The additive miotic effects of dapiprazole and pilocarpine

Background: Since dapiprazole on alpha-adrenergic agent, produces miosis by paralyzing the dilator muscle, and pilocarpine, a parasympathetic drug, causes miosis by affecting the sphincter, we speculated that the two drugs might have additive effects. Methods: The additive miotic actions of pilocarpine 2% and dapiprazole 0.5% were evaluated by comparing the effects of two drugs given together and alone on the reversal of mydriasis induced by tropicamide (0.5%) and phenylephrine (10%) in one eye each of 60 healthy volunteers. Results: Dapiprazole and pilocarpine together induced miosis significantly faster than each drug alone, showing additive effects. Conclusion: Co-administration of dapiprazole and pilocarpine at the end of the eye examination will induce fast pupillary constriction, which might be useful in preventing the development of an acute attack of angle-closure glaucoma in patients with anatomically narrow angles.     

Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study

Objectives

To determine whether the use of the new macrolides (azithromycin, clarithromycin, roxithromycin) during the first trimester of pregnancy is associated with an increased risk of major malformations.

Study design

In a prospective multi-center study, pregnancy outcome was compared between pregnant women exposed to one of the new macrolides during the first trimester of pregnancy and two comparison groups one exposed to other antibiotics and the other to other non-teratogenic medications. All women enrolled in the study called one of the three participating teratogen information services (TIS). Group 1 macrolides (n = 161), group 2 other antibiotics (n = 213) and group 3 non-teratogens (n = 740).

Results

A total of 161 women exposed to the new macrolides (118 were exposed in the first trimester of pregnancy) and 953 from a comparison groups were followed up. The rate of major malformations in the study group was 4.1% compared to 2.1% in the other antibiotics exposed group (OR = 1.41, 95% CI 0.47–4.23) and 3.0% in the non-teratogens exposed group. The rate of elective terminations of pregnancy was significantly higher in the exposed group in compare to both comparison groups.

Conclusion

Our study, although relatively small sized, suggests that the use of the new macrolides during the first trimester of pregnancy does not represent an increased risk for congenital malformations strong enough for an induced abortion after such an exposure. Elective terminations of pregnancy because of early exposure to these medications should be reconsidered.     

Unmasking Myocardial Dysfunction in Patients Hospitalized for Community-Acquired Pneumonia Using a 4-Chamber 3-Dimensional Volume/Strain Analysis

Lower respiratory infection was reported as the most common fatal infectious disease. Community-acquired pneumonia (CAP) and myocardial injury are associated; yet, true prevalence of myocardial injury is probably underestimated. We assessed the rate and severity of myocardial dysfunction in patients with CAP. Admitted patients diagnosed with CAP were prospectively recruited. All the patients had C-reactive protein (CRP), brain natriuretic peptide (BNP), and high-sensitivity cardiac troponin (hs-cTnl) tests added to their routine workup. 2D/3D Doppler echocardiography was done on a Siemens Acuson SC2000 machine ≤ 24 h of diagnosis. 3D datasets were blindly analyzed for 4-chamber volumes/strains using EchobuildR 3D-Volume Analysis prototype software, v3.0 2019, Siemens-Medical Solutions. Volume/strain parameters were correlated with admission clinical and laboratory findings. The cohort included 34 patients, median age 60 years (95% CI 55–72). The cohort included 18 (53%) patients had hypertension, 9 (25%) had diabetes mellitus, 7 (21%) were smokers, 7 (21%) had previous myocardial infarction, 4 (12%) had chronic renal failure, and 1 (3%) was on hemodialysis treatment. 2D/Doppler echocardiography findings showed normal ventricular size/function (LVEF 63 ± 9%), mild LV hypertrophy (104 ± 36 g/m²), and LA enlargement (41 ± 6 mm). 3D volumes/strains suggested bi-atrial and right ventricular dysfunction (global longitudinal strain RVGLS =  − 8 ± 4%). Left ventricular strain was normal (LVGLS =  − 18 ± 5%) and correlated with BNP (r = 0.40, p = 0.024). The patients with LVGLS >  − 17% had higher admission blood pressure and lower SaO₂ (144 ± 33 vs. 121 ± 20, systolic, mmHg, p = 0.02, and 89 ± 4 vs. 94 ± 4%, p = 0.006, respectively). hs-cTnl and CRP were not different. Using novel 3D volume/strain software in CAP patients, we demonstrated diffuse global myocardial dysfunction involving several chambers. The patients with worse LV GLS had lower SaO₂ and higher blood pressure at presentation. LV GLS correlated with maximal BNP level and did not correlate with inflammation or myocardial damage markers.     

