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.

Readressing the role of Toll-like receptor-4 alleles in inflammatory bowel disease: colitis, smoking, and seroreactivity.

BACKGROUND: Toll-like receptor (TLR) polymorphisms, and especially TLR-4 Asp299Gly and TLR-4 Thr399Ile, have been linked with Crohn's disease (CD) and to a lesser extent with ulcerative colitis (UC), CD behavior, and compromised seroreactivity to microbial antigens. Available data, however, are conflicting. AIMS: To address these issues, the distribution of TLR-4 polymorphic alleles was assessed in patients with UC, CD, and healthy controls (HC), considering patient and disease characteristics as well as related serological markers. METHODS: TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms were determined in 187 UC and 163 CD patients and 274 randomly selected HC. C reactive protein, anti-Saccharomyces cerevisiae mannan antibodies, anti-mannobioside carbohydrate antibodies, anti-laminariobioside carbohydrate antibodies IgG, and anti-chitobioside carbohydrate antibodies (ACCA) IgA levels were also assessed. RESULTS: UC and especially pancolitis patients carried the mutant alleles more frequently compared to CD patients and HC or UC patients with different disease extents (P = 0.002 and P < 0.0001, respectively). Involvement of the colon was more frequent in CD patients with mutant TLR-4 compared to those with wild-type alleles (P = 0.004). Levels and positivity rates of ACCA IgA were lower in inflammatory bowel disease (IBD) patients carrying the mutant compared to those with wild-type alleles (0.075 < P < 0.05). Despite the mutant TLR-4 predisposition for UC pancolitis, smoking was associated with more limited disease (P < 0.001). CONCLUSIONS: The presence of TLR-4 Asp299Gly and TLR-4 Thr399Ile polymorphisms is related to UC pancolitis, involvement of the colon in CD, and lower ACCA IgA levels. Smoking reduces the extent of UC, even in the presence of mutant alleles.

On the management of hyperglycaemia in critically ill patients undergoing surgery.

Hyperglycaemia is a major health risk and a negative determinant of surgical outcome. Despite its increasing prevalence, the limited treatments for restoration of normoglycaemia make its effective management a highly complex individualized clinical art. In this context, we review the mechanisms leading to hyperglycaemic damage as the basis for effective management of surgical complications of diabetic and non diabetic critically ill patients.

Practical approaches to effective management of intestinal radiation injury: benefit of resectional surgery.

AIM: To study the outcome of patients undergoing surgical resection of the bowel for sustained radiation-induced damage intractable to conservative management. METHODS: During a 7-year period we operated on 17 cases (5 male, 12 female) admitted to our surgical department with intestinal radiation injury (IRI). They were originally treated for a pelvic malignancy by surgical resection followed by postoperative radiotherapy. During follow-up, they developed radiation enteritis requiring surgical treatment due to failure of conservative management. RESULTS: IRI was located in the terminal ileum in 12 patients, in the rectum in 2 patients, in the descending colon in 2 patients, and in the cecum in one patient. All patients had resection of the affected region(s). There were no postoperative deaths, while 3 cases presented with postoperative complications (17.7%). All patients remained free of symptoms without evidence of recurrence of IRI for a median follow-up period of 42 mo (range, 6-96 mo). CONCLUSION: We report a favorable outcome without IRI recurrence of 17 patients treated by resection of the diseased bowel segment.

Sequence variations in the FII, FV, F13A1, FGB and PAI-1 genes are associated with differences in myocardial perfusion.

AIMS: Coronary artery disease (CAD) is a significant cause of morbidity and mortality in modern societies. The association between genetic markers and CAD is still poorly understood. In this study, we evaluated the effect of five genetic variants: Factor V Leiden (FV:c.1691G>A) (rs6025), Factor II prothrombin (FII:c.20210G>A; rs1799963), plasminogen activator inhibitor 1 (PAI-1) -675(4G/5G; SERPINE1:g.4329_4330insG; rs34857375), ß-fibrinogen -455G>A (FGB:c.4577G>A; rs1800790) and Factor XIII (F13A1:c.103G>T; rs5985) on myocardial perfusion. MATERIALS & METHODS: We examined 523 patients using exercise-rest myocardial perfusion single photon emission computed tomography, where the summed stress score (SSS), summed rest score and summed difference score (SDS) indexes, were calculated. In order to examine the independent prognostic ability of genotype on SSS and SDS, multiple linear regression models were used. RESULTS: It was found that Factor V Leiden, Factor XIII, ß-fibrinogen and PAI-1 genotypes were independent prognostic predictors of SSS and SDS with Factor XIII exhibiting the strongest association. Moreover, Factor II prothrombin proved an independent prognostic predictor of SSS. CONCLUSION: Our study provides the first evidence of an association between these polymorphisms and myocardial perfusion, suggesting that the process of coronary artery disease and also patients' prognosis, may be modified by the FV:c.1691G>A, FII:c.20210G>A, PAI-1 -675 (4G/5G), ß-fibrinogen FGB:c.4577G>A and F13A1:c.103G>T genotypes.

