Prenatal Identification of a Missense Mutation of the L1CAM Gene Associated With Hydrocephalus Using Next-Generation Sequencing.

We present the case of a 35-year-old pregnant woman who visited our department for a routine ultrasonography screening scan for fetus anatomy during the 22nd week of gestation. Our report revealed a male fetus with marked hydrocephalus and severe intrauterine growth retardation. After extensive counseling, the couple decided to proceed with an invasive diagnosis via amniocentesis. The cytogenetic analysis showed findings related to clinical history and ultrasound findings related to the presence of a nucleotide change in c.578T>C with an amino acid change in p.Leu198Pro of the L1CAM gene. The result was reported as a hemizygote missense L1CAM gene variant of unknown significance. After extensive parental counseling, the couple decided on pregnancy termination. We report the present case of L1CAM mutation in p.Leu198Pro to add to the limited knowledge regarding the clinical presentation of mutations of the L1CAM gene with emphasis on prenatal diagnosis.

Transcription-replication conflicts underlie sensitivity to PARP inhibitors.

An important advance in cancer therapy has been the development of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of homologous recombination (HR)-deficient cancers1-6. PARP inhibitors trap PARPs on DNA. The trapped PARPs are thought to block replisome progression, leading to formation of DNA double-strand breaks that require HR for repair7. Here we show that PARP1 functions together with TIMELESS and TIPIN to protect the replisome in early S phase from transcription-replication conflicts. Furthermore, the synthetic lethality of PARP inhibitors with HR deficiency is due to an inability to repair DNA damage caused by transcription-replication conflicts, rather than by trapped PARPs. Along these lines, inhibiting transcription elongation in early S phase rendered HR-deficient cells resistant to PARP inhibitors and depleting PARP1 by small-interfering RNA was synthetic lethal with HR deficiency. Thus, inhibiting PARP1 enzymatic activity may suffice for treatment efficacy in HR-deficient settings.

Microvessel Density (MVD) in Patients with Osteosarcoma: A Systematic Review and Meta-Analysis.

A meta-analysis was designed and conducted to estimate the effect of tumoral microvessel density (MVD) on the survival of patients with osteosarcoma. There was no difference between high and low MVD regarding the overall (OS) and disease-free (DFS) survival. Low MVD tumors displayed a lower DFS at the third year of follow-up. Although primary metastases did not affect the mean MVD measurements, tumors with a good chemotherapy response had a higher MVD value. Although no significant differences between tumoral MVD, OS and DFS were found, good adjuvant therapy responders had a significant higher vascularization pattern.

Large Cyst of Skene Gland: A Rare Perineum Mass.

Objective In this report we present a rare case of a large cyst of Skene gland in a female patient with a palpable vaginal mass persisting for at least 2 years. Case Report A 67-year-old female admitted to the department of urology due to the presence of "a vaginal mass" for the past 2 years. A cyst of Skene's duct was suspected based on clinical manifestation and findings of magnetic resonance imaging showing an extensive cyst formation in the upper vaginal area and anterior to the urethra. Based on these findings, a decision for surgical removement of the cyst was made. The cyst was incised, drained, and marsupialized. The postoperative recovery was uneventful, and the patient was discharged on the second postoperative day. Conclusion High clinical suspicion is important to reach this rare diagnosis. Partial excision and marsupialization of the cyst is a simple procedure with low morbidity, without recurrence, and excellent results.

Ovarian Cancer and Glutamine Metabolism.

Cancer cells are known to have a distinct metabolic profile and to exhibit significant changes in a variety of metabolic mechanisms compared to normal cells, particularly glycolysis and glutaminolysis, in order to cover their increased energy requirements. There is mounting evidence that there is a link between glutamine metabolism and the proliferation of cancer cells, demonstrating that glutamine metabolism is a vital mechanism for all cellular processes, including the development of cancer. Detailed knowledge regarding its degree of engagement in numerous biological processes across distinct cancer types is still lacking, despite the fact that such knowledge is necessary for comprehending the differentiating characteristics of many forms of cancer. This review aims to examine data on glutamine metabolism and ovarian cancer and identify possible therapeutic targets for ovarian cancer treatment.

