Development of an intervention to manage knee osteoarthritis risk and symptoms following anterior cruciate ligament injury.

INTRODUCTION: Anterior cruciate ligament (ACL) injury is a risk factor for developing knee osteoarthritis (OA). We developed an intervention to support people manage risk factors for OA. METHODS: We conducted one-on-one interviews with 20 individuals with OA symptoms 6-15 years post ACL injury and used a nominal group process during a workshop with 40 patients and healthcare professionals (HCPs) to elicit information on the intervention content and delivery characteristics (timing, HCPs, and methods). Interview data were analyzed using content analysis. Nominal group ideas with importance ratings ≥5 of 7 met criteria for inclusion. Results were integrated, considering similarities and differences. RESULTS: Eight content categories were identified: 1. understanding knee injury and expectations about recovery; 2. understanding OA risk; 3. understanding OA signs and symptoms; 4. managing OA risk; 5. managing knee OA symptoms; 6. information for influencers; 7. credible sources; and, 8. updates on new evidence and treatments. Delivery timing reflected a lifespan approach from time of injury through symptomatic knee OA management. Although multiple media for delivery were identified, introductory face-to-face discussions and opportunity for re-accessing HCPs were critical. All HCPs who treat people with ACL should be familiar with and able to deliver the intervention. CONCLUSIONS: This co-development approach identified that an intervention to support people with ACL injury to limit and manage knee OA requires content embedded within an easily accessible, multi-media delivery model with capacity for check-back with HCPs that is appealing to different age groups and personal preferences over the lifespan post injury.

Guidance on prevention of unintended and accidental radiation exposures in nuclear medicine.

Nuclear medicine (NM) procedures for diagnosis and treatment of disease are performed routinely in hospitals throughout the world. These involve preparation and administration to patients of pharmaceuticals labelled with radioactive material. The International Atomic Energy Agency (IAEA) and the World Health Organisation highlighted the need for improvement in prevention of medical radiation incidents and accidents in the Bonn Call-for-Action in 2012. An IAEA Technical Meeting was held on prevention of unintended exposures and accidents in NM in 2018 to address the issue. Exposures can take place at any time when radioactive material is being produced and used, and the risk continues after procedures have been completed. Thus there is potential for staff or members of the general public to be exposed, as well as patients. This paper sets out guidelines for incident prevention based on presentations and discussions at the meeting, and review of reports from the literature. It deals with potential incidents in in-house radionuclide production, radiopharmaceutical preparation, administration to patients, and following a procedure, as well as aspects in management of radioactive materials. Special attention has been paid to therapeutic procedures, as these have the potential to cause more harm to patients from erroneous administrations, including tissue reactions from extravasation of radiopharmaceutical, and could lead to significant contamination events. Administration of NM therapy is generally contraindicated in pregnancy. Identification of any patient who may be pregnant is crucial and it might be necessary to verify this with a pregnancy test for patients within the age band considered to be fertile. Inclusion of NM therapy incidents in the IAEA automated reporting system SAFRON is recommended. In summary, the paper aims to highlight errors that could occur during different phases of NM procedures in order to aid prevention of incidents. The value of periodic audit in evaluating systems in place on a regular basis is emphasised. Approaches to incident investigation and follow-up are described, and the need to ensure corrective action is taken to address any deficiencies stressed.

Shortened therapy of eight weeks with paritaprevir/ritonavir/ombitasvir and dasabuvir is highly effective in people with recent HCV genotype 1 infection.

Paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12 weeks are approved for treatment of chronic HCV genotype 1 infection. This study assessed the efficacy of shortened duration paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 8 weeks among people with recent HCV infection. In this open-label single-arm trial conducted in Australia, England and New Zealand, adults with recent HCV (duration of infection <12 months) received paritaprevir/ritonavir/ombitasvir and dasabuvir (with weight-based ribavirin for genotypes 1a and 1, no subtype) for 8 weeks. The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) population. Thirty people (median age 38 years, male 93%) commenced treatment (with ribavirin, 97%), of whom 77% (n = 23) were HIV-positive, 93% (n = 28) had genotype 1a infection and 53% (n = 16) had ever injected drugs. Median maximum ALT in the preceding 12 months was 433 IU/L (IQR 321, 1012). Acute clinical hepatitis with ALT > 10 x ULN was documented in 83% (n = 25); one participant (3%) had jaundice. At baseline, median estimated duration of infection was 30 weeks (range 11, 51), and median HCV RNA was 5.7 log10 IU/mL (range 2.7, 7.3). SVR12 was achieved in 97% (29/30; early discontinuation at week 2, n = 1; per protocol 100%, 29/29). No relapse or reinfection was observed. In conclusion, paritaprevir/ritonavir/ombitasvir and dasabuvir (with ribavirin) for eight weeks were highly effective among HIV-positive and HIV-negative individuals with recent HCV infection. These data support the use of this shortened duration direct-acting antiviral regimen in this population.