National Scale Real-Time Surveillance of SARS-CoV-2 Variants Dynamics by Wastewater Monitoring in Israel

In this report, we describe a national-scale monitoring of the SARS-CoV-2 (SC-2) variant dynamics in Israel, using multiple-time sampling of 13 wastewater treatment plants. We used a combination of inclusive and selective quantitative PCR assays that specifically identify variants A19/A20 or B.1.1.7 and tested each sample for the presence and relative viral RNA load of each variant. We show that between December 2020 and March 2021, a complete shift in the SC-2 variant circulation was observed, where the B.1.1.7 replaced the A19 in all examined test points. We further show that the normalized viral load (NVL) values and the average new cases per week reached a peak in January 2021 and then decreased gradually in almost all test points, in parallel with the progression of the national vaccination campaign, during February–March 2021. This study demonstrates the importance of monitoring SC-2 variant by using a combination of inclusive and selective PCR tests on a national scale through wastewater sampling, which is far more amendable for high-throughput monitoring compared with sequencing. This approach may be useful for real-time dynamics surveillance of current and future variants, such as the Omicron (BA.1, BA.2) and other variants.     

Prolonged patients’ In-Hospital Waiting Period after discharge eligibility is associated with increased risk of infection,morbidity and mortality: a retrospective cohort analysis

Background

Prolonged, inappropriate hospital stay after patients’ eligibility for discharge from internal medicine departments is a world-wide health-care systems’ problem. Nevertheless, the extent to which such surplus hospital stays are associated with infectious complications, their time frame of appearance and their long-term implications was not previously addressed.

Methods

We conducted a retrospective cohort analysis of patients experiencing an In-hospital Waiting Period (IHWP) after discharge eligibility in a single, tertiary hospital.

Results

We screened the records of 245 patients out of which 104 patients fulfilled our inclusion criteria. The mean length of IHWP was 15.7?±?4.79 day during which 9(8.7 %) patients died. The study primary composite end-point, in-hospital mortality or hospital acquired infection (pneumonia, UTI or sepsis) occurred in 32(31 %) patients. The most hazardous time was during the first 3 IHWP days: 63.7 % of patients experienced a complication and 44 % of the total complications occurred during this period. The occurrence of any complication during IHWP was associated, with statistical significance, with increased risk of mortality during the first year after IHWP initiation (HR?=?6.02, p?=?0.014).

Conclusion

Prolongation of hospital stay after patients are deemed to be discharged from internal medicine departments is associated with increased morbidity and mortality, mainly during the first surplus days of in-hospital stay. Efforts should be made to shorten such hospital stays as much as possible.

     

The importance of timing in melatonin administration in a blind man

An 18-year-old blind man suffered from chronic sleep disturbances associated with daytime fatigue and excessive daytime somnolence. After two unsuccessful treatment regimens with 5 mg and 10 mg melatonin administered at bedtime (2200-2230), a third regimen of 5 mg melatonin administered at 2000 for 3 weeks resulted in a successful resolution of his sleep disturbances. We suggest that the efficacy of melatonin in ameliorating sleep disturbances because of alterations in circadian rhythmicity may be dependent on the time of administration.     

