The Role of Suburbanization in Metropolitan Segregation After 1940.

The three decades from 1940 through 1970 mark a turning point in the spatial scale of Black-White residential segregation in the United States compared with earlier years. We decompose metropolitan segregation into three components: segregation within the city, within the suburbs, and between the city and its suburbs. We then show that extreme levels of segregation were well established in most cities by 1940, and they changed only modestly by 1970. In this period, changes in segregation were greater at the metropolitan scale, driven by racially selective population growth in the suburbs. We also examine major sources of rising segregation, including region, metropolitan total, and Black population sizes, and indicators of redlining in the central cities based on risk maps prepared by the Home Owners Loan Corporation (HOLC) in the late 1930s. In addition to overall regional differences, segregation between the city and suburbs and within suburbia increased more in metropolitan areas with larger Black populations, but this relationship was found only in the North. In contrast to some recent theorizing, there is no association between preparation of an HOLC risk map or the share of city neighborhoods that were redlined and subsequent change in any component of segregation.

List-keepers and other carrier bag stories: Academic mothers' (in)visible labor during the COVID-19 pandemic.

Beginning in 2020, the COVID-19 pandemic disrupted familiar rhythms of work and life when academic women from the United States sheltered-in-place in their homes. The pandemic brought forth challenges which accentuated that caregiving with little or no support disproportionately affected mothers' abilities to navigate their new lives inside the home, where work and caregiving abruptly collided. This article takes on the (in)visible labor of academic mothers during this time-the labor mothers saw and viscerally experienced, yet that which was often unseen/unexperienced by others. Using Ursula K. Le Guin's Carrier Bag Theory as a conceptual framework, the authors engage with interviews of 54 academic mothers through a feminist-narrative lens. They craft stories of carrying (in)visible labor, isolation, simultaneity, and list-keeping as they navigate the mundaneness of everyday pandemic home/work/life. Through unrelenting responsibilities and expectations, they each find ways to carry it all, as they carry on.

Heterologous expression and purification of a multiheme cytochrome from a Gram-positive bacterium capable of performing extracellular respiration.

Microbial electrochemical technologies are emerging as environmentally friendly biotechnological processes. Recently, a thermophilic Gram-positive bacterium capable of electricity production in a microbial fuel cell was isolated. Thermincola potens JR contains several multiheme c-type cytochromes that were implicated in the process of electricity production. In order to understand the molecular basis by which Gram-positive bacteria perform extracellular electron transfer, the relevant proteins need to be characterized in detail. Towards this end, a chimeric gene containing the signal peptide from Shewanella oneidensis MR-1 small tetraheme cytochrome c (STC) and the gene sequence of the target protein TherJR_0333 was constructed. This manuscript reports the successful expression of this chimeric gene in the Gram-negative bacterium Escherichia coli and its subsequent purification and characterization. This methodology opens the possibility to study other multiheme cytochromes from Gram-positive bacteria, allowing the extracellular electron transfer mechanisms of this class of organisms to be unraveled.

Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset.

BACKGROUND: Carcinoma of unknown primary with a "gastrointestinal profile" is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. PATIENTS AND METHODS: 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. RESULTS: 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1-"consistent with lower GI profile" included 34 patients [CDX-2+, CK20+, CK7-] and Cohort 2-"probable lower GI profile" included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. CONCLUSIONS: Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP.

Anti-inflammatory and anti-arthritic activities of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ß-lapachone).

