Epigenetic mechanisms and oral mucositis in children with acute lymphoblastic leukaemia.

This study aimed to investigate the relationship between epigenetic mechanisms and oral mucositis (OM) in paediatric patients with acute lymphoblastic leukaemia. Oral cells were collected from 76 participants, including 15 healthy individuals, 10 patients with acute lymphoblastic leukaemia but without a history of OM and 51 acute lymphoblastic leukaemia patients with a history of OM (35 with active OM and 16 who had recovered from OM). Global DNA methylation in the miR-9-1 and miR-9-3 genes was performed. Seven polymorphisms rs1801131, rs1801133 (MTHFR), rs2228611 (DNMT1), rs7590760, rs1550117 (DNMT3A), rs6087990, rs2424913 (DNMT3B) were genotyped and an analysis of association with global DNA methylation was performed. The global methylation levels were lower in cancer patients recovered from OM than in the other groups. A higher frequency of unmethylated profile for miR-9-1 and partially methylated profile for miR-9-3 was observed in cancer patients regardless of OM history compared to healthy patients. The GG genotype of the rs2228611 (DNMT1) polymorphism was associated with higher levels of global methylation in cancer patients irrespective of OM. It was concluded that global methylation is associated with mucosal recovery. The effect of DNMT1 genotype on the global DNA methylation profile, as well as the methylation profile of miR-9-1 and miR-9-3 in cancer patients is independent of OM.

Lateral Globe Exposure Associated With Graves Upper Eyelid Retraction: The Influence of the Superior Complex Enlargement and Proptosis.

PURPOSE: To investigate the association of the lateral exposure of the globe with proptosis and the enlargement of the superior complex (SC) (levator palpebrae superioris muscle + superior rectus muscle) in patients with Graves upper eyelid retraction. METHODS: Twenty-eight patients with upper lid retraction secondary to Graves orbitopathy and 28 controls matched by age and gender participated in the study. The variables exophthalmometry, margin-reflex distance 1, and upper lid fissure temporal and nasal areas were assessed. Coronal CT scans were evaluated for the measurement of the SC area. A 5% level of significance was assumed for analysis. RESULTS: Abnormal temporal nasal area differences (T-N), defined as values above the superior limit of the control distribution (15.58mm2) were detected in 18 patients. Multiple regression analysis showed a significant correlation of abnormal temporo-nasal asymmetries with the SC area and the proptosis (T-N = -6.7 + 0.62* proptosis + 12.3 SC area, R2 = 0.37; p = 0.003). CONCLUSION: The etiology of the enhanced lateral globe exposure is not unifactorial. SC enlargement and, to a lesser extent, proptosis are important factors correlated to lateral globe exposure.

Blink Lagophthalmos in Graves Orbitopathy.

PURPOSE: To investigate the relationship between the kinematics of spontaneous blinks and the anterior area of the levator palpebrae superioris muscle in patients with Graves orbitopathy (GO). METHODS: This is a case-control study. The authors measured the margin reflex distance of the upper eyelid (margin reflex distance 1), the kinematics of spontaneous blinks, and the anterior area of levator palpebrae superioris muscle in CT coronal scans of patients with Graves upper eyelid retraction (GO) and a control group. The eye with the greatest margin reflex distance 1 was selected for analysis in each group. RESULTS: A total of 68 participants were included, with 36 in the GO group and 32 in the control group. In the GO group, the mean margin reflex distance 1 measured 6.5 mm, while in the control group, it was 3.9 mm. Almost all parameters related to the closing phase of spontaneous blinking activity, including amplitude, velocity, blinking rate, and interblink time, did not differ between the two groups. However, the effectiveness of the blink's amplitude (ratio of blink amplitude to margin reflex distance 1) and the main sequence (relationship between amplitude and velocity) were significantly reduced in the GO group compared with the control group. The area of the levator palpebrae superioris muscle was significantly larger in GO than in controls, with 71.4% of patients' muscles outside of the maximum range of the controls. CONCLUSIONS: In patients with GO, there is a reduction in blinking effectiveness, also known as blink lagophthalmos, which is a factor in the common occurrence of ocular surface symptoms. The increase in velocity with amplitude is also reduced in GO.

Orbital Pigmented Epithelioid Melanocytoma Tumor Associated With Nevus of Ota (Oculodermal Melanocytosis).

