In the vertebrate ventral spinal cord, p2 progenitors give rise to two interneuron subtypes excitatory V2a interneurons and inhibitory V2b interneurons. In the differentiation of V2a and V2b cells, Notch signaling promotes V2b fate at the expense of V2a fate. Later, V2b cells extend axons along the ipsilateral side of the spinal cord and express the inhibitory transmitter GABA. Notch signaling has been reported to inhibit the axonal outgrowth of mature neurons of the central nervous system; however, it remains unknown how Notch signaling modulates V2b neurite outgrowth and maturation into GABAergic neurons. Here, we have investigated neuron-specific Notch functions regarding V2b axon growth and maturation into zebrafish GABAergic neurons. We found that continuous neuron-specific Notch activation enhanced V2b fate determination but inhibited V2b axonal outgrowth and maturation into GABAergic neurons. These results suggest that Notch signaling activation is required for V2b fate determination, whereas its downregulation at a later stage is essential for V2b maturation. Accordingly, we found that a Notch signaling downstream gene, her15.1, showed biased expression in V2 linage cells and downregulated expression during the maturation of V2b cells, and continuous expression of her15.1 repressed V2b axogenesis. Our data suggest that spatiotemporal control of Notch signaling activity is required for V2b fate determination, maturation and axogenesis.

To assess the long-term effects of arthroscopic partial meniscectomy (APM) on the development of radiographic knee osteoarthritis, and on knee symptoms and function, at 5 years follow-up.

Multicentre, randomised, participant- and outcome assessor-blinded, placebo-surgery controlled trial.

Orthopaedic departments in five public hospitals in Finland.

146 adults, mean age 52 years (range 35-65 years), with knee symptoms consistent with degenerative medial meniscus tear verified by MRI scan and arthroscopically, and no clinical signs of knee osteoarthritis were randomised.

APM or placebo surgery (diagnostic knee arthroscopy).

We used two indices of radiographic knee osteoarthritis (increase in Kellgren and Lawrence grade ≥1, and increase in Osteoarthritis Research Society International (OARSI) atlas radiographic joint space narrowing and osteophyte sum score, respectively), and three validated patient-relevant measures of knee symptoms and function (Western Ontario Meniscal Evaluation Tool (WOMET), Lyc knee osteoarthritis and no concomitant benefit in patient-relevant outcomes, at 5 years after surgery.

ClinicalTrials.gov (NCT01052233 and NCT00549172).

ClinicalTrials.gov (NCT01052233 and NCT00549172).We asked whether the physiological and morphologic properties of hypoglossal motor neurons (CNXII MNs) that innervate protruder or retractor tongue muscles are disrupted in neonatal LgDel mice that carry a heterozygous deletion parallel to that associated with DiGeorge/22q11.2 deletion syndrome (22q11.2DS). Disrupted coordination of tongue movement in LgDel mouse pups may contribute to suckling, feeding, and swallowing (S/F/S) disruptions that parallel pediatric dysphagia in infants and toddlers with 22q11.2DS. Using an in vitro rhythmically active medullary slice preparation, we found spontaneous firing as well as IPSC frequency differed significantly in neonatal LgDel versus wild-type (WT) protruder and retractor CNXII MNs that were identified by retrograde tracing from their target muscles. In response to respiration-related activity, initiation and decay of transiently increased firing in WT protruder MNs is delayed in LgDel, accompanied by altered excitatory/inhibitory (E/I) balance. In addition, LgDel retractor MNs have a transient increase in firing with diminished IPSC frequency that is not seen in WT. There were no significant differences in cell body volume of either XII class in WT and LgDel Sholl analysis showed the total numbers of dendritic intersections (at 50- and 90-μm radii from the cell soma) were significantly greater for LgDel versus WT retractor MNs. Thus, the physiological, synaptic and cellular properties of distinct classes of CNXII MNs that coordinate tongue movement in neonatal WT mice are altered in LgDel Such changes could contribute to sub-optimal coordination of S/F/S that underlies pediatric dysphagia in 22q11.2DS.We investigate the evolutionary rescue of a microbial population in a gradually deteriorating environment, through a combination of analytical calculations and stochastic simulations. We consider a population destined for extinction in the absence of mutants, which can survive only if mutants sufficiently adapted to the new environment arise and fix. We show that mutants that appear later during the environment deterioration have a higher probability to fix. The rescue probability of the population increases with a sigmoidal shape when the product of the carrying capacity and of the mutation probability increases. Furthermore, we find that rescue becomes more likely for smaller population sizes and/or mutation probabilities if the environment degradation is slower, which illustrates the key impact of the rapidity of environment degradation on the fate of a population. We also show that our main conclusions are robust across various types of adaptive mutants, including specialist and generalist ones, as well as mutants modeling antimicrobial resistance evolution. We further express the average time of appearance of the mutants that do rescue the population and the average extinction time of those that do not. Our methods can be applied to other situations with continuously variable fitnesses and population sizes, and our analytical predictions are valid in the weak-to-moderate mutation regime.