OBJECTIVE AND DESIGN: The purpose of this study was to evaluate the anti-inflammatory and anti-arthritic activities of 3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione (ß-lapachone; ß-lap) and to elucidate its probable mode of action. METHODS: Carrageenan-induced paw edema, cell migration evaluation and production of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide were used for this study. Freund's complete adjuvant (FCA)-induced arthritis was used as a model of chronic inflammation. ß-Lap was tested in doses of 40 and 60 mg/kg, orally. RESULTS: In the paw edema test, the dose of 60 mg/kg gave a higher percentage inhibition of edema (49.3 %) than control. ß-Lap inhibited neutrophil migration and reduced concentrations of TNF-α, IL-6 and NO in peritoneal exudates of animals with peritonitis. In the arthritis test, ß-lap inhibited edema and NO production in the serum of treated animals. CONCLUSION: Significant anti-inflammatory and anti-arthritic activities were observed in animals treated with ß-lap. The effects of ß-lap can be attributed in part to immunomodulation with reduction of pro-inflammatory cytokines and NO.

tRNA modification enzyme-dependent redox homeostasis regulates synapse formation and memory.

Post-transcriptional modification of RNA regulates gene expression at multiple levels. ALKBH8 is a tRNA modifying enzyme that methylates wobble uridines in specific tRNAs to modulate translation. Through methylation of tRNA-selenocysteine, ALKBH8 promotes selenoprotein synthesis and regulates redox homeostasis. Pathogenic variants in ALKBH8 have been linked to intellectual disability disorders in the human population, but the role of ALKBH8 in the nervous system is unknown. Through in vivo studies in Drosophila, we show that ALKBH8 controls oxidative stress in the brain to restrain synaptic growth and support learning and memory. ALKBH8 null animals lack wobble uridine methylation and exhibit a global reduction in protein synthesis, including a specific decrease in selenoprotein levels. Loss of ALKBH8 or independent disruption of selenoprotein synthesis results in ectopic synapse formation. Genetic expression of antioxidant enzymes fully suppresses synaptic overgrowth in ALKBH8 null animals, confirming oxidative stress as the underlying cause of dysregulation. ALKBH8 animals also exhibit associative learning and memory impairments that are reversed by pharmacological antioxidant treatment. Together, these findings demonstrate the critical role of tRNA modification in redox homeostasis in the nervous system and reveal antioxidants as a potential therapy for ALKBH8-associated intellectual disability.

A Case of Transcranial Direct-Current Stimulation for Childhood Stroke Hemiparesis: A Brief Report.

Purpose: Survivors of childhood stroke incur lifelong physical disability. Treatment options are limited, however, models of motor reorganization after stroke are revealing cortical targets for neuromodulation. Transcranial direct-current stimulation (tDCS) enhances motor learning and may improve motor recovery in adult stroke, but remains uninvestigated in childhood-onset stroke. Here we documented the feasibility and safety of tDCS in an adolescent with chronic stroke-induced hemiparesis.Materials and methods: Over 10 days, the participant underwent occupational therapy paired with contralesional, primary motor cortex-targeting, cathodal tDCS. Clinical motor outcomes, and safety and tolerability measures were completed.Results: tDCS was well-tolerated with no adverse events. Motor outcomes did not regress post-intervention, with clinically significant changes still evident at 6 months.Conclusions: Application of controlled trials of non-invasive neuromodulation are safe and tolerability in childhood-onset stroke.

Sensory-motor network functional connectivity in children with unilateral cerebral palsy secondary to perinatal stroke.

BACKGROUND: Perinatal stroke is the most common cause of unilateral cerebral palsy. Mechanisms of post-stroke developmental plasticity in children are poorly understood. To better understand the relationship between functional connectivity and disability, we used resting-state fMRI to compare sensorimotor connectivity with clinical dysfunction. METHODS: School-aged children with periventricular venous infarction (PVI) and unilateral cerebral palsy were compared to controls. Resting-state BOLD signal was acquired on 3 T MRI and analyzed using CONN in SPM12. Functional connectivity was computed between S1, M1, supplementary motor area (SMA), and thalamus of the left/non-lesioned and right/lesioned hemisphere. Primary outcome was connectivity expressed as a Fisher-transformed correlation coefficient. Motor function was measured using the Assisting Hand Assessment (AHA), and Melbourne Assessment (MA). Proprioceptive function was measured using a robotic position matching task (VarXY). RESULTS: Participants included 15 PVI and 21 controls. AHA and MA in stroke patients were negatively correlated with connectivity (increased connectivity = poorer performance). Position sense was inversely correlated with connectivity (increased connectivity = improved performance) between the non-lesioned S1 and thalamus/SMA. In controls, VarXY was positively correlated with connectivity between the thalamus and bilateral sensorimotor regions. CONCLUSIONS: Resting state fMRI measures of sensorimotor connectivity are associated with clinical sensorimotor function in children with unilateral cerebral palsy secondary to PVI. Greater insight into understanding reorganization of brain networks following perinatal stroke may facilitate personalized rehabilitation.