The authors report a patient with nevus of Ota (oculodermal melanocytosis) who presented with pigmented epithelioid melanocytoma in the right orbit. A 36-year-old female patient attended with proptosis OD and diplopia for 3 months. MRI disclosed an expansive lesion adhered to the right inferior rectus muscle, enlargement of the superior orbital fissure, and filling of the right cavernous sinus. Excision of the orbital mass through a transconjunctival inferior fornix access disclosed a heavily pigmented lesion. Anatomopathological study revealed a diagnosis of pigmented epithelioid melanocytoma. A positron emission tomography scan did not show any metastasis. The patient was submitted to radiotherapy, had an improvement of the proptosis and diplopia, and showed no distant metastases for 3 years now. Pigmented epithelioid melanocytoma belongs to the group of heavily pigmented neoplasms, as do atypical blue nevus, which is characterized by prominent melanin production and a low degree of malignancy.

Rundle's Curve: A Useful Construct That Does Not Fit All.

PURPOSE: The purpose of this study was to analyze Rundle's original data and subsequent articles on Graves orbitopathy (GO) natural history. METHODS: Rundle's texts were analyzed qualitatively and quantitatively. Serial measurements were plotted and fitted with different functions. Subsequent articles in the English literature on the natural history of GO were also analyzed. RESULTS: Different functions such as simple linear regressions, parabolic, saturating exponential growth, and exponential decay functions were well fitted for Rundle's data on measurements of proptosis and supraduction along time. The few quantitative data of the same variables post-Rundle were also well-fitted with various functions. CONCLUSION: Rundle described in his articles, from 1945 to 1957, 2 phases of ocular changes in GO: dynamic and static. However, he did not mention the pathophysiology of these phases nor used the terms inflammatory and cicatricial. Actually, most of his observations and the subsequent data in the literature on proptosis and supraduction did not obey the biphasic pattern of the so-called Rundle's curve.

Medial Oblique Eyelid Split Orbitotomy.

PURPOSE: The authors describe their experience with a variant of the split orbitotomy with a small medial oblique transmarginal incision for approaching a variety of lesions involving the superonasal aspect of the orbit. METHODS: Retrospective review of medical records and clinical photographs of all patients who underwent an unilateral medial oblique incision to access various intraconal lesions abutting the superomedial quadrant of the orbit. The curvature of the medial contour of the operated and contralateral eyelids were expressed with Bézier functions and compared using the R-squared coefficient of determination (R 2 ). RESULTS: Twenty-three patients were submitted to this surgical technique for approaching various unilateral lesions on the superonasal quadrant of the orbit. Excellent cosmesis was achieved in all eyelids, with almost imperceptible scars, and no ptosis or retraction. There was no significant difference between the postoperative medial contour of the operated and the contralateral eyelid, with R 2 ranging from 0.896 to 0.999, mean 0.971. CONCLUSIONS: The authors' results show that the modified eyelid split approach provides a wide exposure of the superonasal quadrant of the orbit with no risk of eyelid dysfunctions or significant scars.

Congenital opticmeningocele: diagnosis, treatment, and follow-up.

Congenital opticmeningoceles were recently described as intraorbital optic nerve cystic lesions, in which neural tissue is found to be part of the lining of the lesion. We describe the case of an eleven-month-old patient with a right opticmeningocele, followed through seven years. He presented with proptosis and hypotropia since birth and imaging exams disclosed an intraconal cystic lesion. A needle puncture revealed a fluid characteristic of cerebrospinal fluid. Surgical drainage performed through a lid crease approach resulted in recurrence of the proptosis. Surgical excision of the capsule finally was definitive, and pathology revealed an epithelial-lined capsule. Eight months after the capsule excision, a strabismus surgery was performed to improve the right hypotropia. Although visual prognosis of opticmeningoceles is poor, a good cosmetic result can be obtained with a multidisciplinary approach involving orbit and strabismus surgeons. The complete capsule excision is believed to be the preferable surgical option for permanently treating the proptosis once needle puncture and cyst drainage are associated with recurrence. The orbital access for approaching the lesion depends on the location of the cyst and should provide wide exposure to avoid new surgical procedures in young patients.

Computed tomography and magnetic resonance imaging of an unusual intraconal orbital osteoma.

We report the case of a 64-year-old male patient with a 5 month history of proptosis, motility limitation and vision loss in OD. Visual acuity (VA) was 20/200 in OD and 20/20 in OS. CT showed a large, round, intraconal lesion, with bony density and no apparent connection to adjacent orbital walls. MRI showed a T1-weighted hypointense lesion surrounded by a contrast enhancing capsule. The orbital tumor was excised through a lateral orbitotomy revealing a nodular, round, osseous structure. Histological examination disclosed well-formed lamellar bone trabeculae, with no necrosis or mitosis figures. Immunohistochemical staining was negative for MDM2 and CDK4. After 3 years, there was no evidence of tumor recurrence and VA had improved to 20/30. Intraconal osteomas with no clear attachment to orbital walls are extremely rare. We are aware of a few reported cases in the lid, hand, thigh, tongue, pterygopalatine fossa and brain. To the authors' knowledge, this is the first report in English literature of an orbital intraconal osteoma without any visible relation to the orbital walls.