Polydactyly: Clinical and molecular manifestations.

Polydactyly is a malformation during the development of the human limb, which is characterized by the presence of more than the normal number of fingers or toes. It is considered to be one of the most common inherited hand disorders. It can be divided into two major groups: Non-syndromic polydactyly or syndromic polydactyly. According to the anatomical location of the duplicated digits, polydactyly can be generally subdivided into pre-, post-axial, and mesoaxial forms. Non-syndromic polydactyly is often inherited with an autosomal dominant trait and defects during the procedure of anterior-posterior patterning of limb development are incriminated for the final phenotype of the malformation. There are several forms of polydactyly, including hand and foot extra digit manifestations. The deformity affects upper limbs with a higher frequency than the lower, and the left foot is more often involved than the right. The treatment is always surgical. Since the clinical presentation is highly diverse, the treatment combines single or multiple surgical operations, depending on the type of polydactyly. The research attention that congenital limb deformities have recently attracted has resulted in broadening the list of isolated gene mutations associated with the disorders. Next generation sequencing technologies have contributed to the correlation of phenotype and genetic profile of the multiple polydactyly manifestations and have helped in early diagnosis and screening of most non-syndromic and syndromic disorders.

Prenatal Identification of a Novel Mutation in the MCPH1 Gene Associated with Autosomal Recessive Primary Microcephaly (MCPH) Using Next Generation Sequencing (NGS): A Case Report and Review of the Literature.

BACKGROUND: MCPH1 is known as the microcephalin gene (OMIM: *607117), of which the encoding protein is a basic regulator of chromosome condensation (BCRT-BRCA1 C-terminus). The microcephalin protein is made up of three BCRT domains and conserved tandem repeats of interacting phospho-peptides. There is a strong connection between mutations of the MCPH1 gene and reduced brain growth. Specifically, individuals with such mutations have underdeveloped brains, varying levels of mental retardation, delayed speech and poor language skills. METHODS: In this article, a family with two affected fetuses presenting a mutation of the MCPH1 gene is reported. During the first trimester ultrasound of the second pregnancy, the measure of nuchal translucency was increased (NT = 3.1 mm) and, therefore, the risk for chromosomal abnormalities was high. Chorionic villi sampling (CVS) was then performed. Afterwards, fetal karyotyping and Next Generation Sequencing were carried out. Afterwards, NGS was also performed in a preserved sample of the first fetus which was terminated due to microcephaly. RESULTS: In this case, the fetuses had a novel homozygous mutation of the MCPH1 gene (c.348del). Their parents were heterozygous for the mutation. The fetuses showed severe microcephaly. Because of the splice sites in introns, this mutation causes the forming of dysfunctional proteins which lack crucial domains of the C-terminus. CONCLUSION: Our findings portray an association between the new MCPH1 mutation (c.348del) and the clinical features of autosomal recessive primary microcephaly (MCPH), contributing to a broader spectrum related to these pathologies. To our knowledge, this is the first prenatal diagnosis of MCPH due to a novel MCPH1 mutation.

Genetics of congenital anomalies of the hand.

Congenital anomalies of the hand are malformations occurring during the development of the human limb, and present as isolated disorders or as a part of a syndrome. During the last years, molecular analysis techniques have offered increasing knowledge about the molecular basis of hand malformations. Disturbances in the signaling pathways during the development of the upper limb result in malformations of the upper extremity. At present, several genes have been identified as responsible for hand anomalies and other have been recognized as suspect genes related to them. Different and new high throughput methods have been introduced for the identification of the gene mutations. In the current editorial, we summarize concisely the current molecular status of isolated hand genetic disorders and the recent progress in molecular genetics, including the genes related to the disorder. This progress improves the knowledge of these disorders and has implications on genetic counselling and prenatal diagnosis.