Robotic TMS mapping of motor cortex in the developing brain.

BACKGROUND: The human motor cortex can be mapped safely and painlessly with transcranial magnetic stimulation (TMS) to explore neurophysiology in health and disease. Human error likely contributes to heterogeneity of such TMS measures. Here, we aimed to use recently pioneered robotic TMS technology to develop an efficient, reproducible protocol to characterize cortical motor maps in a pediatric population. NEW METHOD: Magnetic resonance imaging was performed on 12 typically developing children and brain reconstructions were paired with the robotic TMS system. The system automatically aligned the TMS coil to target sites in 3 dimensions with near-perfect coil orientation and real-time head motion correction. Motor maps of 4 forelimb muscles were derived bilaterally by delivering single-pulse TMS at predefined, uniformly spaced trajectories across a 10 × 10 grid (7 mm spacing) customized to the participant's MRI. RESULTS: Procedures were well tolerated with no adverse events. Two male, eight-year-old participants had high resting motor thresholds that precluded mapping. The mean hotspot coordinate and centre of gravity coordinate were determined in each hemisphere for four forelimb muscles bilaterally. Average mapping time was 14.25 min per hemisphere. COMPARISON WITH EXISTING METHODS: Traditional manual TMS methods of motor mapping are time intensive, technically challenging, prone to human error, and arduous for use in pediatrics. This novel TMS robot approach facilitates improved efficiency, tolerability, and precision in derived, high-fidelity motor maps. CONCLUSIONS: Robotic TMS opens new avenues to explore motor map neurophysiology and its influence on developmental plasticity and therapeutic neuromodulation. Our findings provide evidence that TMS robotic motor mapping is feasible in young participants.

The presence of Waddell signs depends on age and gender, not diagnosis.

AIMS: The aim of this study was to determine if positive Waddell signs were related to patients' demographics or to perception of their quality of life. PATIENTS AND METHODS: This prospective cross-sectional study included 479 adult patients with back pain from a university spine centre. Each completed SF-12 and Oswestry Disability Index (ODI) questionnaires and underwent standard spinal examinations to elicit Waddell signs. The relationship between Waddell signs and age, gender, ODI, Mental Component Score (MCS), and Physical Component Score (PCS) scores was determined. RESULTS: Of the 479 patients, 128 (27%) had at least one positive Waddell sign. There were significantly more women with two or more Waddell signs than men. The proportion of patients with at least one positive Waddell sign increased with age until 55 years, and then declined rapidly; none had a positive sign over the age of 75 years. Functional outcome scores were significantly worse in those with a single Waddell sign (p < 0.01). With one or more Waddell signs, patients' PCS and ODI scores indicated a perception of severe disability; with three or more Waddell signs, patients' MCS scores indicated severe disability. With five Waddell signs, ODI scores indicated that patients perceived themselves as crippled. CONCLUSION: Positive Waddell signs, a potential indicator of central sensitization, indicated a likelihood of having functional limitations and an impaired quality of life, particularly in young women. Cite this article: Bone Joint J 2018;100-B:219-25.

Lumbar magnetic resonance imaging findings in patients with and without Waddell Signs.