Margin rotation for tarsal buckling following ptosis surgery.

PURPOSE: To assess the clinical characteristics of tarsal buckling after ptosis correction and its management with margin rotation techniques. METHODS: Multicenter retrospective review of ten patients who developed upper eyelid entropion following ptosis correction. In all cases the tarsal deformity was corrected with margin rotational procedures with either a lid crease anterior approach or a traditional posterior approach. Data collection included patient demographics, type of ptosis surgery, and photographic documentation of the affected eyelids. RESULTS: Entropion occurred after a variety of different ptosis surgery techniques, including frontalis sling, levator advancement and supramaximal levator resection. A horizontal tarsal fold was detected in all eyelids, being in the upper third of the tarsus in 70% and in the central tarsus in 20% of the cases. Tarsal buckling was corrected in all cases with rotational surgery, with nine cases being operated through an anterior lid crease approach and 1, through the traditional posterior approach. The most reported complication was minimal residual ptosis. CONCLUSION: Tarsal buckling following ptosis surgery is associated with folds located in the upper part of the tarsus. Margin rotation techniques are effective in restoring the natural position of the eyelid margin in these cases.

Single-cell RNA sequencing distinguishes dendritic cell subsets in the rat, allowing advanced characterization of the effects of FMS-like tyrosine kinase 3 ligand.

Tissue-resident dendritic cells (DCs) are essential for immunological homeostasis and hold promise for a variety of therapeutic interventions. The rare nature of tissue-resident DCs and their suboptimal description in the lab rat model has limited their characterization. To address this limitation, FMS-like tyrosine kinase 3 ligand (FLT3L) has been utilized to expand these population in vitro and in vivo for investigative or therapeutic purposes. However, conflicting reports have suggested that FLT3L can either promote immune tolerance or enhance immunogenicity, necessitating clarification of the effects of FLT3L on DC phenotype and functionality. We first paired single-cell RNA sequencing with multicolour spectral flow cytometry to provide an updated strategy for the identification of tissue-resident classical and plasmacytoid DCs in the rat model. We then administered FLT3L to Lewis rats in vivo to investigate its effect on tissue-resident DC enumeration and phenotype in the liver, spleen, and mesenteric lymph nodes. We found that FLT3L expands classical DCs (cDCs) 1 and 2 in a dose-dependent manner and that cDC1 and cDC2 in secondary lymphoid organs had altered MHC I, MHC II, CD40, CD80, CD86, and PD-L1 cell-surface expression levels following FLT3L administration. These changes were accompanied by an increase in gene expression levels of toll-like receptors 2, 4, 7, and 9 as well as inflammatory cytokines IL-6 and TNF-α. In conclusion, FLT3L administration in vivo increases cDC enumeration in the liver, spleen, and mesenteric lymph nodes accompanied by a tissue-restricted alteration in expression of antigen presentation machinery and inflammatory mediators.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2021.

The American Transplant Congress 2021 was a virtual meeting and occurred between June 4 and June 9 through an online platform. We highlighted abstracts discussing machine perfusion preservation, a hot topic that may become the gold standard of organ preservation in the future. A total of 33 abstracts on organ machine preservation (3 for heart, 4 for lungs, 18 for liver, and 8 for kidneys) were presented at the meeting. We selected 23 abstracts that showed advances including new approaches to organ preservation, promising treatments and biomarkers, cellular therapy, and novel research areas. Here, we summarize the new developments concerning machine perfusion in both experimental and clinical studies.

Eye morphology of Guiana dolphins (Sotalia guianensis) and Clymene dolphins (Stenella clymene).

