Medullary Tegmental Cap Dysplasia: Fetal and Postnatal Presentations of a Unique Brainstem Malformation.

BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients' medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

Prenatal diagnosis of rhombencephalosynapsis: neuroimaging features and severity of vermian anomaly.

OBJECTIVES: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Enteroviral infection in patients treated with rituximab for non-Hodgkin lymphoma: a case series and review of the literature.

In recent years, anti-CD20 antibodies have been increasingly used to treat lymphoproliferative and immune disorders. Chronic viral infections are infrequently reported in patients receiving these therapies. Enteroviral infection can cause life-threatening meningoencephalitis and other systemic chronic syndromes in immune deficient patients. We describe the clinical courses and outcomes of 6 patients from 2 tertiary care institutions who developed chronic enteroviral infection with neurological manifestations, after combined chemoimmunotherapy with rituximab for B-cell lymphoma. We review the literature that includes 10 sporadic reported cases of chronic enteroviral meningoencephalitis attributed to rituximab therapy. It is a rare disease, and its diagnosis is often elusive. We propose that low immunoglobulin G levels are the main risk factor for developing chronic enteroviral infection and emphasize the need for a high index of suspicion, early diagnosis, and intervention in this iatrogenic and potentially fatal complication.

Application of a novel prenatal vertical cranial biometric measurement can improve accuracy of microcephaly diagnosis in utero.

OBJECTIVE: To construct a reference range for a new vertical measurement of the fetal head and to assess whether its combination with fetal head circumference (HC) can prevent the misdiagnosis of microcephaly in fetuses with an acrocephalic-like head deformation. METHODS: A new vertical cranial biometric measurement was defined: the foramen magnum-to-cranium distance (FCD), measured between the foramen magnum and the upper inner cranial border along the posterior wall of the brainstem. The measurement was performed in a precise mid-sagittal plane using a three-dimensional multiplanar display of a sagittally acquired sonographic volume of the fetal head. The normal reference range was developed by measuring 396 healthy fetuses of low-risk singleton pregnancies between 15 and 40 gestational weeks. This reference was applied to 25 fetuses with microcephaly diagnosed prenatally (Fmic) based on HC ≥ 3 SD below the mean for gestational age. We determined an optimal FCD cut-off for combination with HC to detect all cases found with microcephaly at birth (micB), while excluding the fetuses with normal head circumference at birth (NHCB), who were described postnatally as having an acrocephalic-like cranial deformation. RESULTS: In the healthy singleton fetuses, FCD increased with gestational age, with a quadratic equation providing an optimal fit to the data (adjusted R(2) = 0.934). The measurement could be assessed in 95.2% of cases. Of the 25 cases diagnosed with Fmic prenatally, on the basis of HC alone, 14 were micB and 11 were NHCB. We observed FCD below the mean - 2SD for gestational age in all 14 micB cases, but in only four of the 11 NHCB cases (P < 0.003). An acrocephalic-like cranial deformation was described at birth in five of the seven NHCB cases with normal FCD. The mean ± SD FCD Z-score of the micB cases was significantly lower (P < 0.001) than that of the false-positive ones: -3.85 ± 0.96 SD and -1.59 ± 1.45 SD, respectively. Based on HC measurement alone, the positive predictive value (PPV) was 56%. Combination of the HC and FCD criteria raised the PPV to 78%, decreasing the number of false positives from 11 to four, without missing any of the 14 micB cases. CONCLUSIONS: Fetal vertical cranial biometric assessment in the mid-sagittal plane is feasible and correlates well with gestational age. In our series, a vertical cranial deformation was a frequent cause of a false Fmic diagnosis made on the basis of HC alone. Combination of the new vertical cranial biometric measurement with HC measurement can exclude these cases and thus improve diagnostic accuracy for Fmic. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of microcephaly at birth using three reference ranges for fetal head circumference: can we improve prenatal diagnosis?