BACKGROUND CONTEXT: Waddell Signs (WS), introduced as a method to establish patients with substantial psychosocial components to their low back pain, carry a negative association despite no literature evaluating whether physical disease is associated with them. PURPOSE: To compare lumbar magnetic resonance imaging (MRI) findings between the patients with and without WS. STUDY DESIGN: Retrospective cohort study based on prospectively collected data. PATIENT SAMPLE: Thirty patients aged 35 to 55 years with an Oswestry Disability Index (ODI) score >50 randomly selected such that there was an even distribution of patients based on the number of WS. OUTCOME MEASURES: ODI and Short Form-12 scores, number of WS, presence and severity of spinal pathology. METHODS: MRIs were reviewed by three spine specialists blinded to clinical exam findings, number of WS, and patient identity. Type and severity of pathology and presence of surgical and non-surgical lesions were assessed, and findings were rank ordered based on the overall impression of the pathology. There was no external funding or potential conflicts of interest for this study. RESULTS: There were significantly more individual pathologic findings in patients without WS (p=.02). However, there was no difference in the severity of pathology based on WS (p=.46). Furthermore, the rank ordering based on overall impression of severity showed no difference between the patients with and without WS (p=.20). Although 100% of the patients without WS showed pathologic findings on MRI, 70% of WS patients also had significant pathology on MRI. The prevalence of spondylolisthesis, stenosis, and disc herniation was similar (p=.41, p=.22, and p=.43, respectively). The prevalence and mean number of lesion amenable to surgery did not differ based on presence of WS (p=.21 and p=.18, respectively). CONCLUSIONS: Patients with WS present a difficult diagnostic challenge for the physician as their organic symptoms are often coexistent with emotional fear avoidance behavior. Although there is more overall pathology in patients without WS, a significant number of these patients appear to have comparable spinal pathology with equivalent severity, which may be contributing to patients' symptoms and disability. Presence of these non-organic symptoms often makes us doubt these patients. However, as part of effective treatment, physicians should better understand both the physical and psychological components of patient disability.

Poly-ε-Caprolactone Microsphere Polymers Containing Usnic Acid: Acute Toxicity and Anti-Inflammatory Activity.

Usnic acid (UA) has been studied by its pharmacological properties; however, it presents moderate toxicity, low solubility, and absorption by biological membranes. The aim of this study was to develop poly-ε-caprolactone microsphere polymers containing UA (UA-micro) and evaluate their acute toxicity and anti-inflammatory activity. The microspheres were prepared by multiple emulsion technique (water/oil/water) and characterized by the encapsulation efficiency, particle size, polydispersity index, and zeta potential. The acute toxicity of UA and UA-micro (25-50 mg/kg; p.o.) was evaluated in mice. The anti-inflammatory activity of UA and UA-micro was evaluated by subcutaneous air pouch and carrageenan-induced paw edema in rat, with measurement of inflammatory cytokines and MPO levels. The UA presented encapsulation efficiency of 97.72%, particle size of 13.54 micrometers, polydispersity index of 2.36, and zeta potential of 44.5 ± 2.95 mV. The UA-micro presented lower acute toxicity (LD50 value up to 2000 mg/kg; p.o.) when compared to UA. UA-micro and UA (25 mg/kg) significantly reduced paw volume and decreased MPO levels, whereas only UA-micro (50 mg/kg) reduced significantly IL-1ß, TNF-α, and NO levels in inflammatory exudate. These results suggest that controlled release systems, as microspheres, can be a promising alternative to reduce the toxicity of UA, making it a viable compound for inflammation therapy.

Hypercalcemia in the neuroleptic malignant syndrome.

The neuroleptic malignant syndrome (NMS) developed in a 32-year-old man following fluphenazine enanthate administration. Hypercalcemia was initially present, perhaps reflecting release of calcium from skeletal muscle stores. The elevated serum calcium levels support the existence of a peripheral muscle abnormality in the pathogenesis of the NMS and provides another point of similarity between NMS and malignant hyperthermia.

