Enlarged parietal foramina: association with cerebral venous and cortical anomalies

OBJECTIVE: To evaluate a series of patients with enlarged parietal foramina for associated brain anomalies. BACKGROUND: Enlarged parietal foramina are usually considered a benign calvarial defect. Methods: Ten patients with enlarged parietal foramina were identified. Seven patients were evaluated with neuroimaging: two by cranial CT and five by CT and/or MRI. Three patients who underwent MRI also underwent MR angiography or MR venography. RESULTS: Six of seven patients had cranial imaging showing a persistent falcine venous sinus. Three of six patients had variations of occipital cortical infolding. One patient had focal encephalomalacia in close proximity to the persistent falcine venous sinus and one had a previously undiagnosed atretic occipital encephalocele. CONCLUSION: This constellation of findings suggests that aberrant vascular evolution during fetal development may affect cerebrovascular, brain, or skull development. Individuals with enlarged parietal foramina (>5 mm) warrant imaging of underlying brain parenchyma and vasculature.     

Prevalence and treatment of chronic idiopathic thrombocytopenic purpura of childhood in Sweden

The frequency and treatment of children with chronic idiopathic thrombocytopenic purpura in Sweden were characterized using a national enquiry based on a questionnaire. Seventy-five children diagnosed as having chronic idiopathic thrombocytopenic purpura on 1 September 1993 were identified. The prevalence in children between 0.5 and 15.5 years of age was calculated to be 4.6/100 000. The median age at the time of diagnosis was 5 years and the male/female ratio was 1:1.2. Almost half of the patients (43%) were not treated at all during the disease. Steroids (43%) and intravenous immunoglobulin (25%) were most commonly used. Only two children were splenectomized.     

Prevalence of antibodies against SARS‐CoV‐2 in the Norwegian population,August 2021

BackgroundOne year into the COVID‐19 pandemic, the cumulative number of confirmed COVID‐19 cases in Norway was still low. In January 2021, when the Norwegian COVID‐19 vaccination campaign started, the national seroprevalence estimate of SARS‐CoV‐2 antibodies was 3.2%. We have conducted a nationwide cross‐sectional study in August 2021 to investigate the overall prevalence of SARS‐CoV‐2 antibodies in Norway after 8 months of COVID‐19 mass vaccination and a third wave of SARS‐CoV‐2 infection.MethodsResidual sera were collected from laboratories across Norway in August 2021. In IgG antibodies against the spike protein, the spike receptor binding domain (RBD) and the nucleocapsid protein of SARS‐CoV‐2 were measured by a bead‐based flow cytometric assay.ResultsIn total, 1926 residual sera were collected from individuals aged 0–98 years; 55.1% were from women. The overall national estimated seroprevalence from vaccination and/or infection was 62.6% (credible interval [CrI] 60.1%–65.2%) based on having antibodies against both spike and RBD. Estimated seroprevalence increased with age. Among all samples, 11.7% had antibodies against nucleocapsid. For unvaccinated children <12 years, the seroprevalence estimate due to SARS‐CoV‐2 infection was 12.5% (95% CrI 9.3%–16.1%). Of seropositive samples from the unvaccinated children, 31.9% lacked anti‐nucleocapsid antibodies.ConclusionsThe high overall SARS‐CoV‐2 seroprevalence estimates are in line with Norwegian registry data. Vaccination, not infection, contributed the most to the high seroprevalence in August 2021. Lack of antibodies against nucleocapsid should not automatically be interpreted as absence of previous infection as this could lead to underestimation of COVID‐19 cases in seroprevalence studies.     

Functional modulation of PTH1R activation and signaling by RAMP2

Receptor-activity-modifying proteins (RAMPs) are ubiquitously expressed membrane proteins that associate with different G protein–coupled receptors (GPCRs), including the parathyroid hormone 1 receptor (PTH1R), a class B GPCR and an important modulator of mineral ion homeostasis and bone metabolism. However, it is unknown whether and how RAMP proteins may affect PTH1R function. Using different optical biosensors to measure the activation of PTH1R and its downstream signaling, we describe here that RAMP2 acts as a specific allosteric modulator of PTH1R, shifting PTH1R to a unique preactivated state that permits faster activation in a ligand-specific manner. Moreover, RAMP2 modulates PTH1R downstream signaling in an agonist-dependent manner, most notably increasing the PTH-mediated Gi3 signaling sensitivity. Additionally, RAMP2 increases both PTH- and PTHrP-triggered β-arrestin2 recruitment to PTH1R. Employing homology modeling, we describe the putative structural molecular basis underlying our functional findings. These data uncover a critical role of RAMPs in the activation and signaling of a GPCR that may provide a new venue for highly specific modulation of GPCR function and advanced drug design.