Modeling complete removal of risk assessment questions in the USA predicts the risk of HIV exposure in blood recipients could increase despite the use of nucleic acid testing.

BACKGROUND AND OBJECTIVES: The safety of the blood supply in a number of countries is achieved by interventions that include behaviour-based time-limited or indefinite deferrals and screening of donated units for transfusion-transmitted infections. The relatively high sensitivity of nucleic acid testing (NAT) used in blood donor screening has raised the question of whether such time-based deferrals can be eliminated in favour of individual risk assessment. MATERIALS AND METHODS: Data on the annual number of incident human immunodeficiency virus (HIV) infections associated with various behaviours and on the performance characteristics of NAT applied to donor screening were used to model the number of potentially infected units that might escape detection in the worst-case scenario in which individual risk assessment was implemented, but was not effective as a screening tool, and donors did not otherwise self-select for lower risk. RESULTS: In the absence of effective individual risk-based screening or donor self-selection, the model predicts that in the United States, an additional 39 (95% CI 35-43) HIV-infected units would escape detection by nucleic acid testing, potentially capable of exposing approximately 68 (95% CI 61-75) individuals to the risk of HIV infection through the administration of prepared blood components. CONCLUSION: Despite some inherent uncertainty, the worst-case scenario of completely ineffective individual risk assessment, absence of donor self-selection and increased reliance on NAT for blood screening is estimated to be associated with an approximately fourfold increase in the risk of HIV exposure through transfusion in the United States.

Long-term functional success and patient-reported outcomes after female one-stage buccal mucosal graft urethroplasty.

INTRODUCTION AND OBJECTIVES: Female urethral strictures are a rare condition that significantly impacts patients' quality of life. Patient-reported outcomes are crucial, yet data regarding sexual function and treatment satisfaction are scarce. We aimed to provide insights from a reconstructive referral center. PATIENTS AND METHODS: We conducted a retrospective analysis of women treated with ventral onlay one-stage buccal mucosa graft urethroplasty for urethral strictures between 2009-2023. We assessed objective (retreatment-free survival, ΔQmax) and subjective outcomes (validated patient-reported outcomes). RESULTS: Of 12 women, 83% and 17% had iatrogenic and idiopathic strictures, respectively. Median number of prior interventions was 6. Strictures were located meatal and mid-urethral in 25% and 75%, respectively, 22% had the bladder neck involved. Median graft length was 2 cm. At median follow-up of 66 months, 33% of patients underwent stricture retreatment, but only one case occurred within the first 2 years postoperatively. The median improvement in maximum flow rate (ΔQmax) was 10 ml/s. Median International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Modules (ICIQ-FLUTS) scores were 8 for filling symptoms, 6 for voiding symptoms, and 3 for incontinence symptoms. Median ICIQ-FLUTSsex score was 4. Higher scores indicate a higher symptom burden. Median ICIQ-Satisfaction outcome and satisfaction scores were 18 and 7, respectively, reflecting high treatment satisfaction. CONCLUSIONS: Buccal mucosal graft urethroplasty by ventral onlay for female urethral strictures yields effective, durable, and positively received outcomes. However, larger studies across multiple institutions are necessary to further assess its efficacy, especially regarding patient-reported experiences and sexual function.

Histone deacetylases and cancer: causes and therapies.

Together, histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones. This acetylation affects the regulation of gene expression, and inhibitors of HDACs have been found to cause growth arrest, differentiation and/or apoptosis of many tumours cells by altering the transcription of a small number of genes. HDAC inhibitors are proving to be an exciting therapeutic approach to cancer, but how do they exert this effect?

Mortality and mental health funding-do the dollars add up? Eating disorder research funding in Australia from 2009 to 2021: a portfolio analysis.