Use of albumin polymers during breast cancer surgery improves postoperative seroma outcome.

The effect of an albumin polymer instillation (Bioglue® Cryolife, Inc., Kenneaw, GA, USA) during breast cancer surgery on postoperative seroma formation was evaluated. Two groups of 34 consecutive patients, treated during operation with and without polymer, were followed postoperatively by weekly ultrasound and clinical evaluation. Seroma was aspirated when the volume exceeded 250 mL. Statistical comparison between 33 of the patients with adhesive- and 32 with non-adhesive-treated patients showed that the former patient group clearly outperformed the latter in production (p<0.001) and duration (p<0.01) of seroma. Seroma outcome depended on body mass index (BMI) (>30 & <30, p<0.007), not on patient age (p<0.240) or nodes ratio (p<0.613). Repeated aspirations were made in 37.5% non-polymer treated- and 21.21% polymer-treated patients. The findings demonstrated that use of albumin polymers during breast cancer surgery lowers postoperative seroma outcome significantly.

The Hellenic type of nondeletional hereditary persistence of fetal hemoglobin results from a novel mutation (g.-109G>T) in the HBG2 gene promoter.

Nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH), a rare hereditary condition resulting in elevated levels of fetal hemoglobin (Hb F) in adults, is associated with promoter mutations in the human fetal globin (HBG1 and HBG2) genes. In this paper, we report a novel type of nd-HPFH due to a HBG2 gene promoter mutation (HBG2:g.-109G>T). This mutation, located at the 3' end of the HBG2 distal CCAAT box, was initially identified in an adult female subject of Central Greek origin and results in elevated Hb F levels (4.1%) and significantly increased Ggamma-globin chain production (79.2%). Family studies and DNA analysis revealed that the HBG2:g.-109G>T mutation is also found in the family members in compound heterozygosity with the HBG2:g.-158C>T single nucleotide polymorphism or the silent HBB:g.-101C>T beta-thalassemia mutation, resulting in the latter case in significantly elevated Hb F levels (14.3%). Electrophoretic mobility shift analysis revealed that the HBG2:g.-109G>T mutation abolishes a transcription factor binding site, consistent with previous observations using DNA footprinting analysis, suggesting that guanine at position HBG2/1:g.-109 is critical for NF-E3 binding. These data suggest that the HBG2:g-109G>T mutation has a functional role in increasing HBG2 transcription and is responsible for the HPFH phenotype observed in our index cases.

Low-Grade Appendiceal Mucinous Neoplasm Presenting as a Surgical Emergency: A Case Report.

We present the case of a female patient admitted to our University Hospital with acute abdominal pain mimicking an intraperitoneal septic condition caused possibly by acute appendicitis. CT and ultrasound scan showed a mass situated in the right iliac fossa. The patient was submitted to laparotomy and right hemicolectomy. The operative findings were suggestive of an appendiceal mucocele. The histology report revealed a low-grade appendiceal mucinous neoplasm. The patient had no clinical, biochemical or visual signs of disease recurrence 6 months postoperatively.

The 5' regulatory region of the human fetal globin genes is a gene conversion hotspot.

The human fetal globin genes consist of the first mammalian genomic loci for which gene conversion was reported. To date, 14 gene conversions have been described in the human Ggamma- and Agamma-globin genes, the vast majority of which are restricted to the coding sequences. Here, we provide evidence for three new gene conversion events in the 5' regulatory region of the human fetal globin genes, identified during a large genetic screening effort in adult individuals with high fetal hemoglobin (Hb) levels. The sequence variations, resulting from these conversion events, are transcriptionally silent polymorphisms that do not contribute to increased fetal Hb levels. Our results suggest that the 5' regulatory region of the human fetal globin genes is a gene conversion hotspot that prevent globin gene promoter sequence diversification, further underlining the need for two functional fetal globin genes in fetal erythropoiesis.

Predominantly post-transcriptional regulation of activation molecules in chronic lymphocytic leukemia: the case of transferrin receptors.