OBJECTIVE: To evaluate the prediction of microcephaly at birth (micB) using established and two new reference ranges for fetal head circumference (HC) and to assess whether integrating additional parameters can improve prediction. METHODS: Microcephaly in utero was defined as a fetal HC 3SD below the mean for gestational age according to Jeanty et al.'s reference range. The records of cases with fetal microcephaly (Fmic) were evaluated for medical history, imaging findings, biometry and postnatal examination/autopsy findings. Microcephaly was confirmed at birth (micB) by an occipitofrontal circumference (OFC) or a brain weight at autopsy 2SD below the mean for gestational age. The new INTERGROWTH-21(st) Project and a recent Israeli reference for fetal growth were applied for evaluation of the Fmic positive predictive value (PPV) for diagnosis of micB cases. Optimal HC cut-offs were determined for each of the new references with the aim of detecting all micB cases whilst minimizing the number of false positives found to have a normal HC at birth. We also assessed the difference between the Z-scores of the prenatal HC and the corresponding OFC at birth, the frequency of small-for-gestational age (SGA), decreased HC/abdominal circumference (AC) and HC/femur length (FL) ratios, the prevalence of associated malformations and family history. RESULTS: Forty-two fetuses were diagnosed as having Fmic according to the Jeanty reference, but micB was confirmed in only 24 (PPV, 57.1%). The optimal INTERGROWTH and Israeli reference HC cut-offs for micB diagnosis were mean - 3SD and mean - 2.3SD, resulting in a statistically non-significant improvement in PPV to 61.5% and 66.7%, respectively. The presence of a family history of microcephaly, SGA, associated malformations and application of stricter HC cut-offs resulted in a higher PPV of micB, although not statistically significant and with a concurrent increase in the number of false-negative results. The deviation of the HC from the mean, by all references, was significantly larger compared with the actual deviation of the OFC at birth, with mean differences between the corresponding Z-scores of -1.15, -1.95 and -0.74 for the Jeanty, INTERGROWTH and Israeli references, respectively. CONCLUSIONS: The evaluated reference ranges all result in considerable over-diagnosis of fetal microcephaly. The use of the two new HC reference ranges did not significantly improve micB prediction compared with that of Jeanty et al., whilst use of additional characteristics and stricter HC cut-offs could improve the PPV with an increase in false negatives. The postnatal OFC deviates significantly less from the mean compared with the prenatal HC, and we propose that adjustment for this would enable better prediction of the actual OFC deviation at birth. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Placental protein 13 and decidual zones of necrosis: an immunologic diversion that may be linked to preeclampsia.

We evaluated the role of placental protein 13 (PP13; galectin 13) in the process of trophoblast invasion and decidual necrosis. Immunohistochemical analysis for PP13, immune cells, human placental lactogen, cytokeratin, and apoptosis markers was performed on 20 elective pregnancy termination specimens between 6 and 15 weeks of gestation. Placental protein 13 was localized to syncytiotrophoblasts in the chorionic villi and to occasional multinucleated luminal trophoblasts within converted decidual spiral arterioles. Cytotrophoblasts, anchoring trophoblasts, and invasive trophoblasts did not stain for PP13. Extracellular PP13 aggregates were found around decidual veins associated with T-cell-, neutrophil- and macrophage-containing decidual zones of necrosis (ZONEs). We hypothesize that PP13 is secreted into the intervillus space, drains through the decidua basalis veins, and forms perivenous PP13 aggregates which attract and activate maternal immune cells. Thus, syncytiotrophoblast-derived PP13 may create a ZONE that facilitates trophoblast invasion and conversion of the maternal spiral arterioles.

Butyrylcholinesterase formulated in liposomes.

Exogenous cholinesterases have the potential to take part in defence against organophosphate toxins, by acting as scavenger systems. Postulating that formulation in liposomes could enhance the toxin-scavenging potential of these enzymes, we have initiated studies of such formulations and are reporting here our first steps, exploring butyrylcholinesterase (BChE) in multilamellar liposomes composed of phosphatidylcholine. We started by developing an essential research tool: a multisample, sensitive and rapid enzyme-activity assay, based on the Ellman reaction, that could be performed directly on liposome-containing samples. Using an ELISA reader equipped to follow time-dependant absorbency changes, 10 min sufficed to assay 96 samples simultaneously. Next, several key properties of liposome-formulated BChE were explored and the major findings were: (i) the encapsulated enzyme was found to retain its activity. (ii) Enzyme activity was found to increase (at constant enzyme concentration) in the presence of the lipid, in a lipid-concentration-dependant manner. Through data analysis it was possible to attribute this effect to changes in k(cat). (iii) Good, reproducible, encapsulation efficiencies (for macromolecules) in the range of 30% were obtained at liposome concentrations of 100 mM lipid. (iv) Free BChE was completely susceptible to proteolysis under conditions mimicking enzymically-hostile biological environments, whereas > or = 60% of the liposome-formulated BChE was protected, found to be inaccessible to the proteolytic enzymes. (v) Short-term exposures of free and liposome-encapsulated BChE to the inhibitor paraoxon, generated significant losses in enzyme activity. Residual activities of both BChE formulations dropped considerably over the paraoxon concentration range of 0.02-0.11 microM, down to 3 and 11% for free and liposome-encapsulated enzyme respectively. These data are a clear indication that the encapsulated BChE was accessible to the inhibitor, indicating that such liposomal formulations have the potential to perform as the desired scavenger systems.

Efficacy of topical application of eosin compared with zinc oxide paste and corticosteroid cream for diaper dermatitis.

