The Poor at Birth: Infant Auxology and Mortality at Philadelphia's Almshouse Hospital, 1848-1873

This paper presents an analysis of birth weights and infant mortality in mid-nineteenth century Philadelphia using obstetrics records of Philadelphia's Almshouse hospital, an institution for the poor and their offspring. Children of the poor weighed between 2,900 and 3,200 grams on average at birth, or about the 10th to 25th percentile of modern birth weight standards. 3rthweights declined during the Civil War decade, consistent with the poor state of the economy in the l80s, because birth weights were lower than modern standards the urban poor suffered from higher rates of infant mortality than today. But infant mortality was far worse than that expected from a modern schedule of mortality by birth weight, and a major determinant of excess mortality appears to be the poor quality of nineteenth century obstetrics.

Characterizing a role for CoREST (SPR-1) in regulating the function of LSD1 (SPR-5)

Mutations in histone modifying enzymes have dramatic effects on transmitting epigenetic information between generations. In C. elegans, the H3K4me2 demethylase, spr-5, and the H3K9me2 methyltransferase, met-2, synergize at fertilization to reprogram the epigenetic landscape and prevent the inappropriate expression of germ specific genes in the early zygote. If either enzyme is lost, developmental defects occur; both spr-5 and met-2 mutants display a progressive sterility phenotype. This phenotype is even more exacerbated in spr-5; met-2 double mutants, which exhibit maternal effect sterility and a severe developmental delay after a single generation. In mammals, orthologs of SPR-5, LSD1, and SPR-1, CoREST, physically associate, and in the absence of CoREST, LSD1 demethylase activity is impaired. In C. elegans, SPR-5 and SPR-1 interact in vitro, and worms deficient in SPR-5 or SPR-1 rescue the egg-laying defect observed in se1-12 mutants. These findings suggest that a more complex co-regulatory mechanism may exist where SPR-1 interacts with and regulates SPR-5 function. We hypothesize that this interaction is required at fertilization to ensure proper epigenetic reprogramming and development of the zygote. To test this hypothesis, we first compared progressive sterility in spr-1 vs. spr-5 mutants. Unlike spr-5 mutants, spr-1 worms do not become progressively sterile over many generations nor do they display any obvious morphological defects. Taking advantage of the severe developmental delay and sterility phenotypes observed in spr-5; met-2 mutants, we assessed whether these same phenotypes were present in met-2; spr-1 mutants. Interestingly, similar to spr-5; met-2 progeny, met-2; spr-1 progeny display sterility and developmental delay in a single generation, albeit not as severe as spr-5; met-2 mutants. While ~ 20% of met-2; spr-1 progeny are sterile in a single generation, we observe an increase to ~ 60% by generation 8, and this increase in sterility is accompanied by a decline in the total number of progeny. By generation 10, we observe an increase in the number met-2; spr-1 adult germlines that phenocopy the disorganized and under developed germline morphology that we observe in spr-5; met-2 mutants. Taken together, our data suggest SPR-1 regulates SPR-5 function, but also leaves open the possibility SPR-5 may interact with other proteins/complexes to program the epigenetic landscape at fertilization. With this, spr-1 emerges as an epigenetic player with implications for regulating epigenetic reprogramming and development

Hepatic steatosis in patients with HIV-Hepatitis C Virus coinfection: is it associated with antiretroviral therapy and more advanced hepatic fibrosis?

<p>Abstract</p> <p>Background and aims</p> <p>Patients with HIV and hepatitis C virus (HCV) coinfection are at increased risk of developing hepatic steatosis. The aims of this study were to assess the prevalence of steatosis in a cohort with HIV-HCV coinfection, and to determine an association, if any, between steatosis, antiretroviral therapy (ART), and advanced hepatic fibrosis.</p> <p>Patients and methods</p> <p>HIV-HCV coinfected patients were retrospectively identified from the HIV clinic. ART was classified as none, nucleoside reverse transcriptase inhibitors (NRTIs) only, highly active antiretroviral therapy (HAART) only, and sequential therapy (initial NRTIs followed by HAART). Fibrosis stage and necroinflammation grade were assessed by the modified HAI (Ishak) scoring method. Steatosis was graded as 0–3.</p> <p>Results</p> <p>Sixty patients were identified. The overall prevalence of hepatic steatosis was 58%. Those that received HAART only had a lower prevalence of steatosis (41%) compared to those on NRTIs only (70%) or sequential therapy (82%). Independent predictors of hepatic steatosis were absence of HAART only therapy, OR 2.9, p = 0.09, and presence of cirrhosis, OR 4.6, p = 0.044. Forty five percent of the patients had advanced fibrosis (fibrosis stage ≥ 3). NI grade (OR 1.9, p = 0.030), and steatosis grade (OR 3.6, p = 0.045), were independent predictors of advanced fibrosis.</p> <p>Conclusion</p> <p>Hepatic steatosis is associated with more advanced hepatic fibrosis in the HIV-HCV coinfected population. HAART only therapy (rather than NRTIs only or sequential therapy) appears to be associated with a lower prevalence of hepatic steatosis. This may be one of the mechanisms by which HAART could attenuate hepatic fibrosis in such a cohort.</p