The Involvement of Collagen Triple Helix Repeat Containing 1 in Muscular Dystrophies

Apolipoprotein E4 (APOE4) genotype is the strongest genetic risk factor for late-onset Alzheimer disease and confers a proinflammatory, neurotoxic phenotype to microglia. Here, we tested the hypothesis that bone marrow cell APOE genotype modulates pathological progression in experimental Alzheimer disease. We performed bone marrow transplants (BMT) from green fluorescent protein–expressing human APOE3/3 or APOE4/4 donor mice into lethally irradiated 5-month-old APPswe/PS1ΔE9 mice. Eight months later, APOE4/4 BMT–recipient APPswe/PS1ΔE9 mice had significantly impaired spatial working memory and increased detergent-soluble and plaque Aβ compared with APOE3/3 BMT–recipient APPswe/PS1ΔE9 mice. BMT-derived microglia engraftment was significantly reduced in APOE4/4 recipients, who also had correspondingly less cerebral apoE. Gene expression analysis in cerebral cortex of APOE3/3 BMT recipients showed reduced expression of tumor necrosis factor-α and macrophage migration inhibitory factor (both neurotoxic cytokines) and elevated immunomodulatory IL-10 expression in APOE3/3 recipients compared with those that received APOE4/4 bone marrow. This was not due to detectable APOE-specific differences in expression of microglial major histocompatibility complex class II, C-C chemokine receptor (CCR) type 1, CCR2, CX3C chemokine receptor 1 (CX3CR1), or C5a anaphylatoxin chemotactic receptor (C5aR). Together, these findings suggest that BMT-derived APOE3-expressing cells are superior to those that express APOE4 in their ability to mitigate the behavioral and neuropathological changes in experimental Alzheimer disease.Humans uniquely have three different apolipoprotein E (APOE) alleles (ɛ2, ɛ3, and ɛ4). APOE4 is the single greatest genetic risk factor for late-onset Alzheimer disease (AD), and there is a gene dosage effect.¹ However, genetic association does not inform function/pathogenesis. Multiple mechanisms have been postulated that predominantly focus on production, metabolism, or clearance of amyloid-β (Aβ) and that are variably supported by multiple observations, including: i) APOE genotype is strongly related to Aβ levels in brain and cerebrospinal fluid of AD patients^2,3; ii) modulation of apolipoprotein E (apoE) protein levels in brain results in alterations of Aβ burden^4,5; iii) Aβ degradation is at least partially apoE dependent^6,7; and iv) Aβ clearance is differentially modulated by apoE isoforms, with APOE4 mice exhibiting reduced central and peripheral Aβ clearance compared with APOE3 mice.^8–10 Aβ degradation and clearance is at least partially dependent on microglia, the innate immune effector cells of the brain. Microglia have migratory and phagocytic capacity, are increased in the vicinity of Aβ plaques, and phagocytose Aβ.^11–13 APOE genotype modulates central nervous system innate immune function in culture,¹⁴ including astrocyte and microglia elaboration of cytokines and chemokines,^15,16 microglia production of reactive oxygen species,¹⁷ microglia-mediated paracrine neurotoxicity,¹⁸ microglia migration,¹⁹ and other functions.²⁰ However, the specific contribution of microglial APOE genotype to AD pathophysiology in vivo is largely unknown.To address this critical question and to test a potential therapeutic application, we used the fact that bone marrow transplantation (BMT) results in the gradual replacement of endogenous (host) microglia (to the near exclusion of other cell types) with microglia derived from donor marrow, in both wild-type mice and transgenic mouse models of AD.^21–24 We used targeted-replacement (TR) APOE mice homozygous for either the APOE3 or APOE4 gene inserted into the mouse APOE regulatory elements^25,26 that coexpressed green fluorescent protein (GFP). We transplanted whole bone marrow (BM) isolated from TR APOE3/3;GFP or TR APOE4/4;GFP mice into lethally irradiated APPswe/PS1ΔE9 mice to determine the specific role of microglial APOE genotype in the pathological progression of AD.     

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.