Adipose stress-sensing kinases: linking obesity to malfunction.

Obesity has been proposed to inflict a variety of stresses on adipose tissue, including inflammatory, metabolic, oxidative and endoplasmic reticulum stress. Through the activation of 'stress-sensing pathways', metabolic and endocrine alterations are produced, which probably contribute to the co-morbidities associated with obesity. Here, we review the evidence supporting the development of various obesity-related stresses and the activation of several stress-sensing pathways, specifically in adipocytes and/or adipose tissue, which manifest metabolic and endocrine dysfunction frequently in obesity. As the central role of adipose tissue in regulating whole-body metabolism is elucidated, understanding adipose tissue stress-sensing pathways might provide potential new therapeutic targets to attenuate obesity-related morbidity.     

Immunoglobulin-Mediated Neuro-Cognitive Impairment: New Data and a Comprehensive Review

Excessive influx of immunoglobulin (IgG) into the brain has been reported to induce central nervous system (CNS) dysfunction. Depressed patients may exhibit immune activation manifested by elevated inflammatory markers and pro-inflammatory cytokines. The brain and especially the limbic system contain high concentrations of high affinity Fc receptors. We reviewed the literature on this phenomena and present data on the behavioral effects of pooled normal IgG on the brain. Many disease states are associated with depression and we examined whether this may be linked to high IgG influx. Female Balb/C mice were injected intra-cerbroventricularly with human immunoglobulin whole molecule, or human IgG F(ab′)₂ or Fc fragments. Control mice were injected with saline. The four groups were subjected to behavioral (staircase, forced swimming test, and elevated plus maze) and cognitive tests (passive avoidance test). IgG-injected mice exhibited depression-like behavior as reflected by significantly higher immobility time in the forced swimming test (p?<?0.05) and hyperactive behavior as reflected by higher number of stairs climbed in the staircase test compared to controls (p?<?0.01). Fc-fragments-injected mice showed hyperactive behavior as reflected by both higher number of stairs climbed and rearing events in the staircase test compared to controls. The results indicate that high levels of normal IgG in the cerebrospinal fluid can cause hyperactivity and depression-like behavior. The mechanism involved in these CNS manifestations include possibly Fc receptor binding.     

An in silico perception for newly isolated flavonoids from peach fruit as privileged avenue for a countermeasure outbreak of COVID-19

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4 was first isolated from a natural source, together with three known compounds, the ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, which were isolated from peach [Prunus persica (L.) Batsch] fruits. These compounds were subjected to different virtual screening strategies in order to examine their activity to combat the COVID-19 outbreak. The study design composed of some major aspects: (a) docking with main protease (M^pro), (b) docking with spike protein, (c) 3D shape similarity study (Rapid Overlay Chemical Similarity-ROCS) to the clinically used drugs in COVID-19 patients, and finally, (d) the rule of five and the estimated pre-ADMT properties of the separated flavonoids. Docking study with M^pro of SARS-CoV-2 (PDB ID:6LU7, and 6Y2F) showed that compound 3, its aglycone part, and compound 4 have a strong binding mode to a protease receptor with key amino acids, especially Gln:166AA, and having a similar docking pose to co-crystalized ligands. Docking with the spike protein of SARS-CoV-2 illustrated that compounds 3 and 4 have a good binding affinity to PDB ID:6VSB through the formation of HBs with Asp:467A and Asn:422A. According to ROCS analysis, compounds 1, 3, and 4 displayed high similarities to drugs that prevent SARS-Co2 entry to the lung cells or block the inflammatory storm causing lung injury. Compounds 3 and 4 are good candidates for drug development especially because they showed predicted activity against SARS-CoV-2 through different mechanisms either by preventing genome replication or by blocking inflammatory storm that trigger lung injury. These compounds were isolated from peach fruit, and the study supports data and continues with the recommendation of peach fruits in controlling and managing COVID-19 cases.