A genetic cause can be identified for an increasing number of pediatric and adult-onset kidney diseases. Preimplantation genetic testing (formerly known as preimplantation genetic diagnostics) is a reproductive technology that helps prospective parents to prevent passing on (a) disease-causing mutation(s) to their offspring. Here, we provide a clinical overview of 25 years of preimplantation genetic testing for monogenic kidney disease in The Netherlands.

This is a retrospective cohort study of couples counseled on preimplantation genetic testing for monogenic kidney disease in the national preimplantation genetic testing expert center (Maastricht University Medical Center+) from January 1995 to June 2019. Statistical analysis was performed through chi-squared tests.

In total, 98 couples were counseled regarding preimplantation genetic testing, of whom 53% opted for preimplantation genetic testing. Staurosporine The most frequent indications for referral were autosomal dominant polycystic kidney disease (38%), Alport syndrome (26%), and autosomal recessive polycystic kidney disease (9%). Of couples with at least one preimplantation genetic testing cycle with oocyte retrieval, 65% experienced one or more live births of an unaffected child. Of couples counseled, 38% declined preimplantation genetic testing for various personal and technical reasons.

Referrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate.

Referrals, including for adult-onset disease, have increased steadily over the past decade. Though some couples decline preimplantation genetic testing, in the couples who proceed with at least one preimplantation genetic testing cycle, almost two thirds experienced at least one live birth rate.Tumor resection followed by chemoradiation remains the current criterion standard treatment for high-grade gliomas. Regardless of aggressive treatment, tumor recurrence and radiation necrosis are 2 different outcomes. Differentiation of tumor recurrence from radiation necrosis remains a critical problem in these patients because of considerable overlap in clinical and imaging presentations. Contrast-enhanced MR imaging is the universal imaging technique for diagnosis, treatment evaluation, and detection of recurrence of high-grade gliomas. PWI and PET with novel radiotracers have an evolving role for monitoring treatment response in high-grade gliomas. In the literature, there is no clear consensus on the superiority of either technique or their complementary information. This review aims to elucidate the diagnostic performance of individual and combined use of functional (PWI) and metabolic (PET) imaging modalities to distinguish recurrence from posttreatment changes in gliomas.

When mapping the ischemic core and penumbra in patients with acute ischemic stroke using perfusion imaging, the core is currently delineated by applying the same threshold value for relative CBF at all time points from onset to imaging. We investigated whether the degree of perfusion abnormality and optimal perfusion parameter thresholds for defining ischemic core vary with time from onset to imaging.

In a prospectively maintained registry, consecutive patients were analyzed who had ICA or M1 occlusion, baseline perfusion and diffusion MR imaging, treatment with IV tPA and/or endovascular thrombectomy, and a witnessed, well-documented time of onset. Ten superficial and deep MCA ROIs were analyzed in ADC and perfusion-weighted images.

Among the 66 patients meeting entry criteria, onset-to-imaging time was 162 minutes (range, 94-326 minutes). Of the 660 ROIs analyzed, 164 (24.8%) showed severely or moderately reduced ADC (ADC ≤ 620, ischemic core), and 496 (75.2%), mildly reduced or normal ADC (ADC  > verely abnormal and have higher accuracy with longer onset-to-imaging times.3D-printed nasopharyngeal swabs for COVID-19 molecular diagnostic testing address the national shortage of swabs. Swab designs for adult use were placed in the public domain in March 2020. Swabs for pediatric use, however, need to be smaller and more flexible to navigate delicate pediatric nasopharyngeal cavities. We describe a novel use of maxillofacial CT scans to aid in the design of pediatric nasopharyngeal swabs.

Unique among the acute neurologic manifestations of Severe Acute Respiratory Syndrome coronavirus 2, the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, is chemosensory dysfunction (anosmia or dysgeusia), which can be seen in patients who are otherwise oligosymptomatic or even asymptomatic. The purpose of this study was to determine if there is imaging evidence of olfactory apparatus pathology in patients with COVID-19 and neurologic symptoms.

A retrospective case-control study compared the olfactory bulb and olfactory tract signal intensity on thin-section T2WI and postcontrast 3D T2 FLAIR images in patients with COVID-19 and neurologic symptoms, and age-matched controls imaged for olfactory dysfunction.

There was a significant difference in normalized olfactory bulb T2 FLAIR signal intensity between the patients with COVID-19 and the controls with anosmia (

= .003). Four of 12 patients with COVID-19 demonstrated intraneural T2 signal hyperintensity on postcontrast 3D T2 FLAIR compared with none of the 12 patients among the controls with anosmia (

= .