Background: Eating Disorders (EDs) are among the deadliest of the mental disorders and carry a sizeable public health burden, however their research and treatment is consistently underfunded, contributing to protracted illness and ongoing paucity of treatment innovation. Methods: We compare absolute levels and growth rates of Australian mental health research funding by illness group for the years 2009-2021, with a specific focus on eating disorders analysed at the portfolio level. Findings: Actual and adjusted data obtained from Australia's three national medical research funding bodies (NHMRC, ARC and MRFF) shows eating disorders receive a disproportionately low allocation of mental health research funding despite having amongst the highest mortality rates. Forty-one category one research grants totalling $AUD28.1 million were funded for eating disorders over the period. When adjusted for inflation, this equates to $2.05 per affected individual, compared with $19.56 for depression, $32.11 for autism, and $176.19 for schizophrenia. Half of all research funded for eating disorders was 'basic' research (e.g., illness underpinning), with little investment in the development of innovative treatment models, novel therapeutics or translation, well reflected by recovery rates of less than 50% in individuals with Anorexia Nervosa. Interpretation: Significant discrepancy remains between research funding dollars and disease burden associated with the mental health disorders. The extent to which eating disorders are underfunded may in part be attributable to inaccuracies in epidemiological and burden of disease data. Funding: This work was in-part funded by the Australian Government Department of Health and the National Eating Disorder Research & Translation Strategy. The funder was not directly involved in informing the development of the current study.

Serum non-coding RNAs as biomarkers for osteoarthritis progression after ACL injury.

OBJECTIVE: The aim of this study was to examine serum non-coding RNAs as potential biomarkers for cartilage damage associated with anterior cruciate ligament (ACL) injury. METHODS: Serum was obtained from 80 patients 1 year after surgery for ACL injury and 60 normal donors without overt skeletal injury. Total serum RNA was isolated, small non-coding RNAs profiled by TaqMan array MicroRNA (miRNA) analysis and individual small RNA assays performed by quantitative TaqMan RT-PCR (qPCR). Semi-quantitative magnetic resonance imaging (MRI) analysis was performed using Whole Organ Magnetic Resonance Knee Score (WORMS) scoring for analysis of cartilage damage. RESULTS: Initial TaqMan array miRNA profiling showed an increased serum concentration of a small nucleolar RNA (snoRNA), U48, in five patients with cartilage damage compared with that in five patients without cartilage damage and six normal donors. Independent qPCR analysis of snoRNAs in serum from all patients and normal donors showed a strong association between the serum level of another snoRNA, U38, and cartilage damage in ACL injury patients and together with snoRNA, U48, clear distinction between ACL injury patients and normal donors. CONCLUSION: SnoRNAs U38 and U48 are significantly elevated in the serum of patients developing cartilage damage at 1 year after ACL injury. Serum levels of U38 have the potential to facilitate early diagnosis of patients with cartilage damage after ACL injury. This study suggests serum non-coding RNAs may serve as novel noninvasive biomarkers for the detection and assessment of cartilage damage after ACL injury.

Patterns and characteristics of hepatitis C transmission clusters among HIV-positive and HIV-negative individuals in the Australian trial in acute hepatitis C.

BACKGROUND: Injecting drug users remain the population at greatest risk of acquiring hepatitis C virus (HCV) infection, although a recent increase in cases of sexually transmitted HCV infection has been observed among human immunodeficiency virus (HIV)-infected individuals. The extent to which these separate epidemics overlap is unknown. METHODS: The Australian Trial in Acute Hepatitis C (ATAHC) enrolled 163 individuals (29% of whom were HIV infected) with recent HCV infection. E1/HVR1 sequences were used to construct phylogenetic trees demonstrating monophyletic clusters or pairs, and viral epidemic history and phylogeography were assessed using molecular clock analysis. Individual clusters were characterized by clinical and demographic characteristics. RESULTS: Transmission through injection drug use occurred for 73% of subjects, with sexual transmission occurring for 18% (92% of whom were HIV infected). Among 112 individuals with available E1/HVR1 sequences, 23 (20%) were infected with a strain of HCV identical to that of another subject, comprising 4 homologous clusters and 3 monophyletic pairs, the majority of which (78%) were HIV infected. Clusters contained individuals with both injection drug use-related and sex-related acquisition, and in all clusters (except for 1 female HIV-uninfected pair), individuals identified as men who have sex with men, irrespective of HIV status. CONCLUSIONS: This large unique study of HIV-infected and HIV-uninfected individuals with recently acquired HCV infection demonstrates that clustering is common in the HIV-infected population and that it occurred almost invariably among men who have sex with men, irrespective of the actual mode of acquisition. These findings suggest the coexistence of both injection drug use and sexual risk behaviors for individuals in the same social networks and have implications for the development of public health messages. Clinical trial registration. NCT00192569.

HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation.

