Post-stroke recrudescence-a possible connection to autoimmunity?

Early recanalization of the occluded vessel is the only efficient intervention that improves outcome after ischemic stroke. In contrast, interventions for chronic issues facing stroke patients are limited. Recent clinical and preclinical studies have shown a correlation between upregulated immune responses to brain antigens and post-stroke recrudescence (PSR), post-stroke fatigue (PSF), and dementia (PSD); all of which are associated with poor long-term stroke outcome. Recent retrospective studies have demonstrated a strong correlation between the onset of PSR and acute infection during acute stroke, suggesting some adaptive immune system mediated pathology. This review will discuss the mechanisms and epidemiology of PSR based on the current clinical and pre-clinical evidence. Accordingly, PSR does appear correlated with populations that are prone to autoimmunity, infection, and subsequent triggers, which corroborate autoimmune responses to self-brain antigens as an underlying mechanism. Moreover, PSR as well as PSF and PSD seem to be partly explained by the development of a neuro-inflammatory response to brain antigens. Therefore, the future of improving long-term stroke outcome could be bright with more accurate pre-clinical models focusing on the role of adaptive immune-mediated post stroke neuroinflammation and more clinical studies of PSR.

Gliomagenesis is orchestrated by the Oct3/4 regulatory network.

Glioblastoma multiforme (GBM) is a lethal brain tumor characterized by developmental hierarchical phenotypic heterogeneity, therapy resistance and recurrent growth. Neural stem cells (NSCs) from human central nervous system (CNS), and glioblastoma stem cells from patient-derived GBM (pdGSC) samples and cultured in both 2D well-plate and 3D monoclonal neurosphere culture system (pdMNCS). The pdMNCS model shows promise to establish a relevant 3D-tumor environment that maintains GBM cells in the stem cell phase within suspended neurospheres. Utilizing the pdMNCS, we examined GBM cell-lines for a wide spectrum of developmental cancer stem cell markers, including the early blastocyst inner-cell mass (ICM)-specific Nanog, Oct3/4,B, and CD133. We observed that MNCS epigenotype is recapitulated using gliomasphere-derived cells. CD133, the marker of GSC is robustly expressed in 3D-gliomaspheres and localized within the plasma membrane compartment. Conversely, gliomasphere cultures grown in conventional 2D culture quickly lost CD133 expression, indicating its variable expression is dependent on cell-culture conditions. Critically, this experiment demonstrates incomplete differentiation of cytoskeleton microtubules and intermediate filaments (IFs) of patient derived cells, similar to commercially available GBM cell lines. Subsequently, in order to determine whether Oct3/4 it was necessary for CD133 expression and cancer stemness, we transfected 2D and 3D culture with siRNA against Oct3/4 and found a significant reduction in gliomasphere formation. These results suggest that expression of Oct3/4,Aand CD133 suppress differentiation of GSCs.

Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance.

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES.

Association of the family environment with behavioural and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome.

BACKGROUND: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. METHOD: Guardians of children with 22q11DS were recruited through two medical genetics clinics. Consenting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. RESULTS: Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social-behavioural and cognitive outcomes in children with 22q11DS. CONCLUSION: Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11DS.

20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder.

Deletions of 20p are rare with the majority of reported cases involving individuals with 20p12 deletions associated with Alagille syndrome. We report on a child with a de novo mosaic 20p11 deletion who presents with panhypopituitarism; hypoplastic pituitary gland and ectopic posterior pituitary gland on MRI of the brain; cleft lip and palate; kyphosis with anterior beaking of L1 and L2 vertebral bodies; pulmonic stenosis; dysmorphic facial features including flat nasal bridge, hypoplastic premaxilla, hypotelorism, preauricular pit, and cupped ears; seizure disorder; variable muscle tone; and global developmental delay. Array comparative genomic hybridization revealed this deletion to be approximately 5.4 Mb in size, containing 35 genes. Previously, an infant with 20p11.22 deletion who had panhypopituitarism, craniofacial, and genital abnormalities was reported, but the precise parameters of that deletion are unavailable. Several other reported cases of 20p11 deletions also have phenotypic overlap with our case. The similarities in clinical features of these patients suggest that the genes at 20p11 have a critical role in development of midline brain structures.

