Correlations between Retinal Microvascular Parameters and Clinical Parameters in Young Patients with Type 1 Diabetes Mellitus: An Optical Coherence Tomography Angiography Study.

OBJECTIVES: In the current study, we investigated the correlations between retinal microvascular parameters using optical coherence tomography angiography (OCTA) and clinical parameters for a group of 69 young patients with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This retrospective, exploratory study enrolled 69 patients between 5 years old and 30 years old who met the inclusion criteria. All the study participants underwent a comprehensive ophthalmic examination and OCTA scans for the evaluation of the retinal microcirculation. The retinal OCTA parameters were correlated with the following clinical parameters: the patient's age at the onset of the disease, the duration of T1DM, the BMI at the time of enrollment in the study, the HbA1C values at onset, the mean values of HbA1C over the period of monitoring the disease and the degree of DKA at onset. RESULTS: For the study group, the foveal avascular zone (FAZ) area and perimeter correlated positively with the mean value of HbA1C (Pearson correlation, Sig.2-Tailed Area: 0.044; perimeter: 0.049). The total vessel density in the superficial capillary plexus (SCP) correlated negatively with the duration of T1DM, based on the superior and inferior analyzed areas (Spearman correlation, Sig.2-Tailed SCP in total region: 0.002; SCP in the superior region: 0.024; SCP in the inferior region: 0.050). The foveal thickness also correlated negatively with the levels of diabetic ketoacidosis (DKA) at onset (Spearman correlation, Sig.2-Tailed: 0.034) and the levels of HbA1C at onset (Spearman correlation, Sig.2-Tailed: 0.047). Further on, the study patients were distributed into two groups according to the duration of the disease: group 1 included 32 patients with a duration of T1DM of less than 5 years, and group 2 included 37 patients with a duration of T1DM of more than 5 years. Independent t-tests were used to compare the OCTA retinal parameters for the two subgroups. While the FAZ-related parameters did not show significant statistical differences between the two groups, the vessel densities in both the SCP and DCP were significantly lower in group 2. CONCLUSIONS: Our data suggest that specific alterations in OCTA imaging biomarkers correlate with various clinical parameters: the FAZ area and perimeter increase with higher mean values of HbA1C, leading to poor metabolic control. Moreover, the SCP total vessel density decreases as the duration of T1DM increases. Regarding the vessel densities in the SCP and the DCP, they decrease with a duration of the disease of more than 5 years.

Retinal Microvascular Alterations in a Patient with Type 1 Diabetes Mellitus, Hemoglobin D Hemoglobinopathy, and High Myopia-Case Report and Review of the Literature.

Type 1 diabetes mellitus (type 1 DM) is one of the most prevalent endocrinological diseases among children and young adults, with a growing incidence rate reaching up to 2.9 new cases per year per 100,000 persons below 15 years of age. We report a rare case of a 20-year-old female patient with type 1 DM, hemoglobin D (HbD) heterozygote variant and high myopia of -10.00 spheric diopters, and describe the retinal microvascular alterations visible on OCT angiography (angio-OCT). The patient also presented with a severe stature deficit (less than three standard deviations) and delayed puberty, which could not be explained only by suboptimal glycemic control and indicated possible hypopituitarism. HbA1c level evaluated with the high-performance liquid chromatography (HPLC) method was 6.5%, a falsely low value due to HbD hemoglobinopathy. On ophthalmic evaluation, the angio-OCT scan showed the following retinal microvascular alterations in the right eye (RE): the FAZ (Foveal Avascular Zone) area was 0.39 mm2, the FAZ perimeter was 2.88 mm, and the circularity index was 0.58. The following alterations were shown in the left eye (LE): the FAZ area was 0.34 mm2, the FAZ perimeter was 3.21 mm, and the circularity index was 0.41. Clinicians should consider high-performance retinal screening methods such as angio-OCT evaluation for young type 1 DM patients, especially for those with associated pathologies like high myopia and hemoglobinopathies. Moreover, multiple evaluation methods of HbA1c values are mandatory as hemoglobinopathies can interfere with the accuracy of HbA1c assay methods.

Early Retinal Microvascular Alterations in Young Type 1 Diabetic Patients without Clinical Retinopathy.