Eighteen histone deacetylases (HDACs) are present in humans, categorized into two groups: zinc-dependent enzymes (HDAC1-11) and NAD(+)-dependent enzymes (sirtuins 1-7). Among zinc-dependent HDACs, HDAC6 is unique. It has a cytoplasmic localization, two catalytic sites, a ubiquitin-binding site, and it selectively deacetylases alpha-tubulin and Hsp90. Here, we report the discovery that the redox regulatory proteins, peroxiredoxin (Prx) I and Prx II are specific targets of HDAC6. Prx are antioxidants enzymes whose main function is H(2)O(2) reduction. Prx are elevated in many cancers and neurodegenerative diseases. The acetylated form of Prx accumulates in the absence of an active HDAC6. Acetylation of Prx increases its reducing activity, its resistance to superoxidation, and its resistance to transition to high-molecular-mass complexes. Thus, HDAC6 and Prx are targets for modulating intracellular redox status in therapeutic strategies for disorders as disparate as cancers and neurodegenerative diseases.

[Vesicovaginal fistulas: diagnosis and surgical management]. / Vesikovaginale Fisteln: Diagnostik und operatives Management.

Vesicovaginal fistulas (VVF) represent a detrimental condition causing psychological, physical and social strain on patients. In developed countries they are predominantly the result of pelvic surgery or radiation therapy, whilst obstetric VVF are common in developing countries due to prolonged and complicated births. The majority of VVF require surgical therapy, thus a comprehensive diagnostic workup is needed. Depending on diagnostic characteristics fistula repair can be performed by a transvaginal, transabdominal or minimally invasive approach. Timing of surgery, appropriate interposition of vascularized grafts, optimized postoperative management and surgical expertise are determining factors for successful treatment. This review describes the diagnostic workup and therapeutic management of VVF including various surgical techniques.

Characteristics and treatment outcomes among HIV-infected individuals in the Australian Trial in Acute Hepatitis C.

BACKGROUND: The Australian Trial in Acute Hepatitis C (ATAHC) is a National Institutes of Health-funded prospective cohort study of the natural history and efficacy of treatment in individuals with recently acquired hepatitis C. Enrollment is open to both human immunodeficiency virus (HIV)-infected and -uninfected individuals. The aim of this article was to evaluate characteristics and virological outcomes among HIV-infected individuals enrolled in ATAHC. METHODS: Eligibility criteria included the first positive result of testing for anti-hepatitis C virus (HCV) antibody within 6 months and either clinical hepatitis diagnosed within the past 12 months or documented anti-HCV seroconversion within the past 24 months. RESULTS: Of the initial 103 patients enrolled, 27 (26%) were HIV infected. HIV-infected patients were more likely to be older, to have HCV genotype 1 infection and high levels of HCV RNA at baseline than were HCV-monoinfected patients. Sexual acquisition accounted for the majority (56%) of HCV infections among HIV-infected patients, compared with only 8% of HCV-monoinfected patients. The median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of pegylated interferon and ribavirin resulted in rates of undetectability of HCV RNA of 95%, 90%, and 80% at weeks 12, 24, and 48, respectively. Undetectability at week 4 was achieved in 44% of patients and yielded positive and negative predictive values for sustained virological response of 100% and 33%, respectively. CONCLUSIONS: Significant differences were demonstrated between HIV-infected and HIV-uninfected individuals enrolled in ATAHC. Treatment responses among HIV-infected individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high-risk individuals and early treatment for recently acquired HCV infection.

Histone deacetylase inhibitors: Potential in cancer therapy.

The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class IV, HDAC 11. Class III HDACs, sirtuins 1-7, have an absolute requirement for NAD(+), are not zinc dependent and generally not inhibited by compounds that inhibit zinc dependent deacetylases. In addition to histones, HDACs have many nonhistone protein substrates which have a role in regulation of gene expression, cell proliferation, cell migration, cell death, and angiogenesis. HDAC inhibitors (HDACi) have been discovered of different chemical structure. HDACi cause accumulation of acetylated forms of proteins which can alter their structure and function. HDACi can induce different phenotypes in various transformed cells, including growth arrest, apoptosis, reactive oxygen species facilitated cell death and mitotic cell death. Normal cells are relatively resistant to HDACi induced cell death. Several HDACi are in various stages of development, including clinical trials as monotherapy and in combination with other anti-cancer drugs and radiation. The first HDACi approved by the FDA for cancer therapy is suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza), approved for treatment of cutaneous T-cell lymphoma.