Identification of a previously unrecognized microdeletion syndrome of 16q11.2q12.2.

We report the identification of microdeletions of 16q11.2q12.2 by microarray-based comparative genomic hybridization (aCGH) in two individuals. The clinical features of these two individuals include hypotonia, gastroesophageal reflux, ear anomalies, and toe deformities. Other features include developmental delay, mental retardation, hypothyroidism, and seizures. The identification of common clinical features in these two individuals and those of one other report suggests microdeletion of 16q12.1q12.2 is a rare, emerging syndrome. These results illustrate that aCGH is particularly suited to identify rare chromosome abnormalities in patients with apparently non-syndromic idiopathic mental retardation and birth defects.

National Retail Data Monitor for public health surveillance.

The National Retail Data Monitor (NRDM) is a public health surveillance tool that collects and analyzes daily sales data for over-the-counter (OTC) health-care products. NRDM collects sales data for selected OTC health-care products in near real time from >15,000 retail stores and makes them available to public health officials. NRDM is one of the first examples of a national data utility for public health surveillance that collects, redistributes, and analyzes daily sales-volume data of selected health-care products, thereby reducing the effort for both data providers and health departments.

Investigation of illness associated with exposure to hydrogen sulfide among Pennsylvania school students.

During 1998, the Pennsylvania Department of Health received complaints about hydrogen sulfide odors believed to be associated with mushroom-composting operations in southeastern Pennsylvania. Many residents were concerned about possible illness in students attending an elementary school near the composting operations. In response, the department conducted health surveys during the spring and autumn at the exposed school and at a nearby control school. The surveys assessed whether exposures to hydrogen sulfide were associated with excess adverse health effects by comparing health effects among students from the exposed school with those among students from the control school. School nurses were trained to complete health questionnaires for the students. The state environmental agency measured daily ambient hydrogen sulfide concentrations at both schools. No consistent association was found between exposure to low levels of hydrogen sulfide and any adverse health effects. It was concluded that the students attending the elementary school near the mushroom-composting operations were not exposed to any significant public health hazard.

Toriello-Carey syndrome: an additional case and summary of previously reported cases.

We report an additional case of Toriello-Carey syndrome, a rare multiple malformation syndrome, and present a summary of previously reported cases.

Fetal valproate syndrome and autism: additional evidence of an association.

Autism has been described in association with a variety of medical and genetic conditions. We previously reported on a patient whose clinical phenotype was compatible with both fetal valproate syndrome (FVS) and autism. Here we present five additional patients with FVS and autism. In all five of our patients, there was evidence of cognitive deficits, manifestations of autism, and typical phenotypic characteristics of FVS. The association between this known teratogen and autism has both clinical and research implications.

Case of partial duplication 2q3 with characteristic phenotype: rare occurrence of an unbalanced offspring resulting from a parental pericentric inversion.

We report on a male infant with partial trisomy 2q (q34-->qter) resulting from a maternal pericentric inversion of chromosome 2 (p25. 2q34). The infant had clinical findings similar to the characteristic phenotype associated with a partial duplication of chromosome 2q3. Carriers of pericentric inversions of chromosome 2 have an increased risk of pregnancy loss but have only rarely been reported to have a liveborn offspring with an unbalanced chromosome constitution. This case further confirms the risks associated with a pericentric inversion of chromosome 2 and is the second report with manifestations of the trisomy 2q3 phenotype.

Mathematical analysis of the relative contributions of decreased production and increased peripheral destruction in idiopathic thrombocytopenic purpura and implications in splenectomy.

We utilize a model of platelet concentration kinetics and bone marrow production based on three terms (a constant loss term, a random loss term and a higher order loss term) to compare a hypoplastic bone marrow patient and a patient with Idiopathic Thrombocytopenic Purpura (ITP) for the same platelet concentration. We compare this model to published data and show that in many ITP patients there is an overall decrease in platelet production. However, for almost all cases of ITP there is an increase in peripheral platelet destruction, even in those cases where total bone marrow production is less than that in a normal individual or is severely depressed. We are able to graphically depict the variable contributions of decreased production and increased peripheral destruction in patients with ITP and hence give insight into their relative contributions in a given patient. We apply a unique feature of our model, the newly postulated destruction term proportional to the platelet concentration squared (the higher order loss term), to explain cases of antibody negative ITP. Application of our model to data on patients splenectomized as treatment for ITP shows promise in predicting which patients are likely to respond.

Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: report of five new cases and review.

The neonatal progeroid syndrome (NPS), or Wiedemann-Rautenstrauch, is a rare autosomal recessive disorder comprised of generalized lipoatrophy except for fat pads in the suprabuttock areas, hypotrichosis of the scalp hair, eyebrows, and eyelashes, relative macrocephaly, triangular face, natal teeth, and micrognathia. We report on 5 new patients who demonstrate phenotypic variability and who represent the single largest series of NPS reported to date. Two of the patients are from an African-American kindred, an ethnic occurrence not reported previously. The fact that there are 2 pairs of sibs among the 5 patients further supports that NPS is an autosomal recessive condition. This report also includes a review of the previously reported 16 patients and compares them with the 5 new patients. Abnormalities in endocrine and lipid metabolism were found in 3 of 5 patients. Skeletal findings in 2 of our patients demonstrated some new findings as well as the typical radiological abnormalities previously noted in NPS. It is apparent, based on the 21 cases, that mild to moderate mental retardation is common in NPS. Long term follow-up of patients with NPS should provide more information relative to their ultimate psychomotor development. NPS is usually lethal by 7 months; however, on rare occasions, patients have survived into the teens. Our 3 surviving patients range in age from 16-23 months. Variability in the phenotype of NPS is clear; however, the phenotype remains distinct enough to allow a secure diagnosis.

Effects of temperature and snowfall on mortality in Pennsylvania.

The relation between exposure to severe cold weather and mortality is examined in a retrospective study of deaths occurring during the month of January from 1991 to 1996 in Pennsylvania. Using division-days as units of observation (n = 1,560) aggregated from death certificates and geographic divisions, the authors estimated mortality rates for total deaths and deaths due to ischemic heart disease, cerebrovascular diseases, and respiratory diseases by analyses based on generalized estimating equations. Total mortality increased on days of "extreme" climatic conditions, that is, when snowfall was greater than 3 cm and when temperatures were below -7 degrees C (rate ratio (RR) = 1.27, 95 percent confidence interval (CI) 1.12-1.44). On days of extreme conditions, mortality due to ischemic heart diseases tripled among males aged 35-49 years (RR = 3.54, 95 percent CI 2.35-5.35), increased for men aged 50-64 years (RR = 1.77, 95 percent CI 1.32-2.38), and rose for males aged 65 years and older (RR = 1.58, 95 percent CI 1.37-1.82), when compared with milder conditions. Among females, mortality for those aged 65 years and older increased for respiratory causes (RR = 1.68, 95 percent CI 1.28-2.21) and cerebrovascular causes (RR = 1.47, 95 percent CI 1.13-1.91). Cold and snow exposure may be hazardous among men as young as 35 years.

Predictive value of fetal ultrasonography in the diagnosis of a lethal skeletal dysplasia.

BACKGROUND: Certain ultrasonographic findings identified in a fetus suspected of having a skeletal dysplasia may be predictive of a lethal outcome. METHODS: We evaluated 27 fetuses suspected of having a skeletal dysplasia using targeted ultrasonography between 16 and 31 weeks' gestation. Clinical examination and skeletal radiography were done after delivery. RESULTS: A skeletal dysplasia was confirmed and a diagnosis established in all but one case. The skeletal dysplasia was lethal in 23 cases and, in each case, the outcome was accurately predicted prenatally; however, three of the infants survived several months. In 11 of the 23 cases (48%), the specific diagnosis was correctly determined before birth. Ultrasonographic findings not considered to reflect a lethal outcome, were accurately predicted in two other cases. In an additional two, sonographic examination suggested a lethal osteochondrodysplasia, though both survived. Findings consistent with a lethal skeletal dysplasia included a femur length < 1st centile, combined with either a bell-shaped thorax, decreased bone echogenicity, or both. Using these criteria provided a positive-predictive value for neonatal deaths of 80% (20/25), and 92% (23/25) if the three that died in infancy were included. CONCLUSIONS: In the fetus suspected of having a skeletal dysplasia, certain findings on targeted ultrasonography frequently are predictive of a lethal outcome; the ability to predict this appears greatest when more than one of these abnormalities is present.