The purpose of this study is to identify and quantify preclinical changes with the help of optical coherence tomography angiography (OCTA) within the retinal microcirculation of young type 1 diabetes (T1D) patients without clinical signs of diabetic retinopathy (DR) and to compare these results with those obtained from healthy age-matched subjects. OCTA is currently used for monitoring diabetic retinopathy; however, there is no current consensus on which OCTA parameter alterations predict the first clinical signs of diabetic retinopathy. The main challenge that young patients with T1D face during the course of the disease is that they can rapidly progress to the development of DR, especially during adolescence. Moreover, they also present an increased risk of rapid progression toward advanced stages of DR and vision loss compared to type 2 diabetes patients, indicating the importance of early diagnosis and intervention. The limitations of the currently used screening procedures that led to the conceptualization of our study are the difficulties in performing fluorescein angiography tests for diagnosing the clinical signs of DR on young patients, namely the invasive procedure of dye injection, the risk of allergic reactions and the long duration of the examination. Moreover, given the long life expectancy of young T1D patients, it is essential to identify the preclinical changes in retinal microvasculature before reaching the first clinical signs quantifiable by FFA. The clinical study enrolled 119 subjects aged between 4 and 30 years old with a mean age of 13 years old, comprising 61 T1D patients with a mean duration of the disease of 4 years and 8 months and 58 healthy age-matched subjects for the control group. OCTA scans were performed using the RevoNX 130 OCTA device (Optopol) to evaluate the following retinal parameters: foveal avascular zone (FAZ) area, perimeter and circularity, overall foveal thickness, and superficial and deep vessel densities. Statistically significant differences between the two groups were identified for the following parameters: the FAZ area in the T1D group (0.42 ± 0.17) was larger than the control group (0.26 ± 0.080), the FAZ circularity (0.41 ± 0.11) was decreased compared to the control group (0.61 ± 0.08) and the FAZ perimeter was larger (3.63 ± 0.97) compared to the control group (2.30 ± 0.50). The overall foveal thickness was decreased in the T1D group (222.98 ± 17.33) compared to the control group (230.64 ± 20.82). The total vessel density of the superficial capillary plexus (SCP) on an investigated area of 6 X 6 mm centered around the fovea was decreased in the T1D group (37.4164 ± 2.14) compared to the control group (38.0241 ± 2.44). Our data suggest that specific imaging biomarkers such as FAZ perimeter, area and circularity, decreased overall foveal thickness and decreased vessel density in the SCP precede the clinical diagnosis of DR in young T1D patients and represent useful parameters in quantifying capillary nonperfusion in T1D patients without clinical signs of DR.

A rare cause of ischemic stroke: cardiac myxoma. Case report and review of literature.

A 46-year-old female diagnosed several years ago with arterial hypertension and an ischemic stroke with significant recovery was admitted for dyspnea on usual physical activity and fatigue. Physical examination revealed signs of heart failure with crackles on both lung bases, distented jugular veins, accentuated pulmonic valve closure (P2) and tricuspid regurgitation murmur. Echocardiography identified a large tumor in the left atrium, suggestive of atrial myxoma, which caused a severe functional mitral stenosis and produced severe pulmonary hypertension. A cardiac embolic source should always be checked in young patients with stroke. Atrial myxoma can mimic a variety of diseases: rheumatic mitral stenosis, infective endocarditis or autoimmune disease. A review on myxoma's histology, immunohistochemistry and genetics together with clinical aspects is presented.

Two girl patients with medulloblastoma. Case reports.

