Persistent Room-Temperature Photodarkening in Cu-Doped ß-Ga_{2}O_{3}.

ß-Ga_{2}O_{3} is an ultrawide band gap semiconductor with emerging applications in power electronics. The introduction of acceptor dopants yields semi-insulating substrates necessary for thin-film devices. In the present work, exposure of Cu-doped ß-Ga_{2}O_{3} to UV light >4 eV is shown to cause large, persistent photo-induced darkening at room temperature. Electron paramagnetic resonance spectroscopy indicates that light exposure converts Cu^{2+} to Cu^{3+}, a rare oxidation state that is responsible for the optical absorption. The photodarkening is accompanied by the appearance of O─H vibrational modes in the infrared spectrum. Hybrid function calculations show that Cu acceptors can favorably complex with hydrogen donors incorporated as interstitial (H_{i}) or substitutional (H_{O}) defects. When Cu_{Ga}-H_{O} complexes absorb light, hydrogen is released, contributing to the observed Cu^{3+} species and O─H modes.

The remarkable influence of M2delta to thienyl pi conjugation in oligothiophenes incorporating MM quadruple bonds.

Oligothiophenes incorporating MM quadruple bonds have been prepared from the reactions between Mo(2)(TiPB)(4) (TiPB = 2,4,6-triisopropyl benzoate) and 3',4'-dihexyl-2,2'-:5',2''-terthiophene-5,5''-dicarboxylic acid. The oligomers of empirical formula Mo(2)(TiPB)(2)(O(2)C(Th)-C(4)(n-hexyl)(2)S-(Th)CO(2)) are soluble in THF and form thin films with spin-coating (Th = thiophene). The reactions between Mo(2)(TiPB)(4) and 2-thienylcarboxylic acid (Th-H), 2,2'-bithiophene-5-carboxylic acid (BTh-H), and (2,2':5',2''-terthiophene)-5-carboxylic acid (TTh-H) yield compounds of formula trans-Mo(2)(TiPB)(2)L(2), where L = Th, BTh, and TTh (the corresponding thienylcarboxylate), and these compounds are considered as models for the aforementioned oligomers. In all cases, the thienyl groups are substituted or coupled at the 2,5 positions. Based on the x-ray analysis, the molecular structure of trans-Mo(2)(TiPB)(2)(BTh)(2) reveals an extended Lpi-M(2)delta-Lpi conjugation. Calculations of the electronic structures on model compounds, in which the TiPB are substituted by formate ligands, reveal that the HOMO is mainly attributed to the M(2)delta orbital, which is stabilized by back-bonding to one of the thienylcarboxylate pi* combinations, and the LUMO is an in-phase combination of the thienylcarboxylate pi* orbitals. The compounds and the oligomers are intensely colored due to M(2)delta-thienyl carboxylate pi* charge transfer transitions that fall in the visible region of the spectrum. For the molybdenum complexes and their oligomers, the photophysical properties have been studied by steady-state absorption spectroscopy and emission spectroscopy, together with time-resolved emission and transient absorption for the determination of relaxation dynamics. Remarkably, THF solutions the molybdenum complexes show room-temperature dual emission, fluorescence and phosphorescence, originating mainly from (1)MLCT and (3)MM(deltadelta*) states, respectively. With increasing number of thienyl rings from 1 to 3, the observed lifetimes of the (1)MLCT state increase from 4 to 12 ps, while the phosphorescence lifetimes are approximately 80 micros. The oligomers show similar photophysical properties as the corresponding monomers in THF but have notably longer-lived triplet states, approximately 200 micros in thin films. These results, when compared with metallated oligothiophenes of the later transition elements, reveal that M(2)delta-thienyl pi conjugation leads to a very small energy gap between the (1)MLCT and (3)MLCT states of <0.6 eV.

Technology assessment, soviet style.

The Soviet Union is actively considering two plans to divert large northern lakes and rivers to the south of the country. If adopted, these would rank among the most expensive and complicated engineering projects ever undertaken, with unforeseeable but possibly far-reaching environmental effects. The plans, now at an advanced stage, have aroused a spirited public controversy, providing an unusual glimpse of Soviet policy-making and technology assessment. Major decisions are due by 1985. The question is, what will happen to the quality and openness of this debate as the political stakes rise and the time of decision draws near?