Preeclampsia, gestational hypertension and incident dementia: A systematic review and meta-analysis of published evidence.

OBJECTIVE: Novel data support a possible correlation between preeclampsia and congenital dysfunction. STUDY DESIGN: A systematic review of the literature and a meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. MAIN OUTCOME MEASURE: To investigate the association between the risk of future of dementia (vascular dementia, AD and dementia of any type) in women with a history of preeclampsia, based on current literature. RESULTS: Overall, three studies and 2.309.946 women were included in the present meta-analysis. There was no statistically significant association between history of preeclampsia or pregnancy hypertension disease and any type of dementia (p = 0.14 and p = 0.29, respectively). In contrast, there was a statistically significant difference between history of preeclampsia and vascular dementia (HR: 2.60; 95 %CI: 2.03-3.33; p < 0.001). Furthermore, history of preeclampsia does not increase the risk for Alzheimer disease (Fixed Effects pooled-HR: 1.17; 95 %CI: 0.98-1.40; p = 0.08). Similarly, women with hypertensive disorder of pregnancy (HDP) had no statistically significant increased risk for later onset of any dementia (Fixed Effects pooled-HR: 1.08; 95 %CI: 0.93-1.25; p = 0.29). CONCLUSIONS: History of preeclampsia increases the risk of vascular dementia. These patients are expected to benefit from screening for early symptoms of dementia, allowing early diagnosis and treatment. However, due to several limitations, further studies with large cohorts are required to elucidate the association between preeclampsia and dementia.

Microvessel density in differentiated thyroid carcinoma: A systematic review and meta-analysis.

BACKGROUND: Microvessel density (MVD) has been proposed as a direct quantification method of tumor neovascularization. However, the current literature regarding the role of MVD in differentiated thyroid carcinoma (DTC) remains inconclusive. AIM: To appraise the effect of tumoral MVD on the survival of patients with DTC. METHODS: This meta-analysis was based on the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The electronic databases Medline, Web of Science, and Scopus were systematically screened. A fixed-effects or random-effects model was used, according to the Cochran Q test. The data were then extracted and assessed on the basis of the Reference Citation Analysis (https://www.referencecitationanalysis.com/). RESULTS: A total of nine studies were included in the present study. Superiority of low MVD tumors in terms of 10-year disease free survival (OR: 0.21, 95%CI: 0.08-0.53) was recorded. Lowly vascularized thyroid cancers had a lower recurrence rate (OR: 13.66, 95%CI: 3.03-61.48). Moreover, relapsing tumors [weighed mean difference (WMD): 11.92, 95%CI: 6.32-17.52] or malignancies with regional lymph node involvement (WMD: 8.53, 95%CI: 0.04-17.02) presented with higher tumoral MVD values. CONCLUSION: MVD significantly correlates with the survival outcomes of thyroid cancer patients. However, considering several study limitations, further prospective studies of higher methodological and quality level are required.

COVID-19 Severity and Mortality after Vaccination against SARS-CoV-2 in Central Greece.

Background: Vaccination against SARS-CoV-2 (COVID-19) has become crucial for limiting disease transmission and reducing its severity, hospitalizations and mortality; however, despite universal acceptance, vaccine hesitancy is still significant. In the present manuscript, we aim to assess COVID-19-attributed mortality after the prevalence of new variants of the virus (Delta and Omicron viral strains) and to evaluate the vaccination effect. Methods: All patients that were hospitalized due to COVID-19 infection in the Respiratory Department of a tertiary referral center in central Greece between 1st of June 2021 and 1st of February 2022 were included in the present study. Results: 760 consecutive patients were included in the study; 89 (11.7%) were diagnosed with severe COVID-19 and 220 (38.7%) patients were fully vaccinated. In logistic regression, increased age (aOR = 1.12, p < 0.001), male gender (aOR = 2.29, p = 0.013) and vaccination against SARS-CoV-2 virus (aOR = 0.2, p < 0.001) were associated with mortality attributed to COVID-19 with a statistically significant association. Moreover, increased age (aOR = 1.09, p < 0.001), male gender (aOR = 1.92, p = 0.025) and vaccination against SARS-CoV-2 virus (aOR = 0.25, p < 0.001) were statistically significantly associated with clinical severity of COVID-19 infection. However, when comparing the length of hospitalization between vaccinated and unvaccinated patients, the difference was not statistically significant between the two groups (p = 0.138). Conclusions: Vaccination against SARS-CoV-2 virus had a protective effect in terms of mortality and clinical severity of COVID-19 during the fourth wave of the pandemic in Central Greece. The national vaccination policy has to focus on vulnerable populations that are expected to benefit the most from the vaccine's protection.

