to both groups. The mean pain score during perineal repair was significantly lower in the LP cream group (3.86 ± 1.59) than the lidocaine infiltration group (5.99 ± 1.47) [p = .001]. The duration of repair was significantly shorter in the LP group than the lidocaine infiltration group (6.37 ± 3.68 versus 8.17 ± 2.75 min, respectively, p = .001). The need for additional anesthesia was quite similar in both groups (p = .371). More women in the LP cream group were satisfied than the other group with statistical significant difference (76.4 versus 30.6%, p = .000). No difference between side effects in both groups (p = .171) Conclusions: Topical application of lidocaine-prilocaine cream is an effective analgesic during repair of perineal tears with no harmful side effects.

Peri-conceptional progesterone treatment in women with unexplained recurrent miscarriage: a randomized double-blind placebo-controlled trial.

OBJECTIVE: The current study aims to evaluate the effect of peri-conceptional progesterone started early in the luteal phase before confirmation of pregnancy in preventing miscarriage in women with history of unexplained recurrent miscarriage (RM). MATERIALS AND METHODS: The current study was a randomized double-blind controlled trial (NCT01608347) conducted at Assiut Women's Health Hospital from 2012 through 2015 included patients of unexplained RM. Participants were randomly assigned to receive either 400 mg progesterone pessaries or placebo twice daily, started in the luteal phase and continued after a positive pregnancy test till 28 weeks of gestation. The main study outcome was the miscarriage rate. RESULTS: Seven hundred women were enrolled (n = 350 in each group). The miscarriage rate was significantly lower in progesterone group (12.4 versus 23.3% in the placebo group, p = 0.001). There was significant improvement in rate of pregnancy continuation beyond 20 weeks as well as the live birth rate in the progesterone group in comparison to placebo group (87.6 versus 76.7% and 91.6 versus 77.4%, respectively, p < 0.05). CONCLUSIONS: Progesterone is more effective than placebo in reducing the risk of miscarriage if administered in the luteal phase of the cycle, before confirmation of pregnancy in women with history of unexplained RM.

Investigating psychosocial attitudes, motivations and experiences of oocyte donors, recipients and egg sharers: a systematic review.

INTRODUCTION: The donation of oocytes has been made feasible as a result of in vitro fertilization (IVF). This treatment offers an answer for infertile women with ovarian conditions, such as primary ovarian insufficiency. Demand for oocyte donors has been on the rise globally, with infertile couples, as well as gay men, increasingly using it as a means to found their families. With an acute shortage of oocyte donors globally, the psychosocial aspects behind oocyte donation are important for fertility clinics to understand. This paper aims primarily to provide an up-to-date systematic review of the psychosocial aspects of oocyte donation from the point of view of oocyte donors and recipients and egg sharers. Its secondary aims are to explore the motives and experiences of donors as well as attitudes towards donor anonymity and disclosure. An emphasis has been placed on the analysis of donors in the UK. No review has analysed together the aforementioned donor groups along with recipient group. METHODS: A systematic search of English peer-reviewed journals of four computerized databases was undertaken, with no time restriction set for publications. RESULTS: There were 62 studies which met the inclusion criteria and were included in the systematic review. Attitudes towards donation were positive from both a donor oocyte and recipient point of view, with medical procedures being well tolerated and excellent post-donation satisfaction among all donor groups. There were distinct differences between the different donor groups and recipients in motivation for oocyte donation and decisions for disclosure. Attitudes towards anonymity issues were reassuring with a significant proportion of donors of all types willing to donate as identifiable donors. However, there were methodological limitations identified in the studies reviewed. CONCLUSION: This review successfully explored the important psychosocial aspects of oocyte donation. In general terms the attitudes and feeling of patients involved from all sides of the donation process were extremely positive. A number of key and consistent issues emerged which demonstrated differences and similarities between the different donor groups, as well as a greater understanding of the recipient. With regard to psychosocial well-being, the results were reassuring throughout all donor groups, especially the egg share donors. Although it seems the 2005 legislative changes in the UK have not caused the anticipated dramatic decrease in gamete donation, oocyte donation still falls far short of demand. The UK has an increasing population of patients from different ethnic backgrounds and same sex relationships seeking oocyte donation, with very few studies including these groups of patients. An increased number of well-designed studies looking into the psychological issues surrounding gamete donation of different patient groups, could allow more directed assessment and counselling of oocyte donors and recipients, with a resulting increase in donor recruitment.