Overconsumption and obesity: peptides and susceptibility to weight gain.

Physiological control of feeding is mediated by tonic and episodic signalling systems. These are sometimes thought of as long-term and short-term control. Tonic signals arise from tissue stores whereas episodic signals oscillate periodically with the consumption of food. These physiological controls are paralleled in the motivation to eat by long-acting enduring traits (such as disinhibition) and by short-acting states (such as hunger). Peptides are usually envisaged to exert an action on appetite control through the modulation of states such as hunger and satiety (fullness). Here we provide evidence that peptides involved in tonic regulation--such as leptin--may express a control over appetite motivation through an effect on traits that confer a constant readiness to eat, whereas episodic peptides such as GLP-1 influence appetite motivation through a state such as hunger. The distinction between tonic and episodic regulation, and between traits and states has implications for understanding overconsumption and the susceptibility to weight gain.

Identification of multiple proteins that interact with functional regions of the human cardiac alpha-actin promoter.

5' Sequences of the human cardiac alpha-actin gene are involved in the tissue-specific and developmental regulation of the gene. Deletion analyses combined with transient expression experiments in muscle cells have demonstrated three primary regions of functional importance (A. Minty and L. Kedes, Mol. Cell. Biol. 6:2125-2136, 1986; T. Miwa and L. Kedes, Mol. Cell. Biol. 7:2803-2813, 1987), and we have previously demonstrated binding of a protein indistinguishable from serum response factor (SRF) to the most proximal region (T.A. Gustafson, T. Miwa, L.M. Boxer, and L. Kedes, Mol. Cell. Biol. 8:4110-4119, 1988). In this report, we examine protein interaction with the remainder of the promoter. Gel shift and footprinting assays revealed that at least seven distinct nuclear proteins interacted with known and putative regulatory regions of the promoter. The transcription factor Sp1 bound to eight sites, as demonstrated by footprinting assays and gel shift analysis with purified Sp1. Purified CCAAT box-binding transcription factor CTF/NF-I and Sp1 were shown to interact with the far-upstream regulatory element at -410, and footprint analysis showed extensive overlap of these two sites. Two unidentified proteins with similar but distinct footprints interacted with the second region of functional importance at -140, which contains the second CArG motif [CC(A + T rich)6GG], and these proteins were shown to be distinct from SRF. SRF was found to bind to the remaining three CArG boxes, two of which were closely interdigitated with Sp1 sites. In addition, CArG box 4 was found to interact with SRF and another distinct protein whose footprint was contained within the SRF-binding site. Sequences surrounding the TATA box were also shown to bind proteins. Sp1 was shown to bind to a site immediately downstream from the TATA box and to a site within the first exon. Thus, each of the three functional upstream regions, as defined by transfection assays, was shown to interact with five factors: Sp1 and CTF/NF-I at the upstream site, two unidentified proteins at the central site, and SRF at the most proximal site. These results suggest that expression of the cardiac actin gene in muscle cells is controlled by complex interactions among multiple upstream and intragenic elements.

Characterization of an interaction between insulin receptor substrate 1 and the insulin receptor by using the two-hybrid system.

Insulin receptor substrate 1 (IRS-1) is a major substrate of the insulin receptor and has been implicated in insulin signaling. Although IRS-1 is thought to interact with the insulin receptor, the nature of the interaction has not been defined. In this study, we used the two-hybrid assay of protein-protein interaction in the yeast Saccharomyces cerevisiae to study the interaction between human IRS-1 and the insulin receptor. We demonstrate that IRS-1 forms a specific complex with the cytoplasmic domain of the insulin receptor when both are expressed as hybrid proteins in yeast cells. We show that the interaction is strictly dependent upon receptor tyrosine kinase activity, since IRS-1 shows no interaction with a kinase-inactive receptor hybrid containing a mutated ATP-binding site. Furthermore, mutation of receptor tyrosine 960 to phenylalanine eliminates IRS-1 interaction in the two-hybrid assay. These data suggest that the interaction between IRS-1 and the receptor is direct and provide evidence that the juxtamembrane domain of the receptor is involved. Furthermore, we show that a 356-amino-acid region encompassed by amino acids 160 through 516 of IRS-1 is sufficient for interaction with the receptor in the two-hybrid assay. Lastly, in agreement with our findings for yeast cells, we show that the insulin receptor is unable to phosphorylate an IRS-1 protein containing a deletion of amino acids 45 to 516 when expressed in COS cells. The two-hybrid assay should provide a facile means by which to pursue a detailed understanding of this interaction.