In childhood, the most common type of brain tumors is medulloblastoma, a highly malignant primary brain tumor that is found in the cerebellum or posterior fossa. The tumor mass increases and generates obstructive hydrocephalus. Risk factors (that might be involved in some cases) include the genetic syndrome such as type 1 neurofibromatosis, exposure to ionizing radiation and Epstein-Barr virus. Medulloblastoma is associated with recessively inherited Turcot disease and with conditions as ataxia-telangiectasia syndrome in several cases. The authors presented two cases of female patients (aged one year and eight months old, respectively 4-year-old), both of them with weight deficiency, with personal history of head trauma. First case, M.D.M., was admitted in Emergency Room of the Emergency County Hospital, Craiova, Romania, for symptoms that included headaches, impaired vision, vomiting, mental disorders, ataxia and body imbalance. The reason for refer to the Surgical Unit care was posterior fossa tumor diagnosed by computed tomography (CT) scan. The second case, V.F., a 4-year-old girl, was admitted to First Pediatrics Clinic of the same Hospital, on October 2014, for seizures, early morning vomiting, loss of appetite, inability to walk and stand and also, mental delay. She had "café au lait" spots on her trunk, suggesting type 1 neurofibromatosis. A brain CT scan revealed a tumor being developed in the fourth ventricle (in the vermis of the cerebellum). Both the girls underwent curative surgery in different Clinics from Bucharest. The two girls with the same diagnosis showed contrasting post-surgical evolution: M.D.M. still survives, while V.F. survived only for six months following first surgical intervention. The first patient, M.D.M., received chemotherapy before and after the surgery, which a slow but favorable recovery noted. For the second patient, the brain CT scan performed four months after surgery showed multiple masses in the cerebral posterior fossa, suggestive of leptomeningeal metastases, but without local recurrence of the medulloblastoma. The patient started chemotherapy and, after two sessions, she went for second surgical treatment. Six months after the second surgery, the second female patient, V.F., died. The objective of this study is to find the reasons of their different clinical evolution. The authors emphasized the clinical similarities of the patients, both being female, having similar symptoms and incidental medical events (upper and lower respiratory tract infections and head trauma) but most important, they stressed out the factors which contributed to the different clinical outcome, the second patient having a more aggressive form of medulloblastoma and receiving chemotherapy only after leptomeningeal metastases were evidenced. In addition, as for the second patient, she might had clinical criteria for type 1 neurofibromatosis (the author specified the number of the "café au lait" spots being over 6, like her brother, mental delay, without other clinical signs), which might have contributed to the poor outcome. The etiology of medulloblastoma can also be involved with chromosome 17 and the diagnosis of such a brain tumor can be an evolutive criterion for neurofibromatosis. The diagnosis can provided only by genetic tests. There is a vital risk and a reason for the lethal evolution of V.F. PATIENT: As medulloblastoma is a very aggressive malignant tumor, the approximate cumulative survival rate for preschool age group having a histological follow-up was found to be 47% over a span of five years of rigorous treatment.

B2 adrenergic receptors and morphological changes of the enteric nervous system in colorectal adenocarcinoma.

AIM: To study the morphology of the enteric nervous system and the expression of beta-2 adrenergic (B2A) receptors in primary colorectal cancer. METHODS: In this study, we included forty-eight patients with primary colorectal cancer and nine patients for control tissue from the excision of a colonic segment for benign conditions. We determined the clinicopathological features and evaluated the immunohistochemical expression pattern of B2A receptors as well as the morphological changes of the enteric nervous system (ENS). In order to assess statistical differences, we used the student t-test for comparing the means of two groups and one-way analysis of variance with Bonferroni's post hoc analysis for comparing the means of more than two groups. Correlations were assessed using the Pearson's correlation coefficient. RESULTS: B2A receptors were significantly associated with tumor grading, tumor size, tumor invasion, lymph node metastasis (P < 0.05), while there were no statistically significant associations with gender, CRC location and gross appearance (P > 0.05). We observed, on one hand, a decrease of the relative area for both Auerbach and Meissner plexuses with the increase of the tumor grading, and on the other hand, an increase of the relative area of other nervous elements not in the Meissner plexus or in the Auerbach plexus with the tumor grading. For G1 tumors we found that epithelial B2A area showed an inverse correlation with the Auerbach plexus areas [r(14) = -0.531, P < 0.05], while for G2 tumors, epithelial B2A areas showed an indirect variation with both the Auerbach plexus areas [r(14) = -0.453, P < 0.05] and the Meissner areas [r(14) = -0.825, P < 0.01]. For G3 tumors, the inverse dependence increased for both Auerbach [r(14) = -0.587, P < 0.05] and Meissner [r(14) = -0.934, P < 0.05] plexuses. CONCLUSION: B2A receptors play an important role in colorectal carcinogenesis and can be utilized as prognostic factors. Furthermore, study of the ENS in colorectal cancer may lead to targeted molecular therapies.

Synaptophysin expression as prognostic factor for survival in colorectal carcinomas.