Quantitative MR imaging evaluation of the cartilage thickness and subchondral bone area in patients with ACL-reconstructions 7 years after surgery.

OBJECTIVE: To evaluate the cartilage thickness (ThC) and subchondral bone area (tAB) of the operated and contra-lateral non-operated (healthy) knees in patients with anterior cruciate ligament (ACL)-reconstruction 7 years after surgery using a quantitative and regional cartilage MR imaging (qMRI) technique. METHODS: Charts of 410 patients with ACL-reconstructions were retrospectively reviewed. Fifty-two patients (male/female, 28/24; mean age, 33.3 years) were included. Patients underwent KT-1000 testing and qMRI of both knees using coronal fat-saturated 3D spoiled gradient-recalled echo (SPGR) sequences (TR/TE, 44/4 ms) at 1.5 T. Quantitative analyses of ThC and tAB in the femoro-tibial cartilage plates were performed using a subregional approach. In addition, qualitative and quantitative assessment of femoral condyle shapes was performed. t tests with Bonferroni corrections were used for statistical analysis of side-to-side differences between the operated and non-operated knees. RESULTS: KT-1000 testing was abnormal in 3/52 patients (6%). Lateral femoral tAB was significantly lower (-9.2%), and medial tibial tAB was significantly larger (+2%) in the operated vs non-operated knee (P<0.001). Regional and subregional ThC side-to-side differences were less than 0.1mm and, except for the external lateral femoral subregion, they were not statistically significant. Flattened and broader shapes of medial femoral condyles (P<0.001) were found in operated knees. No significant association of presence of cartilage or meniscus lesions at surgery with ThC 7 years post-operatively was found (P=0.06-0.98). CONCLUSION: There is evidence for changes in the tAB and femoral shape 7 years post-ACL-reconstruction, but no side-to-side differences in subregional ThC were found between the operated and contra-lateral non-operated knees.

Transient increases in cytosolic free calcium appear to be required for the migration of adherent human neutrophils.

Human neutrophils exhibit multiple increases in cytosolic free calcium concentration [( Ca2+]i) spontaneously and in response to the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (Jaconi, M. E. E., R. W. Rivest, W. Schlegel, C. B. Wollheim, D. Pittet, and P. D. Lew. 1988. J. Biol. Chem. 263:10557-10560). The function of these repetitive increases in [Ca2+]i, as well as the role of Ca2+ in human neutrophil migration, remain unresolved. We have used microspectrofluorometry to measure [Ca2+]i in single fura-2-loaded human neutrophils as they moved on poly-D-lysine-coated glass in the presence of serum. To investigate the role of Ca2+ in human neutrophil migration, we examined cells in the presence and absence of extracellular Ca2+, as well as intracellular Ca2(+)-buffered and Ca2(+)-depleted cells. In the presence of extracellular Ca2+, multiple increases and decreases in [Ca2+]i were frequently observed, and at least one such transient increase in [Ca2+]i occurred in every moving cell during chemokinesis, chemotaxis, and phagocytosis. In addition, neutrophils that extended pseudopodia and assumed a polarized morphology after plating onto a surface were always observed to exhibit [Ca2+]i transients even in the absence of chemoattractant. In contrast, a [Ca2+]i transient was observed in only one of the nonpolarized stationary cells that were examined (n = 15). Although some cells exhibited relatively periodic increases and decreases in [Ca2+]i, resembling the regular oscillations that have been observed in some cell types, many others exhibited increases and decreases in [Ca2+]i that varied in their timing, magnitude, and duration. Buffering of [Ca2+]i or removal of extracellular Ca2+ damped out or blocked transient increases in [Ca2+]i and reduced or inhibited the migration of neutrophils. Under these conditions, polarized cells were often observed to make repeated attempts at migration, but they remained anchored at their rear. These data suggest that transient increases in [Ca2+]i may be required for the migration of human neutrophils on poly-D-lysine-coated glass in the presence of serum by allowing them to release from previous sites of attachment.

Attachment to fibronectin or vitronectin makes human neutrophil migration sensitive to alterations in cytosolic free calcium concentration.