A common factor regulates skeletal and cardiac alpha-actin gene transcription in muscle.

The skeletal and cardiac alpha-actin genes are coexpressed in muscle development but exhibit distinctive tissue-specific patterns of expression. We used an in vivo competition assay and an in vitro electrophoretic mobility shift assay to demonstrate that both genes interact with a common trans-acting factor(s). However, there was at least one gene-specific cis-acting sequence in the skeletal alpha-actin gene that interacted with a trans-acting factor which was not rate limiting in the expression of the cardiac alpha-actin gene. The common factor(s) interacted with several cis-acting regions that corresponded to sequences that are required for the transcriptional modulation of these sarcomeric alpha-actin genes in muscle cells. These regulatory regions contained the sequence motif CC(A + T-rich)6GG, which is known as a CArG box. Results of in vivo competition assays demonstrated that the factor(s) bound by the skeletal alpha-actin gene is also essential for the maximal activity of the cardiac alpha-actin, simian virus 40 (SV40), alpha 2(I)-collagen, and the beta-actin promoters in muscle cells. In contrast, fibroblastic cells contained functionally distinct transcription factor(s) that were used by the SV40 enhancer but that did not interact with the sarcomeric alpha-actin cis-acting sequences. The existence of functionally different factors in these cell types may explain the myogenic specificity of these sarcomeric alpha-actin genes. Results of in vitro studies suggested that both the sarcomeric alpha-actin genes interact with the CArG box-binding factor CBF and that the skeletal alpha-actin promoter contains multiple CBF-binding sites. In contrast, CBF did not interact in vitro with a classical CAAT box, the SV40 enhancer, or a linker scanner mutation of an alpha-actin CArG box. Furthermore, methylation interference and DNase I footprinting assays demonstrated the precise sites of interaction of CBF with three CArG motifs at positions -98, -179, and -225 in the human skeletal alpha-actin gene.

Identification of SH2-Bbeta as a substrate of the tyrosine kinase JAK2 involved in growth hormone signaling.

Activation of the tyrosine kinase JAK2 is an essential step in cellular signaling by growth hormone (GH) and multiple other hormones and cytokines. Murine JAK2 has a total of 49 tyrosines which, if phosphorylated, could serve as docking sites for Src homology 2 (SH2) or phosphotyrosine binding domain-containing signaling molecules. Using a yeast two-hybrid screen of a rat adipocyte cDNA library, we identified a splicing variant of the SH2 domain-containing protein SH2-B, designated SH2-Bbeta, as a JAK2-interacting protein. The carboxyl terminus of SH2-Bbeta (SH2-Bbetac), which contains the SH2 domain, specifically interacts with kinase-active, tyrosyl-phosphorylated JAK2 but not kinase-inactive, unphosphorylated JAK2 in the yeast two-hybrid system. In COS cells coexpressing SH2-Bbeta or SH2-Bbetac and murine JAK2, both SH2-Bbetac and SH2-Bbeta coimmunoprecipitate to a significantly greater extent with wild-type, tyrosyl-phosphorylated JAK2 than with kinase-inactive, unphosphorylated JAK2. SH2-Bbetac also binds to immunoprecipitated wild-type but not kinase-inactive JAK2 in a far Western blot. In 3T3-F442A cells, GH stimulates the interaction of SH2-Bbeta with tyrosyl-phosphorylated JAK2 both in vitro, as assessed by binding of JAK2 in cell lysates to glutathione S-transferase (GST)-SH2-Bbetac or GST-SH2-Bbeta fusion proteins, and in vivo, as assessed by coimmunoprecipitation of JAK2 with SH2-Bbeta. GH promoted a transient and dose-dependent tyrosyl phosphorylation of SH2-Bbeta in 3T3-F442A cells, further suggesting the involvement of SH2-Bbeta in GH signaling. Consistent with SH2-Bbeta being a substrate of JAK2, SH2-Bbetac is tyrosyl phosphorylated when coexpressed with wild-type but not kinase-inactive JAK2 in both yeast and COS cells. SH2-Bbeta was also tyrosyl phosphorylated in response to gamma interferon, a cytokine that activates JAK2 and JAK1. These data suggest that GH-induced activation and phosphorylation of JAK2 recruits SH2-Bbeta and its associated signaling molecules into a GHR-JAK2 complex, thereby initiating some as yet unidentified signal transduction pathways. These pathways are likely to be shared by other cytokines that activate JAK2.