3′-Hydroxy-4′-methoxy-chroman-7-O-β-d-glucopyranoside 4, together with three known compounds, ferulic acid heptyl ester 1, naringenin 2, and 4,2′,4′-trihydroxy-6′-methoxychalcone-4′-O-β-d-glucopyranoside 3, was isolated from peach fruits.     

Delayed clearance of pneumocystis carinii infection, increased inflammation, and altered nitric oxide metabolism in lungs of surfactant protein-D knockout mice

Surfactant protein-D (SP-D), a member of the "collectin" family, has been shown to play a role in innate immunity through modulation of inflammation and clearance of organisms. The role of SP-D in host defense against Pneumocystis carinii pneumonia was assessed using SP-D knockout (KO) mice. When inoculated with P. carinii, both wild-type (wt) and SP-D KO mice required CD4 cell depletion to develop infection. In CD4 cell-depleted models, 2 weeks after infection with P. carinii, SP-D KO mice developed increased intensity of infection, compared with wt mice, despite higher lung-inflammation scores and increased amounts of alveolar inflammatory cells. The increased inflammation seen in SP-D KO mice was accompanied by increases in lung weight, expression of inducible nitric oxide (NO) synthase, total NO levels, and 3-nitrotyrosine levels in lung tissue. These results indicate that SP-D plays a role in host defense against P. carinii in vivo by modulating clearance of organisms, lung inflammation, and metabolism of NO.     

Ranking Adverse Drug Reactions With Crowdsourcing

BackgroundThere is no publicly available resource that provides the relative severity of adverse drug reactions (ADRs). Such a resource would be useful for several applications, including assessment of the risks and benefits of drugs and improvement of patient-centered care. It could also be used to triage predictions of drug adverse events.ObjectiveThe intent of the study was to rank ADRs according to severity.MethodsWe used Internet-based crowdsourcing to rank ADRs according to severity. We assigned 126,512 pairwise comparisons of ADRs to 2589 Amazon Mechanical Turk workers and used these comparisons to rank order 2929 ADRs.ResultsThere is good correlation (rho=.53) between the mortality rates associated with ADRs and their rank. Our ranking highlights severe drug-ADR predictions, such as cardiovascular ADRs for raloxifene and celecoxib. It also triages genes associated with severe ADRs such as epidermal growth-factor receptor (EGFR), associated with glioblastoma multiforme, and SCN1A, associated with epilepsy.ConclusionsADR ranking lays a first stepping stone in personalized drug risk assessment. Ranking of ADRs using crowdsourcing may have useful clinical and financial implications, and should be further investigated in the context of health care decision making.     

