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Biomedical subjects

L Hartley

Publications and source records attributed to L Hartley.

At least 19 recordsLinked to original sources
PubMed1998

Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation.

During early pregnancy, in response to the implanting embryo, the surrounding uterine stroma undergoes a dramatic transformation into a specialized tissue known as the decidua. The decidua encapsulates the developing embryo, facilitating nutrient transfer and limiting trophoblast invasion. Here we show that female mice with a null mutation of the interleukin-11 receptor alpha chain are infertile because of defective decidualization. A temporal analysis revealed IL-11 expression is maximal in the normal pregnant uterus at the time of decidualization, and in situ hybridization studies showed expression of the IL-11 and the IL-11 receptor alpha chain in the developing decidual cells. These observations reveal a previously unrecognized critical role for IL-11 signaling in female reproduction.

Animals↗
PubMed1997

Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1.

Thymic carcinoid is part of the multiple endocrine neoplasia type 1 (MEN1) syndrome occurring predominantly in male patients who were heavy smokers, presenting most commonly in middle age. In contrast with metastatic midgut carcinoids, MEN1-related thymic carcinoid is not associated with carcinoid syndrome, nor is it associated with Cushing syndrome, in contrast with sporadic thymic carcinoids. Local invasion and metastasis are common. Prognosis is poor because of late detection, lack of effective treatment, and the aggressive nature of the tumor. All patients with thymic carcinoids should be investigated for MEN1, including thorough clinical evaluation and family studies. Anterior mediastinal lesions in MEN1 male patients should be considered thymic carcinoids until proven otherwise. All male MEN1 patients and asymptomatic gene carriers should be warned of the risk of thymic carcinoids and the possible link to smoking. Computed tomography (CT) of the chest is recommended on first screening for MEN1 in male patients more than 25 years of age, followed by yearly chest X-rays and chest CT every 3 years. Prophylactic thymectomy should be carried out during subtotal or total parathyroidectomy on MEN1 patients.

Adult↗
PubMed1996

Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut.

The divergent murine homeo box gene Hlx is expressed in restricted hematopoietic cell types and, during embryogenesis, prominently in visceral mesenchyme of the developing liver, gall bladder, and gut. Targeted disruption of the gene has now established that it plays a key role in visceral organogenesis. Embryos homozygous for the mutation died around embryonic day 15 with anemia and severe hypoplasia of the liver and gut. Liver ontogeny commenced normally with formation of the liver diverticulum and differentiation of hepatocytes, but the organ failed to expand and reached only 3% of normal size. The apparent liver hypoplasia was not associated with a notable increase in apoptotic cells. Gut development also began normally, but the intestines failed to undergo extensive elongation and looping and reached only a quarter of normal length. The anemia resulted from a deficiency in the fetal form of hematopoiesis, which occurs in the liver, but no intrinsic defect in Hlx-/- hematopoietic cells was observed in vitro, and liver-derived Hlx-/- hematopoietic stem cells that were transplanted to irradiated normal mice could fully reconstitute hematopoiesis. The impaired fetal hematopoiesis therefore reflects insufficient support function provided by the minute liver. Hlx is normally expressed in visceral mesenchyme lying adjacent to the developing liver and gut epithelia affected by the mutation, but not in the epithelia themselves. Hence, Hlx regulates a mesenchymal-epithelial interaction that drives a vital growth phase in visceral organogenesis. Moreover, because mutation of Hlx blocked liver growth but not its specification, early morphogenesis, or differentiation, development of this organ appears to occur by step-wise inductive interactions under separate genetic control.

Animals↗
PubMed1996

Mesoderm-specific expression of the divergent homeobox gene Hlx during murine embryogenesis.