The aim of this study is to assess the status of synapses in normal colorectal tissue compared to neoplastic colorectal tissue, and to correlate this status with survival in patients with colorectal neoplasia. Our study included 61 patients diagnosed with colorectal adenocarcinoma, representing the study group, and 53 patients diagnosed with benign conditions, that required a resection of a colorectal segment, representing the control group. We performed the immunohistochemical staining by using anti-synaptophysin antibody, which identifies synaptic vesicles and, so, we managed to analyze the expression of synapses in colorectal adenocarcinoma. Regarding both the signal area and integrated optical density (IOD) of the synaptophysin, the univariate analysis with a log-rank (Mantel-Cox) test indicated that patients with a low level of synaptophysin had a better overall survival rate than those with a high-level synaptophysin. Also, we noticed that tumor size, tumor invasion and lymph node metastasis were significantly associated with the overall survival rate, whereas the other clinicopathological features were not. In conclusion, the status of synaptic vesicles evaluated via synaptophysin expression in patients with colorectal cancer positively correlates with the survival rate and it can play a role in the neoplastic therapy process.

Odontal-Periodontal Changes in Patients with Type 1 Diabetes.

Diabetes mellitus is a complex disease characterized by insufficient insulin secretion and / or an inefficiency of target tissues to its metabolic action. Periodontal disease was recognized as the sixth leading complication of a diabetes. Gingival sulcus bleeding is considered as an important clinical parameter in the diagnosis of periodontal disease. This research is based on comparison of the clinical and paraclinical data between groups of patients with type 1 diabetes and periodontal disease on the one hand and groups of patients with periodontal disease without diabetic disease on the other hand. We can conclude that there is sufficient data to confirm the existence of a bidirectional relationship between metabolic changes in type 1 diabetes and periodontal (odontal-periodontal) disorder of patients, especially in adolescents and young adults. Both diseases can influence each other more or less, so for diabetics there is a predilection to develop periodontal disease as diabetes is a risk factor for severe parodontopathies.

Neuro-neoplastic interrelationships in colorectal level - immunohistochemical aspect in three cases and review of the literature.

Colorectal cancer represents a severe public health issue. Recent studies have shown the essential role played by nerves and their neurotransmitters in tumor initiation and progression. The aim of this study is to asses the expression of beta 2-adrenergic receptors (ß2A) for adrenaline and noradrenaline, and the expression of M3 muscarinic receptors (M3R) for acetylcholine (neurotransmitters produced and released by sympathetic and parasympathetic afferents of the digestive tract and also by the enteric nervous system) in different tumor gradings of colorectal adenocarcinoma, and also the tropomyosin receptor kinase A (TrkA) for the nerve growth factor produced by the cells of colorectal adenocarcinoma. Beta 2-adrenergic receptors were expressed both in normal colic tissue and in the tumor tissues, from the three patients included in the study. It was observed that both area and integrated optical density (IOD) are more elevated for this type of receptor in tumor tissues than in normal colic tissue. For the M3 muscarinic receptors, similarly to beta 2-adrenergic receptors, it was observed a growth both of the area and of the IOD with the tumor grading. The presence of TrkA receptors was also observed both in the normal colic mucosa and in the tumor tissues examined, but with a significant reduction of the signal in the poorly differentiated tumor tissue. Understanding the neurobiology of cancer in this context becomes necessary for establishing much more complex and targeted molecular targeted therapies.

Hirschprung's disease in different settings - a series of three cases from a tertiary referral center.

Failure of neural crest cells to migrate from neural crests during intrauterine development result in partial or total aganglionosis of the colon in newborn. Hirschprung's disease (HD) represents the clinical manifestation of this pathogenic process, currently accounting for the majority of lower intestinal obstruction in the first period of life. Our aim was to present a series of three cases presenting to our tertiary care center with a range of symptoms, all benefiting from surgery and consequent pathology examination of biopsy or resection pieces. The first case was of a male newborn that presented several years ago with common symptoms for HD (abdominal distension, vomiting and the total lack of intestinal passage for feces). Coming from young healthy parents after normal labor, the newborn displayed signs of Down's disease after physical examination. After abdominal radiography, the patient underwent surgery and consecutive pathology revealed notable signs of Crohn's disease (CD): massive stasis in the serosa and submucosa, chronic inflammatory infiltrate and lack of nervous cells in both plexuses and mucosa. Immunohistochemistry revealed low intensity CD34 membrane staining for fibroblast-like ganglion cells while CD117 staining showed few nervous cells within the mucosa. The second case presented before one year of age with an infectious background, already being operated upon with colostoma. We performed corrective surgery of the colostoma and consecutive pathology showed low CD117 cytoplasmic staining and intensely positive NSE (neuron specific enolase) staining within myenteric plexuses. Finally, the third and most recent case was that of a 4-year-old boy with an early diagnosis of megacolon and no previous surgery, who we evaluated by laparoscopy with five biopsies and consecutive S100 staining revealed a small number of nervous cells within nervous plexuses. In conclusion, an early diagnosis of HD is essential for successful therapeutic measures. Histology and, more recently, immunohistochemistry, represent the gold-standard procedures needed to objectify the diagnosis.