From the Cover: Father's brain is sensitive to childcare experiences

Although contemporary socio-cultural changes dramatically increased fathers'' involvement in childrearing, little is known about the brain basis of human fatherhood, its comparability with the maternal brain, and its sensitivity to caregiving experiences. We measured parental brain response to infant stimuli using functional MRI, oxytocin, and parenting behavior in three groups of parents (n = 89) raising their firstborn infant: heterosexual primary-caregiving mothers (PC-Mothers), heterosexual secondary-caregiving fathers (SC-Fathers), and primary-caregiving homosexual fathers (PC-Fathers) rearing infants without maternal involvement. Results revealed that parenting implemented a global “parental caregiving” neural network, mainly consistent across parents, which integrated functioning of two systems: the emotional processing network including subcortical and paralimbic structures associated with vigilance, salience, reward, and motivation, and mentalizing network involving frontopolar-medial-prefrontal and temporo-parietal circuits implicated in social understanding and cognitive empathy. These networks work in concert to imbue infant care with emotional salience, attune with the infant state, and plan adequate parenting. PC-Mothers showed greater activation in emotion processing structures, correlated with oxytocin and parent-infant synchrony, whereas SC-Fathers displayed greater activation in cortical circuits, associated with oxytocin and parenting. PC-Fathers exhibited high amygdala activation similar to PC-Mothers, alongside high activation of superior temporal sulcus (STS) comparable to SC-Fathers, and functional connectivity between amygdala and STS. Among all fathers, time spent in direct childcare was linked with the degree of amygdala-STS connectivity. Findings underscore the common neural basis of maternal and paternal care, chart brain–hormone–behavior pathways that support parenthood, and specify mechanisms of brain malleability with caregiving experiences in human fathers.Throughout human history and across cultures, women have typically assumed primary caregiving responsibility for infants (1, 2). Although humans are among the few mammalian species where some male parental caregiving is relatively common, father involvement varies considerably within and across cultures, adapting to ecological conditions (1, 3). Involved fathering has been linked with children''s long-term physiological and social development and with increases in mothers'' caregiving-related hormones such as oxytocin and prolactin (3–6). In addition, animal studies demonstrated structural brain alterations in caregiving fathers (7, 8). It has been suggested that, although maternal caregiving is triggered by neurobiological processes related to pregnancy and labor, the human father''s brain, similar to other biparental mammals, adapts to the parental role through active involvement in childcare (1–3). Despite growing childcare involvement of fathers (3, 5, 6), mechanisms for human fathers'' brain adaptation to caregiving experiences remain largely unknown, and no study to our knowledge has examined the brain basis of human fatherhood when fathers assume primary responsibility for infant care.For social species with lengthy periods of dependence, parental caregiving is key to survival and relies on brain structures that maximize survival (2, 9). Animal studies have demonstrated that mammalian mothering is supported by evolutionarily ancient structures implicated in emotional processing, vigilance, motivation, and reward, which are rich in oxytocin receptors, including the amygdala, hypothalamus, nucleus accumbens, and ventral tegmental area (VTA), and that these regions are sensitive to caregiving behavior (9, 10). Imaging studies of human mothers found activation in similar areas, combined with paralimbic insula-cingulate structures that imbue infants with affective salience, ground experience in the present moment and enable maternal simulation of infant states (11–13). These structures implicate a phylogenetically ancient network of emotional processing that rapidly detects motivationally salient and survival-related cues (14) and enables parents to automatically identify and immediately respond to infant distress, thereby maximizing survival. In humans, this emotional processing network is complemented by a cortical mentalizing network of frontopolar-medial-prefrontal-temporo-parietal structures involved in social understanding, theory of mind, and cognitive empathy, including the medial prefrontal cortex (mPFC), frontopolar cortex, superior temporal sulcus (STS), and temporal poles (15). The mentalizing network plays an important role in individuals'' ability to infer mental states from behavior, is already activated during the parents'' first weeks of parenting, and enables parents to cognitively represent infant states, predict infant needs, and plan future caregiving (11–13).The few studies examining the human father''s brain showed activation in similar areas, including the STS, lateral and medial frontal regions, VTA, inferior frontal gyrus (IFG), and orbitofrontal cortex (OFC) (16, 17). Only one study compared maternal and paternal brain response to infant cues, reporting mothers'' greater amygdala activation, fathers'' greater superior-temporal and medial-frontal activation, and maternal and paternal oxytocin''s different associations with amygdala vs. cortical activation (18). Oxytocin, a nine-amino acid neuropeptide that underpins the formation of affiliative bonds (19), supports the development of human parental caregiving (20). Research has shown that maternal and paternal oxytocin levels are associated with parent–infant synchrony, which is the parent''s careful adaptation of caregiving behavior to infant''s social signals (21). However, although oxytocin levels are similar in mothers and fathers, oxytocin is differentially linked with the parent-specific repertoire, for instance, with affectionate contact in mothers and stimulatory play in fathers (5, 20).Ethological perspectives emphasize the importance of studying the neurobiology of parenting in its natural habitat and of using a behavior-based approach to test parents'' brain adaptation to ecological pressures (22). Consistent with findings in other mammals (10), studies on brain–behavior associations in human mothers describe links between mother–infant synchrony and brain activation in the mother''s subcortical regions, including the amygdala, nucleus accumebens, and hippocampus (11, 13). In contrast, the one study testing human fathers'' brain–behavior associations showed correlations with cortical activation (17). Overall, these findings suggest that distinct brain–hormone–behavior pathways may underpin maternal and paternal care; therefore, oxytocin and parenting behavior may be associated with the emotional processing network in mothers but with the socio-cognitive circuit in fathers. Furthermore, animal studies indicate that active caregiving in biparental fathers leads to greater integration of multiple brain networks involved in nurturance, learning, and motivation (7). Hence, active involvement in caregiving may possibly facilitate integration of both parenting-related networks in human fathers, particularly among those who undertake the primary caregiver role.The present study sought to examine the brain basis of human fatherhood by using a “natural experiment,” afforded for the first time in human history, to our knowledge, by contemporary socio-cultural changes. Throughout history, infants without mothers were cared for by other women (2). Current social changes enable the formation of two-father families raising children with no maternal involvement since birth (3). Such a context provides a unique setting to assess changes in the paternal brain on assuming the traditionally maternal role. Moreover, understanding mechanisms of brain adaptation to caregiving experiences in primary-caregiving fathers may shed further light on processes that refine all fathers'' responses to childcare activities.We visited the homes of two-parent families rearing their firstborn child: heterosexual mother-father couples comprising primary-caregiving mothers (PC-Mothers) and secondary-caregiving fathers (SC-Fathers) and homosexual couples comprising two primary-caregiving fathers (PC-Fathers) (SI Materials and Methods). We videotaped parent–infant interaction in the natural habitat, measured parental oxytocin, and used the videotaped parent–child interactions as stimuli for functional MRI (fMRI) to test parental brain response to infant-related cues. Five hypotheses were proposed. First, we expected activation in both subcortical areas involved in vigilance and reward and cortical circuits implicated in social understanding in all parents raising a young infant. Second, we expected greater subcortical activation in mothers, particularly in the amygdala, which has been repeatedly linked with mammalian mothering (23, 24), and greater activation in cortical socio-cognitive circuits in fathers. Third, the brain–hormone–behavior constellation underpinning maternal care was expected to center around the emotional-processing network, whereas the brain–hormone–behavior links in fathers were expected to coalesce with the socio-cognitive network. Fourth, consistent with the context-specific evolution of human fathering (1), we expected greater variability in fathers'' brain response as mediated by actual caregiving experiences. Such variability would be particularly noted among the primary-caregiving fathers raising infants without mothers and may involve functional integration of the subcortical and cortical networks subserving parenting. Finally, we expected that the pathways leading from the parent''s primary caregiving role to greater parent–infant synchrony would be mediated by parental brain activation and oxytocin levels.     