Interaction of nuclear proteins with muscle-specific regulatory sequences of the human cardiac alpha-actin promoter.

The human cardiac alpha-actin promoter is involved in the muscle-specific transcriptional regulation of the gene. In this study, we utilized gel mobility shift, methylation interference, and DNase I protection assays to examine protein factor interaction with the promoter in vitro. All assays demonstrated specific interaction of nuclear factors with a region of the promoter encompassed by nucleotides -93 to -113 base pairs from the transcriptional start site. This region contains a CC(A + T-rich)6GG element, termed a CArG box, which has previously been implicated in the muscle-specific transcriptional regulation of the gene by functional assays. Although the gene is only expressed in muscle cells, identical binding activity was present in nuclear extracts of all cell types examined, including those of muscle (C2, L8, and L6 cells) and nonmuscle (HeLa, NIH 3T3, HuT12, and L cells) origin. Furthermore, methylation interference assays showed that identical nucleotides interacted with factors isolated from C2 and HeLa cells. Competition studies showed that the CArG-binding factor, designated as CBF, also interacts with the c-fos serum responsive element, which contains a CArG element, but not with the simian virus 40 enhancer and early promoter. Thus, a region of the human cardiac alpha-actin promoter known to be functionally involved in muscle-specific regulation of the gene appears to interact in vitro, and in an identical manner, with a factor(s) which is neither muscle nor gene specific, suggesting a more complex mode of regulation than previously envisioned.

Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain.

The SHC proteins have been implicated in insulin receptor (IR) signaling. In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR. The interaction is mediated by SHC amino acids 1 to 238 and is therefore independent of the Src homology 2 domain. The interaction is dependent upon IR autophosphorylation, since the interaction is eliminated by mutation of the IR ATP-binding site. In addition, mutational analysis of the Asn-Pro-Glu-Tyr (NPEY) motif within the juxtamembrane domain of the IR showed the importance of the Asn, Pro, and Tyr residues to both SHC and IR substrate 1 (IRS-1) binding. We conclude that SHC interacts directly with the IR and that phosphorylation of Tyr-960 within the IR juxtamembrane domain is necessary for efficient interaction. This interaction is highly reminiscent of that of IRS-1 with the IR, and we show that the SHC IR-binding domain can substitute for that of IRS-1 in yeast and COS cells. We identify a homologous region within the IR-binding domains of SHC and IRS-1, which we term the SAIN (SHC and IRS-1 NPXY-binding) domain, which may explain the basis of these interactions. The SAIN domain appears to represent a novel motif which is able to interact with autophosphorylated receptors such as the IR.

Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes.

Activated insulin receptor (IR) interacts with its substrates, IRS-1, IRS-2, and Shc via the NPXY motif centered at Y960. This interaction is important for IRS-1 phosphorylation. Studies using the yeast two-hybrid system and sequence identity analysis between IRS-1 and IRS-2 have identified two putative elements, the PTB and SAIN domains, between amino acids 108 and 516 of IRS-1 that are sufficient for receptor interaction. However, their precise function in mediating insulin's bioeffects is not understood. We expressed the PTB and SAIN domains of IRS-1 in HIRcB fibroblasts and 3T3-L1 adipocytes utilizing replication-defective adenoviral infection to investigate their role in insulin signalling. In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin-induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1-associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen-activated protein kinase (MAPK) phosphorylation. However, epidermal growth factor-induced Shc and MAPK phosphorylation was unaffected by the overexpressed proteins. These findings were associated with a complete inhibition of insulin-stimulated cell cycle progression. In 3T3-L1 adipocytes, PTB or SAIN expression extinguished IRS-1 phosphorylation with a corresponding 90% decrease in IRS-1-associated PI 3-K activity. p70s6k is a downstream target of PI 3-K, and insulin-stimulated p70s6k was inhibited by PTB or SAIN expression. Interestingly, overexpression of either PTB or SAIN protein did not affect insulin-induced AKT activation or insulin-stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin. Thus, interference with the IRS-1-IR interaction inhibits insulin-stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression. In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin-stimulated AKT activation or glucose transport. These results indicate a bifurcation or subcompartmentalization of the insulin signalling pathway whereby some targets of PI 3-K (i.e., p70s6k) are dependent on IRS-1-associated PI 3-K and other targets (i.e., AKT and glucose transport) are not. IR-IRS-1 interaction is not essential for insulin's effect on glucose transport, and alternate, or redundant, pathways exist in these cells.