BACKGROUND: Corticosteroids, zinc paste and eosin 2% are well-known topical agents for the treatment of moderate to severe diaper dermatitis. Among these treatments, the aqueous solution of eosin 2% is extensively used in several European countries, but not in the USA or Israel. OBJECTIVE: To assess the therapeutic efficacy of eosin 2% solution compared to the other treatment modalities for diaper dermatitis. METHODS: Fifty-four infants with diaper dermatitis, recruited from hospital wards and community clinics, were randomly assigned to three treatment groups: zinc oxide paste (containing allantoin 0.5%, cod liver oil 17% and zinc oxide 47epercnt;); clobetasone butyrate 0.05%, and aqueous solution of eosin 2%. The severity of the disorder was graded on a 6-point scale by observation and quantitative measurement of the lesions. The groups were compared for rates and time to heal. Due to the red color of eosin, a double-blind controlled study was impossible. RESULTS: Following 5 days of treatment, the rate of complete healing in the group treated with eosin (61%) was significantly higher (p = 0.0479) than that in the zinc oxide paste and corticosteroid groups (22 and 33%, respectively). Furthermore, in cases of partial healing, the degree of improvement was higher in the eosin group than the other two (p = 0.0205). The fastest improvement was observed in the group treated with corticosteroid cream. CONCLUSION: Considering the potential hazards of topical corticosteroids and the greater overall efficacy of eosin 2% solution, we suggest that eosin is the preferred treatment for diaper dermatitis.

Follicular carcinoma of the thyroid.

BACKGROUND: Follicular carcinomas of the thyroid are less common than papillary carcinomas of the thyroid, and the available data on prognostic factors are relatively scant. A retrospective study covering four decades was undertaken to evaluate clinical and pathologic findings with regard to their effect on prognosis. METHODS: In 195 cases of follicular carcinoma treated from 1954 to 1991 age, sex, histologic type (minimally invasive vs. widely invasive), tumor size, and local, regional, and distant spread as well as the contribution of treatment to survival were evaluated in relation to prognosis. RESULTS: Age was a significant prognostic factor: there was 100% survival of patients younger than 20 years of age at diagnosis and only one death in the 20-39 year age group. Sex was not a significant prognostic factor, although there was a tendency to a better prognosis in females. Tumor size was significant, more than 6 cm having a poor prognosis. Blood vessel invasion influenced prognosis for the first 10 years. The presence of distant metastases was significant regarding survival. Lymph node involvement had a negative effect on the outcome. CONCLUSIONS: The factors of age, tumor size, invasion of blood vessels, and distant metastases are significant predictors of survival for patients with follicular carcinoma, whereas sex is not; regional spread needs to be evaluated further.

Molecular and cellular studies of hyaluronic acid-modified liposomes as bioadhesive carriers for topical drug delivery in wound healing.

Liposomes, modified into bioadhesive systems by the covalent anchoring of hyaluronic acid (HA) to their surface, were investigated for their abilities to act as site-adherent and sustained-release carriers of drugs for the topical therapy of wounds and burns. Epidermal growth factor (EGF) served as the test drug for growth factors and monolayers of the A431 cell line served as models of the in vivo designated targets. The hyaluronic acid was radiolabeled to carry 3H, through a deacetylation-reacetylation procedure, yielding specific activities in the range of 1 x 10(6) dpm/mg. The HA was bound to the surface of the liposomes, using carbodiimide to crosslink its carboxyl residues to amine residues at the liposomal surface. The latter was provided through the inclusion of phosphatidylethanolamine in the liposome formulation. Varying the initial HA/lipid ratio over the range 1-500 mg HA/mmol lipid, it was found that the increase in bound HA was linear, providing up to 80 mg HA/mmol lipid. The HA-modified, but not the nonmodified, liposomes were found to bind with high affinity (delta G degree in the range of -7 to -9 Kcal/mol) to monolayers of the A431 cell line. The HA-modified liposomes were found to encapsulate EGF at high yields (% encapsulation, > 87) and to act as sustained-release depots, the rate constant for the release of the encapsulated EGF in the range of 1.4 x 10(-3) h-1. Taking all of these findings together, it is concluded that these liposomes are bioadhesive sustained-release carriers of drugs, as desired, meriting further cellular and in vivo studies.

Bilateral transposition of maxillary canines and first premolars: case report.

Transposition of teeth is a rare phenomenon. A case of bilateral transposition of maxillary canines and first premolars in a 27-year-old man is described.

Cerebral infarct associated with lupus anticoagulant in an adolescent girl: a case report with review of the literature.

A 15-year-old girl with right-sided cerebral infarct in association with lupus anticoagulant is described. The literature on the primary antiphospholipid syndrome and its neurological complications is reviewed.

Effect of pH on mutagenesis by thiols in Salmonella typhimurium TA102.

The mutagenicity of thiol (SH)-containing compounds was tested in Salmonella typhimurium TA102 in the liquid preincubation method. Cysteinyl-glycine (CG), cysteine ethyl ester (CEE), L- and D-penicillamine (PA), cysteine (Cys) and glutathione (GSH) were mutagenic to strain TA102 without metabolic activation. On a molar basis, CG was the most potent mutagen. The mutagenicity of the remaining compounds decreased in the order specified above. The mutagenic response of each thiol-containing compound was a function of the pKa of the thiol group and the pH of the preincubation mixture. This indicates that a thiolate anion, rather than a free thiol, is required for mutagenesis.