Randomized controlled study of pre-conception thromboprophylaxis among patients with recurrent spontaneous abortion related to antiphospholipid syndrome.

OBJECTIVES: To investigate the effects of pre-conception thromboprophylaxis among patients with recurrent spontaneous abortion and antiphospholipid syndrome. METHODS: A randomized placebo-controlled trial enrolled patients with a history of recurrent spontaneous abortions and antiphospholipid syndrome who attended an Egyptian center between January 2011 and June 2013. Using a computer-generated sequence, patients were randomly allocated to receive 41 mg enoxaparin subcutaneously plus 81 mg aspirin daily pre-conception, or to receive placebo pre-conception. All patients received enoxaparin and aspirin following identification of fetal heart pulsation. The primary outcomes were live-birth rate and clinical-pregnancy rate at 0-6 months, and at 6-12 months. Intention-to-treat analyses were performed. Clinicians, investigators, and data analysts were masked to the treatment assignments. RESULTS: The study enrolled 180 patients(90 in each group). No significant difference was observed between the intervention and control groups in the live-birth rate (67[74%] vs 59[66%]; P=0.25). At 0-6 months, the clinical-pregnancy rate was higher in the intervention group (50[56%]vs 30[33%], P=0.02). No significant difference between the intervention and control groups was observed in the clinical-pregnancy rate at 6-12 months (32[36%] vs 35[39%], P=0.52). CONCLUSION: Among patients with recurrent spontaneous abortion and antiphospholipid syndrome, pre-conception enoxaparin increased the clinical-pregnancy rate at 0-6 months, but did not affect the clinical-pregnancy rate at 6-12 months or the live-birth rate. ClinicalTrials.gov: NCT01661439.

Adding L-carnitine to clomiphene resistant PCOS women improves the quality of ovulation and the pregnancy rate. A randomized clinical trial.

OBJECTIVE: To evaluate the effectiveness of L-carnitine on improving the ovulation and pregnancy rates as well as adverse metabolic indices in clomiphene-resistant PCOS. DESIGN: Single center, double blinded, superiority, randomized controlled clinical trial. SETTING: Women's Health Hospital, Assiut University. METHODS: One hundred and seventy women diagnosed with PCOS were found to be clomiphene resistant. The women were randomly allocated into two groups: Group A (n=85), where patients received 250 mg clomiphene citrate from day three until day seven of the cycle plus L-carnitine (LC) 3g daily; and Group B (n=85) received 250 mg clomiphene citrate with placebo. OUTCOME: Primary outcome is cumulative clinical pregnancy rate. Secondary outcomes are changes in serum glucose level and lipid profile. RESULTS: The combination of L-carnitine and CC significantly improve both the ovulation and the cumulative pregnancy rates in clomiphene resistant PCOS (55 (64.4%) vs. 15 (17.4%) and 44 (51.5) % vs. 5 (5.8) %). The number of stimulated follicles reaching ≥17 mm diameter was significantly more in Group A to Group B (2.2 ± 0.77 vs. 0.16 ± 0.79; p<0.0001). Group A needed significantly fewer days for adequate follicular maturation, had a thicker endometrium and higher oestradiol concentration at the time of human chorionic gonadotrophin injection (10.1 ± 0.1mm vs. 6.8 ± 0.4mm; p<0.0001). The same group had a higher mean luteal-phase serum progesterone compared with the control group (13.55 ± 0.99 vs. 10.6 ± 0.98 ng; p<0.0001). A significant difference was found regarding the clinical pregnancy rates (42 (49.4%) vs. (1) 1.1% respectively p value <0.0001). CONCLUSION: Adding L-carnitine when treating clomiphene-resistant PCOS patients not only improved the quality of ovulation and the pregnancy rate with an acceptable patient tolerability, but also enhanced the patient lipid profile and body mass index.

Recurrent headaches: a case of neurological Behçet's disease.