Hedgehog signaling is activated in canine transitional cell carcinoma and contributes to cell proliferation and survival.

Transitional cell carcinoma (TCC) is the most commonly diagnosed tumor of the canine urinary system. Hedgehog (HH) signaling represents one possible novel therapeutic target, based on its recently identified central role in human urothelial carcinoma. The purpose of this study was to determine if HH mediators are expressed in canine TCC and the effect of inhibition of this pathway on cell growth and survival. HH pathway mediators were found to be expressed in five canine TCC cell lines. Indian HH was expressed in tumor cells in five canine bladder tumor tissues, but not in normal canine bladder tissue. Inhibition of HH signaling with cyclopamine and GANT61 led to significantly decreased cell proliferation but had a smaller effect on apoptosis. These results support future investigation of inhibitors of HH signaling in the treatment of canine TCC.

Shape memory polymers with visible and near-infrared imaging modalities: Synthesis, characterization and in vitro analysis.

Shape memory polymers (SMPs) are promising for non-invasive medical devices and tissue scaffolds, but are limited by a lack of visibility under clinical imaging. Fluorescent dyes are an alternative to radiocontrast agents in medical applications, they can be utilized in chemical sensors and monitors and may be anti-microbial agents. Thus, a fluorescent SMP could be a highly valuable biomaterial system. Here, we show that four fluorescent dyes (phloxine B (PhB), eosin Y (Eos), indocyanine green(IcG), and calcein (Cal)) can be crosslinked into the polymer backbone to enhance material optical properties without alteration of shape memory and thermomechanical properties. Examinations of the emission wavelengths of the materials compared with the dye solutions showed a slight red shift in the peak emissions, indicative of crosslinking of the material. Quantitative analysis revealed that PhB enabled visibility through 1 cm of blood and through soft tissue. We also demonstrate the utility of these methods in combination with radio-opaque microparticle additives and the use of laser-induced shape recovery to allow for rapid shape recovery below the glass transition temperature. The crosslinking of fluorescent dyes into the SMP enables tuning of physical properties and shape memory and independently of the fluorescence functionality. This fluorescent SMP biomaterial system allows for use of multiple imaging modalities with potential application in minimally invasive medical devices.

Insulin receptor substrate-1 enhances growth hormone-induced proliferation.