Matrix metalloproteinase -7, -8, -9 and -13 in gingival tissue of patients with type 1 diabetes and periodontitis.

There is scientific data to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting the diabetic status. Our study aims to investigate the expression of MMP-7, -8, -9 and -13 in the gingiva of the young patients with aggressive periodontitis (AP) and type 1 diabetes mellitus (T1D). Gingival biopsies were harvested from five adult patients aged 19-29 years with T1D+AP with moderate (three cases) to severe (two cases) forms of AP and from four adult patients aged 18-28 years with moderate AP without T1D. The MMP-7 immunoreaction was positive in the five cases with T1D+AP with different staining patterns. The MMP-8 immunostaining was positive in all cases. The reaction was more intense in cases with T1D+AP, especially in those with severe periodontitis. The MMP-9 immunoreaction was present in all the structures of the gingival mucosa with different intensity, being frequently present surrounding the blood vessels of the chorion. In most of the patients, reaction to MMP-9 was intense, localized at the level of the cells in the superficial chorion and very rarely at the level of some dispersed cells in the connective vascular islands. MMP-13 was present in all cases, but it was more intense in the two cases with T1D+AP with probing depth (PD)>6 mm when it had similar patterns as MMP-9 staining and in one case with AP when the staining was observed strictly in the lamina propria associated with moderate chronic inflammatory infiltrate. The expression of MMP-7, -8, -9 and -13 in the gingiva of the young patients with aggressive periodontitis and T1D was positive in all studied cases supporting the hypothesis that both are inflammatory diseases with common pathogenic mechanisms involving inflammatory mediators and may be possible biomarkers of disease status.

Terminal deletion 2q37.3 in a patient with Klippel-Trenaunay-Weber syndrome.

Klippel-Trenaunay-Weber syndrome (KTWS) is a rare congenital disorder, characterized by capillary, venous and lymphatic vascular malformations in association with bone and soft tissue hypertrophy. We report a KTWS patient with extensive hemangiomatosis of the right lower limb, trunk and upper limbs; bone and soft tissue hypertrophy of upper limbs, scapular girdle and right lower limb; and muscle atrophy on left lower limb with marked body asymmetry, scoliosis and toe malformations. These pathological features are associated with moderate mental retardation, mild renal and hepatic abnormalities. We identified by array CGH (Comparative Genomic Hybridization) a submicroscopic deletion 2q37.3 that could be related to impaired cognitive function. To our knowledge this is the first reported 2q37.3 microdeletion in a patient with KTWS.

The metabolic syndrome--new and old data.

Initially called the "X Syndrome" by Reaven, then the "Killer Quartet" by Kaplan, the MS prevalence has dramatically increased in the past decades. The first criteria elaborated by WHO in 1998, and afterwards reformulated in 1999, were conceived by diabetologists as a working instrument for clinical practice and they shall consequently be updated in accordance with the new acquisitions in this field. MS expresses the complex disorder of the organism energetic metabolism, having as central element insulin resistance and compensatory hyperinsulinism, associated with the presence of some risk factors involved in the etiology and/or physiology of atherosclerosis. The interaction between the genetic factors and the acquired ones induces a series of functional anomalies, which finally lead to a high risk of cardiovascular diseases. Abdominal obesity seems to be the most important component of the MS, which may be correlated with systemic inflammation and the decrease of adiponectin concentration. We should not overlook the part played by the other components: plasmatic TG, HDL, LDL - cholesterol, plasmatic glycaemia, blood pressure, microalbuminuria, plasmatic uric acid. The MS patient will be clinically and paraclinically examined by calculating the vascular and metabolic risks and, thus, establishing the therapeutical objectives and targets of every factor in order to maximally reduce the cardiovascular and DM risks. The treatment will be individualized, as present definitions include MS both in patients with clearly expressed diseases (Type 2 DM, Hypertension, coronary disease) as well as in patients with limit modifications. This fact will involve both improvement of lifestyle and drugs treatment, as well. MS prevention more and more imposes itself by individual and populational strategies of preventing obesity, through the educating population to adopt a healthy lifestyle, involving the whole medical staff.