The Significance of Peritoneal Washing as a Prognostic Indicator for Ovarian Cancer Patients.

BACKGROUND/AIM: During ovarian cancer (OC) debulking surgery, the surgeon can examine the peritoneal cavity for malignant cancer cells with peritoneal washing (PW) cytology. The goal of this study was to examine the significance of peritoneal washing as a prognostic indicator for ovarian cancer patients. PATIENTS AND METHODS: Information considering the prognostic factors of OC and their impact in PW's result was collected, compared, and combined. RESULTS: Omental metastasis, tumor type, tumor invasion, tumor size, tumor grade/ stage, tumor's cytoreduction, and recurrence affect both the peritoneal washing result and the patient's prognosis. The correlation that most of the above factors have with a positive PW and dismal prognosis, led us to the assumption that PW has a significance as a prognostic indicator. CONCLUSION: The significance of PW as a prognostic indicator remains an assumption.

When the endometrioid adenocarcinoma and the endometrial stromal sarcoma meet: A report of an extremely rare case.

Introduction: Collision tumors are characterized by the coexistence of two adjacent, but histologically distinct tumors. This entity can occur between tumors originating from the same organ or between metastases from other sites. Case presentation: A 49-year-old postmenopausal female with abnormal vaginal bleeding and abdominal pain was diagnosed with two coexistent tumors, a grade 1 endometrioid carcinoma and a pT2 undifferentiated stromal sarcoma (USS). On the first time, the patient underwent a total abdominal hysterectomy with bilateral salpingo-oopherectomy and one month later, she was diagnosed with recurrence. Then, a second surgical excision of the recurrent tumor was performed including exploratory laparotomy and anterior pelvic exenteration. She had an uneventful postoperative period, but unfortunately a month following the second operation she passed away. Conclusion: We aim to raise awareness of these rare synchronous malignancies and highlight the importance of having a broad differential diagnosis in a patient presenting with abnormal vaginal bleeding. Further studies with larger patient populations are needed to shed light in etiology and pathogenesis of the concurrence of two malignancies with different embryological origin in the same organ, in order to optimize management of these patients.

Placental Ultrasonographic Findings Due to COVID-19 Infection During Pregnancy: A Case Report.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy can lead to several adverse events. Here, we report a case of a 40-year-old Caucasian female, gravida 1, para 0, with a spontaneous singleton pregnancy, who presented to the emergency room during her 17th week of gestation with fever (38.8ºC), fatigue, shortness of breath, and palpitations. She tested positive for coronavirus disease 2019 (COVID-19). Ultrasonography examination revealed signs of placental involvement compatible with malperfusion, chorangiosis, deciduitis, and subchorionitis. Findings remained stable until the 20th week and gradually resolved around the 32nd week of pregnancy. A normal male neonate was delivered via elective caesarian section during the 39th week, weighing 2830 gm. The present report points toward a correlation between clinical symptomatology of COVID-19 during pregnancy and ultrasonographical features. Early detection of placental damage through the use of specific ultrasound findings could indicate which pregnancies are at increased risk for complications; however, further studies including a larger population are required to confirm these findings.

Placental Ultrasonographical Findings during SARS-CoV-2 Infection.