GH exerts a variety of metabolic and growth-promoting effects. GH induces activation of the GH receptor (GHR)-associated cytoplasmic tyrosine kinase, JAK2, resulting in tyrosine phosphorylation of the GHR and activation of STAT (signal transducer and activator of transcription), Ras-mitogen-activated protein kinase, and phosphoinositol 3-kinase signaling pathways, among others. GH-stimulated tyrosine phosphorylation of insulin receptor substrate (IRS) proteins has been demonstrated in vitro and in vivo. IRS-1 is a multiply phosphorylated cytoplasmic docking protein involved in metabolic and proliferative signaling by insulin, IL-4, and other cytokines, but the physiological role of IRS-1 in GH signaling is unknown. In this study, as noted by others, we detected in murine 3T3-F442A pre-adipocytes GH-dependent tyrosine phosphorylation of IRS-1 and specific GH-induced coimmunoprecipitation with JAK2 of a tyrosine phosphoprotein consistent with IRS-1. We further examined this interaction by in vitro affinity precipitation experiments with glutathione-S-transferase fusion proteins incorporating regions of rat IRS-1 and, as a source of JAK2, extracts of 3T3-F442A cells. Fusion proteins containing amino-terminal regions of IRS-1 that include the pleckstrin homology, phosphotyrosine-binding, and Shc and IRS-1 NPXY-binding domains, but not those containing other IRS-1 regions or glutathione-S-transferase alone, bound JAK2 from cell extracts. Tyrosine-phosphorylated JAK2 resulting from GH stimulation was included in the amino-terminal IRS-1 fusion precipitates; however, neither tyrosine phosphorylation of JAK2 nor treatment of cells with GH before extraction was necessary for the specific JAK2-IRS-1 interaction to be detected. In contrast, in this assay, specific insulin receptor association with the IRS-1 phosphotyrosine-binding, and Shc and IRS-1 NPXY-binding domains was insulin and phosphotyrosine dependent, as previously shown. To test for significance of IRS-1 with regard to GH signaling, IRS- and GHR-deficient 32D cells were stably reconstituted with the rabbit (r) GHR, either alone (32D-rGHR) or with IRS-1 (32D-rGHR-IRS-1). As assayed by three independent methods, GH induced proliferation in 32D-rGHR cells, even in the absence of transfected IRS-1. Notably, however, GH-induced proliferation was markedly enhanced in cells expressing IRS-1. Similarly, GH-induced mitogen-activated protein kinase activation was significantly augmented in IRS-1-expressing cells relative to that in cells harboring no IRS-1. These results indicate that IRS-1 enhances GH-induced proliferative signaling.

Childhood sexual abuse and obesity.

The causes of the current obesity epidemic are multifactorial and include genetic, environmental, and individual factors. One potential risk factor may be the experience of childhood sexual abuse. Childhood sexual abuse is remarkably common and is thought to affect up to one-third of women and one-eighth of men. A history of childhood sexual abuse is associated with numerous psychological sequelae including depression, anxiety, substance abuse, somatization, and eating disorders. Relatively few studies have examined the relationship between childhood sexual abuse and adult obesity. These studies suggest at least a modest relationship between the two. Potential explanations for the relationship have focused on the role of disordered eating, particularly binge eating, as well as the possible "adaptive function" of obesity in childhood sexual abuse survivors. Nevertheless, additional research on the relationship between childhood sexual abuse and obesity is clearly needed, not only to address the outstanding empirical issues but also to guide clinical care.

The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors.

Grb7, Grb10 and Grb14 comprise a family of adaptor proteins that interact with numerous receptor tyrosine kinases upon receptor activation. Between the pleckstrin homology (PH) domain and the Src homology 2 (SH2) domain of these proteins is a region of approximately 50 residues known as the BPS (between PH and SH2) domain. Here we show, using purified recombinant proteins, that the BPS domain of Grb10 directly inhibits substrate phosphorylation by the activated tyrosine kinase domains of the insulin receptor and the insulin-like growth factor 1 (IGF1) receptor. Although inhibition by the BPS domain is dependent on tyrosine phosphorylation of the kinase activation loop, peptide competition experiments indicate that the BPS domain does not bind directly to phosphotyrosine. These studies provide a molecular mechanism by which Grb10 functions as a negative regulator of insulin- and/or IGF1-mediated signaling.

Outbreak of acute pulmonary histoplasmosis in members of a wagon train.

In August 1980, an outbreak of acute pulmonary histoplasmosis occurred among participants in a wagon train as it traveled through eastern Tennessee. Of the 85 people on the train 69 (81 percent) had evidence of infection with Histoplasma capsulatum. Fifty-four people had symptomatic disease. The source of infection was traced to the site of a former winter blackbird roost in Charleston, Tennessee, that had been partially cleared five years earlier to make a park. Fourteen of 25 soil samples from this site were culture-positive for H. capsulatum. This is the first reported outbreak to involve a large migrant group. The outbreak is unusual in that exposure occurred without excavation, construction or tree-cutting at the site.

An outbreak of airborne nosocomial varicella.