Hyperprolactinemia in multiple endocrine adenomatosis, type 1.

Three cases are described in which hyperprolactinemia occurred as a feature of multiple endocrine adenomatosis, type 1 (MEA-1); enlargement of the sella turcica varied from gross to absent, and serum prolactin (PRL) levels ranged from 21 to 1,000 ng/ml in these cases. Since PRL-secreting pituitary tumors may occur with variable presentation in MEA-1, periodic measurements of serum PRL levels should be carried out to detect this abnormality.

Comparison of inhibitory effects of 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3,',5'-triiodothyronine (rT3), and 3,3'-diiodothyronine (T2) on thyrotropin-releasing hormone-induced release of thyrotropin in the rat in vitro.

In order to compare, in vitro, the TSH suppressive effects of iodothyronines, rat pituitary quarters were first preincubated with T4, T3, rT3, or 3,3'-diiodothyronine (T2) in Gey and Gey buffer containing 1% bovine serum albumin for 2 h at 37 C and then incubated at 37 C for 1 h with the iodothyronine under study and TRH. TSH released into the medium during incubation was compared to that released by control pituitary fragments, which were not exposed to iodothyronines. All four iodothyronines (T3, T4, rT3, and T2) were able to significantly inhibit the TRH-induced release of TSH from pituitary fragments in a dose range of 0.015-2.2 microgram/ml. However, much larger doses of sodium iodide (1.25 mg/ml) and diiodotyrosine (10 and 30 microgram/ml) had no significant effect on the release of TSH. Among T3, rT3, and T4, T3 was the most potent and rT3 was the least potent. The relative potency of T3:T4:rT3 appeared to be approximately 100:12:1 when estimated from the lowest doses that caused significant inhibition of TRH-induced release of TSH, and approximately 100:6:0.5 when estimated from the doses that caused 50% inhibition of TSH release; the TSH inhibiting potency of T2 was similar to that of rT3. The activity of T4 could not be explained entirely on the basis of contamination of T4 with T3 or by in vitro conversion of T4 to T3. Similarly, the available data suggested that rT3 and T2 possess some, albeit modest, intrinsic TSH-Suppressive activity. TSH-inhibiting activities of T3, T4, and rT3 were also studied using pituitary fragments from starved and iodine-deficient rats. There was no evidence of a change in the sensitivity of the thyrotroph to either T3 or T4 in starvation. Similarly, comparison of the responses to several doses of rT3 did not indicate any significant abnormality in the sensitivity of the thyrotroph to rT3 in starvation or iodine deficiency. However, comparison of the TSH-suppressive effects of T4 in the iodine-deficient and normal rat indicated a significant increase in the sensitivity of the thyrotroph to T4 in iodine deficiency. A similar trend was also evident in the effect of T3 in iodine deficiency, but it fell short of statistical significance.

Morphine and naloxone: effects on beta-endorphin immunoreactivity in canine plasma and secretions from rat pituitaries.

Morphine and naloxone were administered to five dogs to assess their effects on endogenous opioid release. Morphine (3 mg/20 kg) produced a significant (P less than 0.05) increase in plasma beta-endorphin immunoreactivity(beta EI) compared to saline control. The peak stimulation [19.2 +/- 4.97 baseline to 48.1 +/- 6.82 (SEM) pg/ml] occurred at +10 min and rapidly returned to preinjection levels at +60. At a dose 10 times equipotent to circulating basal beta EI, morphine (4-6 micrograms) failed to affect beta EI release. Naloxone, surprisingly, also caused a significant (P less than 0.025) release of beta EI. After naloxone, beta EI rose from a preinjection baseline of 36.4 +/- 5.82 pg/ml to a peak of 172 +/- 44.1 pg/ml at 45 min post injection. Naloxone pretreatment also obscured the effect of subsequently injected morphine (3 mg/20 kg). In three naloxone-treated dogs, gel chromatography of pooled basal and peak plasma revealed a preponderance of beta-lipotropin compared to beta-endorphin. To determine the site of stimulation of beta EI by opiates and opioids, a series of rat anterior pituitary incubations were performed. Neither morphine (10(-6) M) nor D-Ala2-methionine enkephalinamide (10(-6) M) nor naloxone (10(-6) M) had an effect significantly different from control medium on the release of beta EI from the pituitaries. In a second set of experiments we compared the effect on beta EI release of hypothalamic median eminence extract alone or with morphine. Hypothalamic median eminence extract at two concentrations produced significant release of beta EI, which was unaffected by the addition of morphine. These results suggest that stimulation of release of endogenous opioid peptides by opiates occurs at a suprapituitary level.