Recent studies showed that vision and hearing in dolphins are mechanisms for perception of the environment, and transmission of information among individuals. Considering that Guiana dolphins (Sotalia guianensis) are distributed in costal regions, and Clymene dolphins (Stenella clymene) are found in oceanic environments, the objective of this study was to compare the morphology of the eyes of these two species, assessing the differences in eye structures in both environments. Five specimens of Sotalia guianensis and four specimens of Stenella clymene were analyzed. All the specimens were found stranded in the northeastern coast of Brazil. Samples were fixated in 10% formaldehyde, dissected, photographed, processed, and analyzed by optical microscopy. The inferior palpebral region of the two species showed a granular layer, subcutaneous lymphoid tissue, and innervation. Morphometric values of the eyelid structures and eye bulb were greater in S. clymene. The cornea showed four layers in S. clymene: anterior epithelium, anterior lamina, stroma, and posterior lamina. The sclera of S. guianensis showed more melanocytes and presence of mechanoreceptors next to the Harderian gland. It is possible to suggest that the geographical distribution of these cetaceans determine their eye morphology, which is an adaptation to the intrinsic characteristics of the aquatic environment.

Progressive chronic calvarial osteomyelitis in rhino-orbital mucormycosis associated with COVID-19.

We describe two cases of extensive indolent calvarial osteomyelitis after rhino-orbital-mucormycosis in diabetic patients previously diagnosed with COVID-19. Both patients presented with acute rhino-orbital symptoms about one month after being diagnosed with COVID-19. Treatment with intravenous liposomal Amphotericin B and prompt radical surgical debridement was instituted, but calvarial osteomyelitis ensued and persisted chronically despite maintenance of antifungal therapy and partial debridement of necrotic calvarial bone. The patients were discharged to continue antifungal therapy on a day-hospital regime. After more than 8 months of treatment, they remain with radiological signs of osteomyelitis but with no symptoms or intracranial extension of the infection. Calvarial indolent osteomyelitis secondary to mucormycosis is extremely rare, and little is known regarding its treatment. We believe it can be controlled with medical treatment and partial bony debridement although more studies are necessary to better define therapy.

Modifying organs with gene therapy and gene modulation in the age of machine perfusion.

PURPOSE OF REVIEW: This review aims to highlight current advances in gene therapy methods, describing advances in CRISPR-Cas9 gene editing and RNA interference in relevance to liver transplantation, and machine perfusion. RECENT FINDINGS: In order to minimize rejection, increase the donor pool of available organs, and minimize the effects of ischemia-reperfusion injury, gene therapy and gene modification strategies are, thus, required in the context of liver transplantation. SUMMARY: Gene therapy has been used successfully in a diverse array of diseases, and, more recently, this technique has gained interest in the field of organ transplantation. Biological and logistical challenges reduce the rate of successful procedures, increasing the waiting list even more. We explore the exciting future implications of customized gene therapy in livers using machine perfusion, including its potential to create a future in which organs destined for transplant are individualized to maximize both graft and recipient longevity.

Interleukin-10 and Transforming Growth Factor-ß Cytokines Decrease Immune Activation During Normothermic Ex Vivo Machine Perfusion of the Rat Liver.

Normothermic ex vivo liver perfusion (NEVLP) is a novel system for organ preservation that may improve over static cold storage clinically and offers the chance for graft modification prior to transplantation. Although recent studies have shown the presence of inflammatory molecules during perfusion, none have yet shown the effects of NEVLP on liver-resident immune cell activation. We investigated the effects of NEVLP on liver-resident immune cell activation and assessed the ability of anti-inflammatory cytokines interleukin 10 (IL10) and transforming growth factor ß (TGF-ß) to improve organ function and reduce immune activation during perfusion. Rat livers were perfused for 4 hours at 37°C with or without the addition of 20 ng/mL of each IL10 and TGF-ß (n = 7). Naïve and cold storage (4 hours at 4°C) livers served as controls (n = 4). Following preservation, gene expression profiles were assessed through single-cell RNA sequencing; dendritic cell and macrophage activation was measured by flow cytometry; and cytokine production was assessed by enzyme-linked immunosorbent assay. NEVLP induced a global inflammatory gene expression signature, most notably in liver-resident macrophages and dendritic cells, which was accompanied by an increase in cell-surface levels of major histocompatibility complex (MHC) II, CD40, and CD86. Immune activation was partially ameliorated by IL10 and TGF-ß treatment, but no changes were observed in inflammatory cytokine production. Overall levels of liver damage and cellular apoptosis from perfusion were low, and liver function was improved with IL10 and TGF-ß treatment. This is the first study to demonstrate that liver-resident immune cells gain an activated phenotype during NEVLP on both the gene and protein level and that this activation can be reduced through therapeutic intervention with IL10 and TGF-ß.

Iodine knowledge is associated with iodine status in Portuguese pregnant women: results from the IoMum cohort study.