An outbreak of nosocomial varicella was traced to airborne spread from an immunocompromised child hospitalized from Nov 11-19, 1980. Seventy potentially susceptible children were hospitalized on the ward during that period. Although the index patient remained in strict room isolation throughout his hospital stay, eight of these patients contracted varicella. The afternoon of November 12 was the period of highest risk for acquiring varicella. Eight of 36 patients (22%) present that afternoon, compared to none of 34 patients not present that afternoon, acquired the infection. A patient's risk of contracting varicella was significantly related to how near he/she came to the index patient's room that afternoon. Airflow studies, using the tracer gas, sulfur hexafluoride (SF6), demonstrated that patient rooms on this ward were at positive pressure with respect to the corridor. Despite isolation procedures, SF6 released in the index patient's room achieved concentrations in the corridor as high as 10% of those inside the room. Airborne spread of varicella has rarely been reported, but it may be a common mode of transmission in hospitals. We suggest that patients hospitalized with varicella be placed in strict isolation in negative-pressure rooms to reduce the risk of nosocomial transmission.

Functional inactivation of the IGF-I receptor delays differentiation of skeletal muscle cells.

Skeletal myoblasts are inherently programmed to leave the cell cycle and begin the differentiation process following removal of exogenous growth factors. Serum withdrawal results in a marked induction of IGF production which is essential for skeletal muscle differentiation in vitro. However, the potential role of the tyrosine kinase IGF-I receptor (thought to be the principal mediator of both IGF-I and II signaling in skeletal muscle) in the decision of myoblasts to begin differentiation following serum withdrawal is unknown. To explore the role of the IGF-I receptor in this decision by skeletal myoblasts, we functionally inactivated endogenous IGF-I receptors in mouse C2C12 cells using a dominant negative, kinase-inactive IGF-I receptor in which the ATP-binding site lysine (K) at residue 1003 has been mutated to alanine (A). Cell lines with the greatest degree of mutant IGF-I receptor expression (A/K cells) demonstrated functional inactivation of endogenous IGF-I receptors as determined by their impaired ability to phosphorylate the principal substrate of the IGF-I receptor, IRS-1, in response to treatment with IGF-I. In addition, the proliferative response of myoblasts to IGF-I was completely abolished in A/K cells. Following withdrawal of exogenous growth factors, A/K cells demonstrated a marked delay in the induction of the gene expression of myogenin, a skeletal muscle-specific transcription factor essential for differentiation, and a subsequent delay in the induction of muscle creatine kinase activity. Delayed differentiation in A/K cells was associated with prolonged phosphorylation of the cell cycle regulatory retinoblastoma (Rb) protein; it is the un- (or hypo-) phosphorylated form of Rb which is known to promote differentiation in skeletal myoblasts. Thus, the IGF-I receptor regulates the timing of myoblast differentiation induced by serum withdrawal. The delayed differentiation of skeletal myoblasts with functionally inactive IGF-I receptors may result, at least in part, from delayed induction of myogenin gene expression and prolonged phosphorylation of the Rb protein.

Practical risk-adjusted quality control charts for infection control.

BACKGROUND: Control chart methodology has been widely touted for monitoring and improving quality in the health care setting. P charts and U charts are frequently recommended for rate and ratio statistics, but their practical value in infection control may be limited because they (1) are not risk-adjusted, and (2) perform poorly with small denominators. The Standardized Infection Ratio is a statistic that overcomes both these obstacles. It is risk-adjusted, and it effectively increases denominators by combining data from multiple risk strata into a single value. SETTING: The AICE National Database Initiative is a voluntary consortium of US hospitals ranging in size from 50 to 900 beds. The infection control professional submits monthly risk-stratified data for surgical site infections, ventilator-associated pneumonia, and central line-associated bacteremia. METHODS: Run charts were constructed for 51 hospitals submitting data between 1996 and 1998. Traditional hypothesis tests (P values <.05) flagged 128 suspicious points, and participating infection control professionals investigated and categorized each flag as a "real problem" or "background variation." This gold standard was used to compare the performance of 5 unadjusted and 11 risk-adjusted control charts. RESULTS: Unadjusted control charts (C, P, and U charts) performed poorly. Flags based on traditional 3-sigma limits suffered from sensitivity <50%, whereas 2-sigma limits suffered from specificity <50%. Risk-adjusted charts based on the Standardized Infection Ratio performed much better. The most consistent and useful control chart was the mXmR chart. Under optimal conditions, this chart achieved a sensitivity and specificity >80%, and a receiver operating characteristic area of 0. 84 (P <.00001). CONCLUSIONS: These findings suggest a specific statistic (the Standardized Infection Ratio) and specific techniques that could make control charts valuable and practical tools for infection control.