Infection with SARS-CoV-2 virus (COVID-19) during pregnancy has been associated with several complications. Increasing evidence suggests that COVID-19 infection leaves tell-tale signs of placental injury. During ultrasound examination and placental evaluation of COVID-19 infected pregnancies, we recorded signs of placental involvement, with findings indicating malperfusion, chorangiosis, deciduitis, and subchorionitis. Early detection of placental damage through the use of specific ultrasound findings could indicate which pregnancies are at increased risk for complications.

Vulnerability of ß-Thalassemia Heterozygotes to COVID-19: Results from a Cohort Study.

Background: The assignment of mortality risk from SARS-CoV-2 virus (COVID-19) to vulnerable patient groups is an important step toward containment of the pandemic. Methods: A total of 760 patients with a positive molecular test for SARS-CoV-2 who were unvaccinated against COVID-19 were recruited between 1 January and 30 June 2021. Patients were grouped by age; sex; and common morbidities, such as atrial fibrillation, chronic respiratory disease, coronary disease, diabetes type II, neoplasia, hypertension and ß-Thalassemia heterozygosity. As a primary endpoint, we assessed mortality risk from COVID-19, and as secondary endpoints, we considered clinical severity and need for Intense Care Unit (ICU) admission. Results: In multivariate analysis, male sex (p < 0.001, OR = 2.59), increasing age (p < 0.001, OR = 1.049), ß-Thalassemia heterozygosity (p = 0.001, OR = 2.41) and chronic respiratory disease (p = 0.018, OR = 1.84) were identified as risk factors associated with mortality due to COVID-19. Moreover, male sex (p < 0.001, OR = 1.98), increasing age (p < 0.001, OR = 1.052) and ß-Thalassemia heterozygosity (p = 0.001, OR = 2.59) were associated with clinical severity in logistic regression. Regarding ICU admission, the risk factors were identified as male sex (p = 0.002, OR = 1.99), chronic respiratory disease (p = 0.007, OR = 2.06) and hypertension (p < 0.001, OR = 5.81). Conclusions: An increased mortality risk from COVID-19 was observed for older age, male sex, ß-Thalassemia heterozygosity and respiratory disease. Carriers of ß-Thalassemia were identified as more vulnerable for severe clinical symptomatology, but there was no increased possibility for ICU admission. Readjustment of these findings to consider impacts of variant strains prevailing during the latest viral outbreak among vulnerable patient groups may offer timely relief from the pandemic.

Maternal serum pregnancy-associated plasma protein-A concentration at 11-14 weeks of gestation and preeclampsia risk of women with common congenital anatomic uterine abnormalities.

To evaluate maternal serum pregnancy-associated plasma protein-A (PAPP-A) levels at 11-14 weeks of gestation and preeclampsia risk in women with common congenital anatomic uterine abnormalities (AUAs). First trimester screening markers were compared between 12 AUA pregnancies, 60 age matched controls and 12 cases of early preeclampsia. PAPP-A level and birth weight were significantly lower in AUA compared to control and early preeclampsia group (p<.001). Preeclampsia was absent in the AUAs pregnancies group. Birth weight were similar in AUA group when we compared AUA and control group regarding weeks of gestation at delivery and lower but not significantly, when we compared AUA and early preeclampsia group. Our findings suggest that AUA pregnancies are associated with low first trimester maternal serum PAPP-A concentrations not predictive of susceptibility to preeclampsia.Impact statementWhat is already known on this subject? During first trimester screening for preeclampsia based on maternal pregnancy-associated plasma protein A (PAPP-A) levels, various parameters are used, such as the somatometric characteristics of pregnant woman, single or multiple pregnancy, smoking status, family history, diabetes, hypertension and measurement of blood pressure and uterine artery Dopplers.What do the results of this study add? Our pioneer study revealed that there is drastic difference in PAPP-A concentration in women with common anatomic uterine abnormalities (AUAs), in comparison with their age matched control women with normal uterus.What are the implications of these findings for clinical practice and further research? Based on our results, uterine anatomical deviations, is another factor which must be taken in account for preeclampsia risk calculation and further clinical consultation and follow up in those pregnancies. Lower PAPP-A levels in AUA cases is a weak predictor of susceptibility to preeclampsia and could be associated to smaller placental size rather than poor placentation and in future research the calculation of the uterine cavity functional dimension may lead to a more accurate clinical assessment.