Inactivation of cloned Na channels expressed in Xenopus oocytes

This study investigates the inactivation properties of Na channels expressed in Xenopus oocytes from two rat IIA Na channel cDNA clones differing by a single amino acid residue. Although the two cDNAs encode Na channels with substantially different activation properties (Auld, V. J., A. L. Goldin, D. S. Krafte, J. Marshall, J. M. Dunn, W. A. Catterall, H. A. Lester, N. Davidson, and R. J. Dunn. 1988. Neuron. 1:449-461), their inactivation properties resemble each other strongly but differ markedly from channels induced by poly(A+) rat brain RNA. Rat IIA currents inactivate more slowly, recover from inactivation more slowly, and display a steady-state voltage dependence that is shifted to more positive potentials. The macroscopic inactivation process for poly(A+) Na channels is defined by a single exponential time course; that for rat IIA channels displays two exponential components. At the single-channel level these differences in inactivation occur because rat IIA channels reopen several times during a depolarizing pulse; poly(A+) channels do not. Repetitive stimulation (greater than 1 Hz) produces a marked decrement in the rat IIA peak current and changes the waveform of the currents. When low molecular weight RNA is coinjected with rat IIA RNA, these inactivation properties are restored to those that characterize poly(A+) channels. Slow inactivation is similar for rat IIA and poly(A+) channels, however. The data suggest that activation and inactivation involve at least partially distinct regions of the channel protein

Messenger RNA coding for only the alpha subunit of the rat brain Na channel is sufficient for expression of functional channels in Xenopus oocytes

Several cDNA clones coding for the high molecular weight (alpha) subunit of the voltage-sensitive Na channel have been selected by immunoscreening a rat brain cDNA library constructed in the expression vector lambda gt11. As will be reported elsewhere, the amino acid sequence translated from the DNA sequence shows considerable homology to that reported for the Electrophorus electricus electroplax Na channel. Several of the cDNA inserts hybridized with a low-abundance 9-kilobase RNA species from rat brain, muscle, and heart. Sucrose-gradient fractionation of rat brain poly(A) RNA yielded a high molecular weight fraction containing this mRNA, which resulted in functional Na channels when injected into oocytes. This fraction contained undetectable amounts of low molecular weight RNA. The high molecular weight Na channel RNA was selected from rat brain poly(A) RNA by hybridization to a single-strand antisense cDNA clone. Translation of this RNA in Xenopus oocytes resulted in the appearance of tetrodotoxin-sensitive voltage-sensitive Na channels in the oocyte membrane. These results demonstrate that mRNA encoding the alpha subunit of the rat brain Na channel, in the absence of any beta-subunit mRNA, is sufficient for translation to give functional channels in oocytes

The Great Compression: The Wage Structure in the United States at Mid- Century

The structure of wages narrowed considerably during the 1940's, increased slightly during the 1950's and 1960's, and then expanded greatly after 1970. The era of wage stretching of the past two decades has been a current focus, but we return attention here to the decade that was witness to an extraordinary compression in the wage structure. Wages narrowed by education, job experience, region, and occupation, and compression occurred within these cells as well. For white men, the 90-10 differential in the log of wages was 1.414 in 1940 but 1.060 in 1950. By 1985 it has risen back to its 1940 level. Thus the recent widening of the wage structure has returned to it a dispersion characteristic of fifty years ago. We explore various explanations for the rapid compression in the wage structure during the 1940's and for its maintenance during the subsequent decade or more. We first assess the hypothesis that the Great Depression left the wage structure in 1939 more unequal than in the late 1920's, but we find evidence to the contrary. World War II and the National War Labor Board share some of the credit for the Great Compression. But much belongs to a rapid increase in the demand for unskilled labor at a time when educated labor was greatly increasing in number. These same factors caused the wage structure to remain compressed until its expansion during the past two decades.

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2-/- mice were injected intraperitoneally with caerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 h and 24 h after the final dose of caerulein and up to 96 h post L-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone-marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1(Pdx1)-expressing cells. Stat2-/- mice were protected from caerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels including TNFα and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNFα improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre ) reduced pancreatic TNFα expression, but not histological injury or serum amylase. WT/Stat2-/- bone-marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow derived cells. This article is protected by copyright. All rights reserved

An automated pattern recognition system for the quantification of inflammatory cells in hepatitis-C-infected liver biopsies

This paper presents an automated system for the quantification of inflammatory cells in hepatitis-C-infected liver biopsies. Initially, features are extracted from colour-corrected biopsy images at positions of interest identified by adaptive thresholding and clump decomposition. A sequential floating search method and principal component analysis are used to reduce dimensionality. Manually annotated training images allow supervised training. The performance of Gaussian parametric and mixture models is compared when used to classify regions as either inflammatory or healthy. The system is optimized using a response surface method that maximises the area under the receiver operating characteristic curve. This system is then tested on images previously ranked by a number of observers with varying levels of expertise. These results are compared to the automated system using Spearman rank correlation. Results show that this system can rank 15 test images, with varying degrees of inflammation, in strong agreement with five expert pathologists

In Memorium: Robert W. Fogel

Economic