Transcriptional and post-transcriptional control mechanisms have a differential impact on cellular physiology depending on activation status. Several lines of evidence suggest that chronic lymphocytic leukemia (CLL) malignant B cells resemble antigen-experienced and activated B cells. In the present study, we investigated the expression of transferrin receptor 1 (TfR1, CD71), one of the "classical" markers up-regulated upon B-cell activation, and TfR2, a novel receptor for transferrin, in peripheral blood CD19+ B cells from ten healthy individuals and 76 patients with CLL so as to gain insight into potential disease-related differences in underlying regulatory mechanisms. Marked differences in the production and expression of these receptors were detected in malignant but not in normal B cells. Specifically, TfR1 mRNA and protein levels were significantly higher in comparison to TfR2, both in normal and malignant B cells. Furthermore, discrepancies between TfR mRNA and protein expression were observed in CLL; in contrast, mRNA and protein expression levels were generally concordant in normal B cells. Exposure to actinomycin D decreased TfR1 and TfR2 mRNA levels in normal CD19+ B cells but had no effect on CLL malignant cells. The protein synthesis inhibitor cycloheximide had opposing effects in normal vs. CLL malignant B cells: thus, TfR1 and TfR2 mRNA levels were increased in normal B cells, whereas they were unaffected or even suppressed in CLL malignant B cells. These results allude to differential regulation of TfR1 and TfR2 expression in normal B cells vs. CLL. In normal B cells, transcriptional mechanisms exert a critical control over TfR1 and TfR2 expression, whereas in CLL post-transcriptional mechanisms seem to play a complementary and perhaps more important role. This type of control appears to be especially suited for modulation of genes implicated in proliferation of activated cells, like CLL malignant B cells.

Growth hormone, insulin-like growth factor I, and leptin interaction in human cultured lutein granulosa cells steroidogenesis.

OBJECTIVE: To investigate the effect of leptin on the actions of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in ovarian steroidogenesis in vitro. DESIGN: In vitro cell culture study. SETTING: Research laboratory of a university hospital. PATIENT(S): Luteinized granulosa cells (GC) were obtained from 20 healthy women undergoing ovarian stimulation for IVF treatment. INTERVENTION(S): Granulosa cells were cultured in serum free conditions for 72 hours with either GH or IGF-I, or their combination, in the absence or presence of leptin (1, 10, and 100 ng/mL). MAIN OUTCOME MEASURE(S): At 24 and 72 hours of the culture estradiol (E(2)) and progesterone (P) concentrations were measured in culture supernatants by enzyme immunoassays. RESULT(S): Leptin at the doses of 1 and 10 ng/mL significantly stimulated, whereas at the dose of 100 ng/mL it significantly suppressed E(2) and P production as compared to control. Estradiol production was significantly stimulated by both GH (72 hours) and IGF-I (24 and 72 hours) and that of P only by IGF-I (72 hours). Leptin at the low doses enhanced, whereas at the high dose it suppressed the effect of GH or IGF-I on E(2) and P synthesis. CONCLUSION(S): These results demonstrate for the first time that leptin can modulate the effect of GH on steroids production by human luteinized GC in culture.

Large-scale population genetic analysis for hemoglobinopathies reveals different mutation spectra in central Greece compared to the rest of the country.

We have undertaken a large population screening study to identify the molecular basis of hemoglobinopathies in the central Greece region. A total of 845 unrelated beta-thalassemia patients and alpha-, beta-, and deltabeta-thalassemia carriers have been recruited and screened for mutations in the alpha- and beta-globin gene clusters. The alpha(-MED) deletion and the Turkish inversion/deletion are the most frequent genetic rearrangements leading to alpha- and deltabeta-thalassemia respectively, contrary to the situation in the rest of the country, while the beta -101 (C>T) promoter mutation is surprisingly frequent in the central part of Greece. Our data indicate that determination of mutation frequencies in different regions is vital for accurate provision of genetic services and counseling and for precise estimation of genetic diversity.

Serum and follicular fluid leptin levels are correlated with human embryo quality.

This prospective study was undertaken to reassess the prognostic value of leptin during critical stages of in vitro fertilization-embryo transfer (IVF-ET) and address its role in the functional staging of assisted reproductive technologies at the level of embryo quality. Serum and follicular fluid samples of 100 selected women undergoing the long IVF-ET protocol were collected for leptin and embryo quality determination. The highest serum leptin concentration (52.11 +/- 4.27 ng/ml) was observed on ovum pick up day, while follicular fluid leptin was higher than all serum samples examined (62.59 +/- 5.73 ng/ml). Serum leptin above 59.48 +/- 7.6 ng/ml was associated with 'poor' embryo quality and above 56.87 +/- 5.52 ng/ml with pregnancy failure. Elevated leptin concentrations were associated with reduced ovarian stimulation and response, follicle maturation, embryo quality and pregnancy success. Our findings suggest that leptin modulates embryo quality and may serve as a sensitive marker of IVF outcome.