Lack of knowledge about iodine has been suggested as a risk factor for iodine deficiency in pregnant women, but no studies have addressed this issue in Portugal. So, the aim of this study was to investigate iodine knowledge among Portuguese pregnant women and its association with iodine status. IoMum, a prospective observational study, included 485 pregnant women recruited at Centro Hospitalar e Universitário de S. João, Porto, between the 10th and 13th gestational weeks. Partial scores for knowledge on iodine importance, on iodine food sources or on iodised salt were obtained through the application of a structured questionnaire. Then, a total iodine knowledge score was calculated and grouped into low, medium and high knowledge categories. Urinary iodine concentration (UIC) was measured in spot urine samples by inductively coupled plasma MS. Of the pregnant women, 54 % correctly recognised iodine as important to neurocognitive development, 32 % were unable to identify any iodine-rich food and 71 % presented lack of knowledge regarding iodised salt. Of the women, 61 % had a medium total score of iodine knowledge. Knowledge on iodine importance during pregnancy was positively associated with iodine supplementation and also with UIC. Nevertheless, median UIC in women who correctly recognised the importance of iodine was below the cut-off for adequacy in pregnancy (150 µg/l). In conclusion, knowledge on iodine importance is positively associated with iodine status. Despite this, recognising iodine importance during pregnancy may not be sufficient to ensure iodine adequacy. Literacy-promoting actions are urgently needed to improve iodine status in pregnancy.

The association of milk and dairy consumption with iodine status in pregnant women in Oporto region.

The role of milk and dairy products in supplying iodine to pregnant women is unknown in Portugal. The aim of this study was to evaluate the association between milk and dairy product consumption and the iodine status of pregnant women in the IoMum cohort of the Oporto region. Pregnant women were recruited between 10 and 13 weeks of gestation, when they provided a spot urine sample and information on lifestyle and intake of iodine-rich foods. Urinary iodine concentration (UIC) was determined by inductively coupled plasma MS. A total of 468 pregnant women (269 iodine supplement users and 199 non-supplement users) were considered eligible for analysis. Milk (but not yogurt or cheese) intake was positively associated with UIC, in the whole population (P = 0·02) and in the non-supplement users (P = 0·002), but not in the supplement users (P = 0·29). In non-supplement users, adjusted multinomial logistic regression analysis showed that milk consumption <3 times/month was associated with a five times increased risk of having UIC < 50 µg/l when compared with milk consumption ≥2 times/d (OR 5·4; 95 % CI 1·55, 18·78; P = 0·008). The highest UIC was observed in supplement users who reported consuming milk once per d (160 µg/l). Milk, but not yogurt or cheese, was positively associated with iodine status of pregnant women. Despite the observed positive association, daily milk consumption may not be sufficient to ensure adequate iodine intake in this population.

Optic Disc Edema and Posterior Globe Flattening Secondary to Ocular Hypotony: Case Report and Discussion Regarding Pathophysiology and Clinical Findings.

ABSTRACT: We describe a case of a young female patient presenting with ocular hypotension (4 mm Hg) secondary to cyclodialysis, and optic disc edema (ODE) after a blunt trauma in the right eye (right eye). MRI showed posterior globe flattening of the right eye, drawing our attention to the pathophysiology behind these findings. The combination of ODE and posterior globe flattening, as observed in the present case of ocular hypotony, is known from other conditions such as intracranial hypertension and space-flight neuro-ocular syndrome, pointing to a common pathophysiological mechanism, possibly resulting from axoplasmic stasis at the level of the lamina cribrosa due to a high translaminar pressure difference.

Origin and insertion of the nerves constituting the braquial plexus of the roadside hawk.

The roadside hawk (Rupornis magnirostris) is a free-living bird that commonly has wing injuries caused by man-made obstacles when flying. Studies that describe the topographic anatomy of the wings of this species are necessary to assist in the treatment of possible wing lesions. For this reason, the present work aimed to describe the origin and insertion of the nerves that constitute the brachial plexus in roadside hawks. Five roadside hawk carcasses donated to the Animal Anatomy Laboratory of the São Judas University Center, UNIMONTE campus, by CEPTAS (Center for Research and Screening of Wild Animals) were used for the study. The brachial plexus of the roadside hawk was formed by the union of the ventral branches of the spinal nerves located between C9-C10-T1-T2-T3. The ventral branches joined together and formed four short trunks which later united again by exchanging nerve fibers and constituting a big caliber branch. This is divided into two nerve cords (dorsal and ventral) which are destined to specific muscular groupings. The dorsal cord originates the axillary, anconeal and radial nerves, and is responsible for innervating the extensor muscles. The ventral cord originates the pectoral, bicipital, median-ulnar, median and ulnar nerves, and is responsible for innervating the flexor muscles.