Susceptibility of ß-Thalassemia Heterozygotes to COVID-19.

BACKGROUND: ß-Thalassemia is the most prevalent single gene blood disorder, while the assessment of its susceptibility to coronavirus disease 2019 (COVID-19) warrants it a pressing biomedical priority. METHODS: We studied 255 positive COVID-19 participants unvaccinated against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), consecutively recruited during the last trimester of 2020. Patient characteristics including age, sex, current smoking status, atrial fibrillation, chronic respiratory disease, coronary disease, diabetes, neoplasia, hyperlipidemia, hypertension, and ß-thalassemia heterozygosity were assessed for COVID-19 severity, length of hospitalization, intensive care unit (ICU) admission and mortality from COVID-19. RESULTS: We assessed patient characteristics associated with clinical symptoms, ICU admission, and mortality from COVID-19. In multivariate analysis, severe-critical COVID-19 was strongly associated with male sex (p = 0.023), increased age (p < 0.001), and ß-thalassemia heterozygosity (p = 0.002, OR = 2.89). Regarding the requirement for ICU care, in multivariate analysis there was a statistically significant association with hypertension (p = 0.001, OR = 5.12), while ß-thalassemia heterozygosity had no effect (p = 0.508, OR = 1.33). Mortality was linked to male sex (p = 0.036, OR = 2.09), increased age (p < 0.001) and ß-thalassemia heterozygosity (p = 0.010, OR = 2.79) in multivariate analysis. It is worth noting that hyperlipidemia reduced mortality from COVID-19 (p = 0.008, OR = 0.38). No statistically significant association of current smoking status with patient characteristics studied was observed. CONCLUSIONS: Our pilot observations indicate enhanced mortality of ß-thalassemia heterozygotes from COVID-19.

The O-Linked N-Acetylglucosamine Containing Epitope H (O-GlcNAcH) is Upregulated in the Trophoblastic and Downregulated in the Fibroblastic Cells in Missed Miscarriage Human Chorionic Villi With Simple Hydropic Degeneration.

Epitope H contains an O-linked N-acetylglucosamine (O-GlcNAcH) residue in a specific conformation and/or environment recognized by the mouse monoclonal antibody H. O-GlcNAcH is present in several types of cells and in several polypeptides, including cytokeratin 8 and vimentin, on the latter in cells under stress. In the present work, we examined the expression of the O-GlcNAcH in 60 cases of endometrial curettings from missed miscarriage cases containing normal and simple hydropic degenerated chorionic villi in each case, using monoclonal antibody H and indirect immunoperoxidase and Western blot immunoblot. In all cases examined the expression of the O-GlcNAcH was cytoplasmic as follows: (1) syncytiotrophoblastic cells showed very low expression in chorionic villi (CV) with nonhydropic degeneration (NHD) and high expression in hydropic degenerated (HD) CV; (2) cytotrophoblastic cells showed low expression in CV with NHD and high expression in HD CV; (3) fibroblastic cells showed high expression in CV with NHD and very low expression in HD CV; (4) histiocytes showed very low expression in both types of CV; (5) endothelial cells showed high expression in both types of CV. An immunoblot of CV from one case of a legal abortion from a normal first-trimester pregnancy showed 5 polypeptides with 118.5, 106.3, 85, 53, and 36.7 kD bearing the epitope H and the 53 kD corresponded to cytokeratin 8. The expression of the O-GlcNAcH is upregulated in the trophoblastic cells and downregulated in the fibroblastic cells in the HD CV in comparison to the NHD CV.