Molecularly proven hypochondroplasia with cloverleaf skull deformity: a novel association.

We report on a case of cloverleaf skull deformity in a patient with hypochondroplasia, a disorder which has not been previously associated with this anomaly. Hypochondroplasia is a bone dysplasia caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Cloverleaf skull is a trilobar skull deformity which is etiologically and genetically heterogeneous and occurs in association with a number of disorders which result from mutations in the fibroblast growth factor receptor genes. Our patient demonstrated one of the common FGFR3 mutations identified in hypochondroplasia, a C-to-A change at nucleotide 1620 (C1620A) in the tyrosine kinase domain. The occurrence of a cloverleaf skull deformity appears to represent an example of variable expressivity in hypochondroplasia and suggests that additional factors other than a specific mutation can modify the phenotype in this disorder. In addition, identification of another FGFR mutation associated with cloverleaf skull further illustrates the genetic heterogeneity of this anomaly.

Mathematical modeling of platelet survival with implications for optimal transfusion practice in the chronically platelet transfusion-dependent patient.

BACKGROUND: It is known that in vivo platelet survival varies as the platelet count changes. Previous attempts at curve fitting fail to predict the decreased platelet survival in thrombocythemia. Therefore, mathematical relations that more closely approximate platelet survival were derived and used in models of platelet transfusion practice. STUDY DESIGN AND METHODS: A differential equation for platelet loss was derived that included a constant (constant homeostatic loss), a first-order term (senescent loss), and a second-order term (one proportional to the square of the platelet concentration and whose contribution is expected to be significant only at higher platelet concentrations). Data derived from this model was compared to platelet survival data in normal, thrombocytopenic, and thrombocythemic patients and to the platelet decay after high-dose chemotherapy. To provide further validation of this model, predicted and actual platelet requirements were calculated or obtained (chart review) in bone marrow patients with uncomplicated thrombocytopenia after ablation and at two platelet-transfusion thresholds (20 and 10 x 10(9)/L). RESULTS: The equations accurately modeled normal, thrombocytopenic, and thrombocythemic platelet survival. Chart review demonstrated a 12.5 percent reduction in platelet transfusion requirements when the transfusion threshold was reduced from 20 to 10 x 10(9) per L. The model predicted a reduction of 14.0 percent. For 100 days of uncomplicated thrombocytopenia and a transfusion threshold of 10 x 10(9) per L, transfusion of 3 units of platelet concentrates compared to a 6-unit pool of platelet concentrates, resulted in a 22-percent savings of platelet units. CONCLUSION: Platelet survival as a function of platelet concentration can be modeled by use of a differential equation. This model challenges current dogma regarding platelet destruction and predicts decreased platelet survival in thrombocythemic patients. The model illustrates that large doses of platelets would result in greater time between transfusions, however, more units of platelets are used. Consideration should be given to the more frequent use of smaller doses of platelets in patients who chronically require platelet transfusion support.

The surgical management of the upper extremity anomalies associated with Du Pan syndrome.

Du Pan syndrome is a rare condition comprising complex brachydactyly with fibular hypoplasia that is inherited in an autosomal recessive manner. This article describes experience gained through the management of four patients with this disorder. The surgical management of the upper limb abnormalities is discussed and a detailed timetable for their treatment is suggested.

Changing phenotype in Floating-Harbor syndrome.

We report on a girl with Floating-Harbor syndrome, trigonocephaly due to metopic suture synostosis, preauricular pit, hypoplastic thumb, subluxated radial head, and Sprengel deformity. A review suggests that trigonocephaly may be an important craniofacial manifestation in this syndrome that is recognizable in infancy. With time, this finding appears to become less noticeable, and the face develops a triangular shape, accentuated by a broad and bulbous nose.