Craniofacial fibrous dysplasia (CFD) of the maxilla in an 11-year old boy: A case report

We present the case of a surgically treated 11-year old boy with a diagnosis of craniomaxillofacial fibrous dysplasia (CFD) in the maxillary sinus. When first seen in the outpatient clinic of our department he had minimal symptoms. After initial radiological diagnostics by computed tomography scans (CT-scans) the patient was treated operatively by radical excision of the tumor. The radiographs showed the typical intramedullary located and well-defined lesions, which eroded the cortical bone with the typical appearance of fibrous dysplasia. The histopathology showed the typical curved extending fibrous trabeculae in C, O and Y-shape which were embedded in a moderately cellular morphologically inconspicuous stroma, confirming the initial suspicion of fibrous dysplasia of the maxillary bone. Cone beam tomography was a valuable tool in determining the re-ossification of bone at the affected side. Local resection can be curative in limited disease.     

Protrusion of an Artificial Femoral Head : A Rare Complication of Chronic Dislocation of the Prosthetic Hip

Chronic dislocation is considered a rare complication after total hip arthroplasty. We have treated a patient with a complication related to chronic dislocation—protrusion of the prosthetic femoral head through the skin. This 86-year-old bedridden patient with a known dislocated total hip arthroplasty presented with fever and protrusion of an artificial femoral head after 2 months of a nonhealing pressure sore. The care of this patient was partial removal of the prosthetic components and intravenous antibiotics. Chronic dislocation is rarely reported, yet it may cause severe complications in debilitated and demented patients. Special attention should be warranted to these patients as they might benefit from earlier surgical treatment.