A 48-year-old black male, of Nigerian heritage, presented with a 24-hour history of frontal headache of gradual onset. The headache characteristic was migranous, being described as throbbing in nature and located to the right frontal area with associated blurring of vision. Although similar to prior frequent headaches, there was now increasing unsteadiness on walking. Diagnosed 10 years earlier with Behçet's disease, the initial presentation was with oral and genital ulceration. Recurrent episodes of headache caused by neurological flare-ups resulted in a stroke at the age of 46 years. This previous stroke was ischaemic in character with involvement of the brainstem, pons, midbrain and right cerebral peduncle with extension into the right internal capsule. Surveillance brain imaging (computed tomographic and magnetic resonance imaging with venography) 10 months earlier showed brainstem disease activity (Figure 1a) with disease quiescence a month later (Figure 1b) following an escalation of immunosuppressant therapy. Regular medications comprised prednisolone 10 mg (however, regular recurrences had resulted in him taking doses of between 20 and 30 mg/day of prednisolone for most of the past 24 months) and azathioprine 150 mg daily, aspirin 75 mg daily, one adcal D3 twice daily with weekly alendronic acid, and omeprazole 20 mg daily. For headache he took topiramate 25 mg daily and for depression mirtazepine 15 mg daily. The patient was also addicted to a high level of cannabis use which he was reluctant to stop as he felt it helped his symptoms. On examination he was apyrexial and cardiovascularly stable. Neurological examination revealed a residual horizontal nystagmus to the right on lateral gaze, mild left hemiparesis with moderate spasticity, in addition to dysarthria and dysphonia from his prior stroke. A new feature was an exacerbation of gait unsteadiness. Blood tests were unremarkable and specifically the erythrocyte sedimentation rate was normal at 2 mm/hr (normal range 0-10 mm/hr). Immediate therapy involved an increase in steroid dosage to methyl prednisolone 1 g/day for 3 days, followed by oral prednisolone 60 mg daily. This was maintained for 2 weeks and then reduced by 10 mg/week to a maintenance dose of 10 mg/day. Magnetic resonance scanning revealed a marked increase in inflammation of the brainstem (Figure 1c). The patient required physiotherapy and occupational therapy with psychiatric input and was able to leave the hospital after 29 days.

Evaluation of peritoneal fluid hemosiderin-laden macrophages in biopsy-proven endometriosis.

OBJECTIVE: To evaluate peritoneal fluid hemosiderin-laden macrophages (H-LMs) in patients with endometriosis compared to controls. STUDY DESIGN: Consecutive series of 46 patients during a year undergoing laparoscopy for benign gynecologic conditions were included. The presence of H-LMs in peritoneal fluid was evaluated. We compared clinical factors in patients with or without endometriosis in respect to H-LM status. To assess the potential of H-LMs to diagnose endometriosis, the sensitivity and specificity were calculated. RESULTS: Patients with endometriosis were significantly more likely to have positive H-LM test results than controls (p = 0.0013). The presence of H-LM has a low sensitivity of 52% but an acceptable specificity of 87% in diagnosing endometriosis. The presence of H-LMs was not related with any other of the clinical factors studied. CONCLUSION: The presence of specific findings of H-LMs related to endometriosis strongly suggests abnormalities in peritoneal iron metabolism.

Adding phytoestrogens to clomiphene induction in unexplained infertility patients--a randomized trial.

This study investigated the role of oral phytoestrogens in improving pregnancy rate and cycle outcomes with clomiphene citrate. Patients with unexplained infertility and recurrent clomiphene citrate induction failure, were randomly divided into two groups: group I (n = 60) and group II (n = 59). Both groups received clomiphene citrate 150 mg per day (days 3 to 7). Group I received additional oral phytoestrogen (Cimicifuga racemosa) 120 mg/day from days 1 to 12. Human chorionic gonadotrophin (HCG) injection (10,000 IU i.m.) was given and timed intercourse was recommended when a leading follicle reached >17 mm and serum oestradiol exceeded 200 (pg/ml). There was a non-significant shortening of induction cycles in group I. Oestradiol and LH concentrations were higher in group I compared with group II. Endometrial thickness, serum progesterone and clinical pregnancy rate were significantly higher in group I (8.9 +/- 1.4 mm versus 7.5 +/- 1.3 mm, P < 0.001; 13.3 +/- 3.1 ng/ml versus 9.3 +/- 2.0 ng/ml, P < 0.01; 36.7% versus 13.6%, P < 0.01, respectively). It is concluded that adding C. racemosa rhizome dry extract to clomiphene citrate induction can improve the pregnancy rate and cycle outcomes in these couples.