Transient increases in cytosolic free calcium concentration, [Ca2+]i, appear to be required for the migration of human neutrophils on poly-D-lysine-coated glass in the presence of dilute serum (Marks, P. W., and F. R. Maxfield. 1990. J. Cell Biol. 110:43-52). In contrast, no requirement for [Ca2+]i transients exists when neutrophils migrate on albumin-coated glass in the absence of serum. To determine the mechanism that necessitates [Ca2+]i transients on poly-D-lysine in the presence of serum, migration was examined on substrates consisting of purified adhesive glycoproteins. In the absence of external Ca2+, a treatment which causes the cessation of [Ca2+]i transients, migration on fibronectin (fn) and vitronectin (vn) was significantly inhibited. Migration was also inhibited in Ca2(+)-buffered cells on these substrates, indicating that this effect was the result of an alteration of [Ca2+]i. In the absence of external Ca2+, the inhibition of migration on fn or vn was more pronounced when soluble fn or vn was added to cells migrating on these substrates. This effect of soluble adhesive glycoprotein was specific: in the absence of external Ca2+, soluble fn did not affect the migration of cells on vn, and soluble vn did not affect the migration on fn. No additional inhibition of migration was observed in Ca2(+)-buffered cells with the addition of soluble adhesive glycoprotein. These data indicate that [Ca2+]i transients are involved in continued migration of human neutrophils on fn or vn, proteins which are part of the extracellular matrix that neutrophils encounter in vivo.

Erythropoietin effects on fetal mouse erythroid cells. I. Cell population and hemoglobin synthesis.

The effect of the hormone, erythropoietin, on cultures of erythroblasts derived from the livers of fetal C57BL/6J mice was examined. An increase both in the content and in the rate of synthesis of normal adult mouse globin chains was detected in hormone-treated cultures. The rate of protein synthesis by individual erythroblasts does not increase in response to the hormone, whereas the absolute number of hemoglobin-synthesizing cells does increase and accounts for the observed stimulation of hemoglobin synthesis. The principal effect of erythropoietin appears to be upon the population of immature erythroid precursor cells which persists in the presence of the hormone, the cells maintaining their ability to replicate, and their capacity to differentiate into hemoglobinizing erythroblasts. In the absence of hormone, already committed erythroblasts continue their development, but erythropoiesis is not sustained.

Globin composition and synthesis of hemoglobins in developing fetal mice erythroid cells.

Fetal mouse erythropoiesis proceeds initially in yolk-sac blood islands (8 to 12 days) and, subsequently, in liver (12 to at least 16 days). Yolksac cells synthesize three hemoglobins, Hb E(I), Hb E(II) and Hb E(III). Hb E(I) has x- and y-globin chains; Hb E(II) has alpha and y; HB E(III), alpha and z. No detectable beta-globin is formed in these cells. Liver erythroid cells form only adult hemoglobin, composed of alpha- and beta-chains.

Revegetation following Forest Cutting: Mechanisms for Return to Steady-State Nutrient Cycling.

Dense stands of a woody, successional species, Prunus pensylvanica L., develop rapidly, with early closure of canopy and rapid attainment of high values of net annual production and nutrient accumulation. Such rapid growth following disturbance tends to minimize losses of nutrients from the ecosystem, thus promoting a return to steady-state cycling characteristic of a mature forest.

Protein synthesis: its control in erythropoiesis.

Erythropoiesis in the fetal mouse provides a model to study several important aspects of the regulation of cell differentiation and differentiated protein synthesis. Changes in the patterns of hemoglobins formed during fetal and postfetal development are shown to be associated with the substitution of the liver erythroid cell line. In the course of differentiation of yolk sac erythroid cells there are at least two classes of proteins distinguishable with respect to dependence on continued RNA formatoin. The bulk of nuclear proteins, "nondifferentiated" proteins, appear to be dependent on relatively short-lived messenger RNA while synthesis of differentiated proteins, the hemoglobins, proceeds on relatively stable molecules of messenger RNA. Hemoglobin formation occurs in those cells which are actively synthesizing DNA and dividing. On the average, two to three cell divisions may occur after the formation and stabilization of the messenger RNA for globin. Yolk sac erythropoiesis, at least from day 10 of gestation, is unresponsive to erythropoietin. By comparison, in fetal liver erythropoiesis, the hormone, erythropoietin, acts selectively on the most immature erythroid cell precursor to induce differentiation, cell replication, and hemoglobin formation. The erythropoietin responsive cell in the liver is apparently differentiated from the progenitor, pluripotential stem cell and committed to erythroblast formation and hemoglobin synthesis on exposure to the hormone. The initial effects of erythropoietin on macromolecular synthesis are to stimulate RNA synthesis, which temporally is followed by cell replication and the increase in hemoglobin formation. During liver erythropoiesis, there appears to be a transition from hemoglobin synthesis dependent on RNA formation to hemoglobin synthesis directed by relatively stable messenger RNA.