G protein–coupled receptors(GPCRs) represent the largest class of membrane-bound proteins and are involved in a multitude of biological processes (1). They are characterized by a seven-transmembrane helix structure, which undergoes a characteristic rearrangement upon binding of agonists. Agonist binding to its cognate receptor induces conformational changes in the transmembrane helices, which are transmitted to the cytosolic face of the receptors and ultimately result in receptor activation, which represents the key step of signal transduction. The combination of crystallographic and cryogenic electron microscopy studies and the employment of optical biosensors to study the reorganization of the seven transmembrane domains has allowed a detailed understanding of the general mechanisms of GPCR activation (2–5).Earlier structural studies suggest that GPCRs undergo similar conformational changes upon activation, including, most prominently, an outward movement of the transmembrane helix 6 at the cytosolic face, thereby creating a pocket to which the G protein α-subunit can couple (5). More recent studies, however, have revealed that the exact type of changes may depend on the receptor class and the specific receptor (6–8). Class- and receptor-specific differences may also exist in the interaction of receptors not only with downstream G proteins and β-arrestins but also with accessory and modulatory proteins (9).Studies of the kinetic steps that govern the structural rearrangements which underlie receptor activation (10) showed that its speed might depend on the receptor class and the specific receptor. For example, when exposed to saturating agonist concentrations, most class A GPCRs switch into the active state within tens of milliseconds. The same process takes 1 to 2 ms for a class C GPCR and may take up to a second for class B receptors (11–15). Little is known whether the activation kinetics of GPCRs can be modulated by their cellular context and whether proteins other than the receptors themselves might play a role in shaping signaling kinetics and specificity.Here, we study the parathyroid hormone 1 receptor (PTH1R), a prototypical member of class B GPCRs characterized by a large N-terminal domain that binds a major part of their cognate peptide agonists (16, 17). Compared to class A GPCRs, PTH1R activation is relatively slow and occurs in a two-step process: The initial N-terminal binding step has a time constant of ∼140 ms, followed by an interaction of the ligand with the transmembrane core, which changes into its active conformation with a time constant of ∼1 s (11, 14). Pleiotropic in its downstream coupling, PTH1R signals primarily via G_s but can also couple to G_q (18), G_12/13 (19), and G_i (20) and interacts with and signals via β-arrestins (21, 22). The two endogenous agonists, parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP), trigger PTH1R activation with similar kinetics and specificity for the various intracellular pathways (23–25). However, PTH can induce prolonged signaling from intracellular sites, while PTHrP signals exclusively from the cell surface (26).PTH1R has been reported to interact with modulatory proteins of the receptor-activity-modifying protein (RAMP) family (27–29). RAMPs constitute a family of single transmembrane helix proteins with three members: RAMP1, RAMP2, and RAMP3.It is controversial whether PTH1R interacts only or preferentially with RAMP2 (28) or all three RAMPs (28, 29). In RAMP2 knock-out mice, PTH1R function is deregulated, and placental dysfunction is observed (30), suggesting a major physiological role of the PTH1R/RAMP2 interaction. Yet, the molecular mechanisms of how RAMPs may modulate the activation dynamics of PTH1R and their signaling properties remain to be elucidated.To address these questions, we develop and employ biosensors for PTH1R activation and investigate an array of downstream signaling pathways to assess the effects of RAMPs on the activation dynamics and signaling properties of PTH1R in response to its two endogenous ligands, PTH and PTHrP. We observe that RAMP2 specifically interacts with PTH1R and modulates its activation kinetics as well as signaling dynamics in an agonist-dependent manner.     

Long-term exocrine function of the pancreas transplant

The long-term exocrine function of fifty-nine pancreaticoduodenal isografts was evaluated in rats for up to one year post transplantation. At one, three, six, nine, and twelve months after transplantation the grafts were cannulated and the exocrine secretion was collected. The volume, protein content, pH, amylase and trypsin concentrations, and electrolyte composition of the secretion were compared with those obtained from the host pancreas in nineteen control rats. Twenty-four hour secretion studies demonstrated normal basal function of the pancreas transplant when compared with that of the host. Pancreozymin stimulation caused an increase in volume, trypsin concentration, and amylase concentration of the graft pancreas secretion that was similar to those seen in the host. These studies indicate that there is normal exocrine secretion of pancreas transplants in the absence of rejection and that denervation of the gland has little direct effect on over-all pancreatic function.