GABAergic/Glycinergic and Glutamatergic Neurons Mediate Distinct Neurodevelopmental Phenotypes of STXBP1 Encephalopathy.

An increasing number of pathogenic variants in presynaptic proteins involved in the synaptic vesicle cycle are being discovered in neurodevelopmental disorders. The clinical features of these synaptic vesicle cycle disorders are diverse, but the most prevalent phenotypes include intellectual disability, epilepsy, movement disorders, cerebral visual impairment, and psychiatric symptoms ( Verhage and Sørensen, 2020; Bonnycastle et al., 2021; John et al., 2021; Melland et al., 2021). Among this growing list of synaptic vesicle cycle disorders, the most frequent is STXBP1 encephalopathy caused by de novo heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as MUNC18-1; Verhage and Sørensen, 2020; John et al., 2021). STXBP1 is an essential protein for presynaptic neurotransmitter release. Its haploinsufficiency is the main disease mechanism and impairs both excitatory and inhibitory neurotransmitter release. However, the disease pathogenesis and cellular origins of the broad spectrum of neurological phenotypes are poorly understood. Here we generate cell type-specific Stxbp1 haploinsufficient male and female mice and show that Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons causes developmental delay, epilepsy, and motor, cognitive, and psychiatric deficits, recapitulating majority of the phenotypes observed in the constitutive Stxbp1 haploinsufficient mice and STXBP1 encephalopathy. In contrast, Stxbp1 haploinsufficiency in glutamatergic neurons results in a small subset of cognitive and seizure phenotypes distinct from those caused by Stxbp1 haploinsufficiency in GABAergic/glycinergic neurons. Thus, the contrasting roles of excitatory and inhibitory signaling reveal GABAergic/glycinergic dysfunction as a key disease mechanism of STXBP1 encephalopathy and suggest the possibility to selectively modulate disease phenotypes by targeting specific neurotransmitter systems.

The age of transfused blood predicts hematocrit response among critically ill surgical patients.

BACKGROUND: In vitro data suggest that erythrocytes undergo storage time-dependent degradation, eventuating in hemolysis. We hypothesize that transfusion of old blood, as compared with newer blood, results in a smaller increment in hematocrit. METHODS: We performed an analysis of packed red blood cell transfusions administered in the surgical intensive care unit. Age of blood was analyzed as continuous, dichotomized at 14 days (old vs new), and grouped by weeks old. RESULTS: A total of 136 U of packed red blood cells were given to 52 patients; 110 (80.9%) were 14 days old or more. A linear, inverse correlation was observed between the age of blood and the increment in hematocrit (r(2) = -.18, P = .04). The increment in hematocrit was greater after transfusion of new as compared with old blood (5.6% vs 3.5%, respectively; P = .005). A linear relationship also was observed between the age of transfused blood in weeks and the increment in hematocrit (P = .02). CONCLUSIONS: There is an inverse relationship between the age of blood and the increment in hematocrit. The age of blood should be considered before transfusion of surgical patients with intensive care unit anemia.

Different setting, different care: integrating prevention and clinical care in school-based health centers.

School-based health centers (SBHCs) are widely credited with increasing students' access to care by making health services affordable and convenient. SBHCs can also provide a qualitatively different type of health care for children and adolescents than that delivered by community providers. Health services offered in a school setting can integrate clinical care with public health interventions and environmental change strategies. This ability to reach outside the walls of the exam room makes SBHCs uniquely positioned to address the multiple determinants of health. We describe innovative California SBHC programs focusing on obesity prevention, asthma, mental health, and oral health that represent new models of health care for children and adolescents.