Hypercalcemia in rats bearing growth hormone- and prolactin-secreting transplantable pituitary tumors.

We evaluated the effects of chronic massive elevations of serum GH and PRL on calcium metabolism in rats bearing the MStT/W15 and 7315a transplantable pituitary tumors. MStT/W15 tumor rats manifest elevated serum GH and PRL levels, hypercalcemia, hypercalciuria, and elevated serum levels of PTH and 1,25-dihydroxyvitamin D. The hypercalcemia was not reversed by dexamethasone or propranolol treatment, but was ameliorated by starvation. Parathyroidectomy produced hypocalcemia in the MStT/W15 tumor rats, confirming the parathyroid dependence of the hypercalcemia. The 7315a tumor produced a milder degree of hypercalcemia, along with elevated serum levels of PRL, ACTH, and corticosterone; serum GH was normal. In high concentrations, PRL and/or GH may stimulate the secretion of PTH as well as enhance dietary calcium absorption, in part through the mediation of 1,25-dihydroxyvitamin D.

Carbidopa plus L-dopa pretreatment inhibits the prolactin (PRL) response to thyrotropin-releasing hormone and thus cannot distinguish central from pituitary sites of prolactin stimulation.

Contrary to a previous report, pretreatment of normal men with carbidopa plus L-dopa (Sinemet 25/250) markedly inhibited the PRL response to TRH, a stimulus that acts directly on the pituitary. Thus, the results of carbidopa/L-dopa testing cannot be used to determine whether agents that stimulate PRL secretion act on the pituitary or at a higher central nervous system level.

Prolactin stimulation by protein is mediated by amino acids in humans.

In normal humans, ingestion of protein stimulates PRL secretion. I investigated the mechanism of this effect by feeding free amino acids, both singly and in combination, to normal subjects. The serum PRL response to a high protein liquid mixed meal was duplicated by ingestion of an equivalent free amino acid mixture, indicating that intact protein or peptides are not required. The time course of the response and the presence of normal responses in two vagotomized subjects suggest that neither traditional gut hormones nor vagus nerve activity is involved in this response. Of the single amino acids tested, phenylalanine and tyrosine were the most potent stimulators of PRL secretion and can account for most, if not all, of the PRL-releasing activity of the mixed meal. D-Phenylalanine, the biologically inactive optical isomer, was nearly ineffective in releasing PRL. Administration of naloxone, phentolamine, or propranolol did not alter the PRL response to the various test meals, indicating that neither opioid, alpha-adrenergic, nor beta-adrenergic stimulation is involved in meal-induced PRL secretion.

Cimetidine, an H2-antihistamine, stimulates prolactin secretion in man.

Intravenous administration of cimetidine, a histamine (H2) receptor antagonist, provoked an immediate 2 to 3-fold rise in serum prolactin concentrations in 8 normal men; serum thyrotropin, growth hormone, thyroxine, and triiodothyronine were not significantly affected. Diphenhydramine, an H1-antagonist, was without effect on any of the hormones measured. The results suggest that histamine may have an important function in the regulation of prolactin secretion in man.