We have determined the expression pattern of the divergent homeobox gene Hlx during post-implantation mouse development, utilizing in situ hybridization. Expression was mesoderm-specific and occurred in a complex tissue distribution. Transcripts were first detected at 9.5 days post coitum (p.c.) in splanchnic mesoderm of the midgut and hindgut region, then during organogenesis, prominently in mesenchyme of the developing liver, gall bladder, and intestines, as well as their mesenteric tissues. In the foregut, lung mesenchyme became positive from 10.5 days p.c. Hlx transcripts were also detected in a subset of skeletal myogenic cells: those within branchial arches from 9.5 days p.c. and within limb buds from 12 days p.c. Hlx was not expressed in myogenic cells which are derived from the myotome and populate the trunk. However, from 10 days p.c., expression was seen in a region of the sclerotome immediately adjacent to the myotome and corresponding to precursors of the ribs and vertebral neural arches. In the anterior-posterior aspect of the developing sclerotome, Hlx expression was out of register with original segmental boundaries (intersomitic fissures), a pattern consistent with a classical hypothesis that the developing vertebral column undergoes resegmentation. Hlx expression was also observed in vibrissae, pericardium, snout mesenchyme, and meningeal epithelium. Overall, expression of Hlx in only a subset of individual lineage progenitors and at know sites of inductive tissue interactions, suggests that the gene regulates local patterning or growth through cell:cell signalling at those embryonic sites.

Animals↗
PubMed1996

Migration of enteric neural crest cells in relation to growth of the gut in avian embryos.

Neural crest cell migration in the gut and the growth of the mid- and hindgut of avian embryos was investigated by a combination of whole-mount immunofluorescence of the HNK-1 neural crest marker epitope, chorioallantoic membrane grafting and morphometry. HNK-1-labelled cells advanced rostrocaudally in the gut of quail embryos (to the duodenum by stage HH 21, to the umbilicus by HH 25, to the ceca by HH 27, to the cloaca by HH 33). The timetable in chick embryos appeared to be slightly slower, but neural cells were obscured by background fluorescence in this species. More rostral regions of the gut commenced rapid growth earlier than more caudal regions (preumbilical small intestine after HH 26, postumbilical small intestine after HH 27 and colorectum after HH 28), and the small intestine and ceca grew most rapidly in length while the colorectum grew most rapidly in diameter. The rates of growth of the gut were low prior to the stage when HNK-1-labelled cells normally arrive in the small intestine, ceca and rostral colorectum, but increased dramatically after arrival. In the caudal colorectum rapid growth had commenced at the time of arrival of these cells. These data are consistent with the idea that a delay in arrival of vagal neural crest cells at any point in the intestine could jeopardize the ability of the cells to fully populate the remainder of the gut, due to the normal growth spurt causing the migration end-point to recede faster than the rate of neural crest cell migration. Thus, a mismatch in timing of neural crest cell migration and gut growth could play a role in the etiology of some forms of Hirschsprung's disease.

Animals↗
PubMed1996

Development of critical paths for post-acute brain injury rehabilitation: lessons learned.

One important tool for case management is critical path analysis. This article explains four critical pathways developed by an interdisciplinary team for a post-acute brain injury rehabilitation program. The heterogeneity of the brain injury population mandates the need for systematic coordination of direct care services. Yet, variations in the neurobehavioral consequences of brain injury necessitate differing goals and treatment tracks for individual clients. The critical pathways in this setting define and describe the procedures and services to be rendered from admission to discharge to achieve optimal goals for four treatment program tracks: Return to Work, Return to School, Functional Independence, and Neurorehabilitation. The tracks reflect a hierarchy of expectations for information processing and functional performance. Critical pathways provide a tool for enhancing communication among service providers and external case managers and for determining the extent to which a client's course of treatment compares with a clinical standard considered to be ideal. This article compares the four critical pathways, provides representative case samples, and discusses lessons learned in the development and implementation process.

Activities of Daily Living↗
PubMed1995

Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene.

The scl gene encodes a basic-helix-loop-helix transcription factor which was identified through its involvement in chromosomal translocations in T-cell leukemia. To elucidate its physiological role, scl was targeted in embryonic stem cells. Mice heterozygous for the scl null mutation were intercrossed and their offspring were genotyped. Homozygous mutant (scl-/-) pups were not detected in newborn litters, and analysis at earlier time points demonstrated that scl-/- embryos were dying around embryonic day 9.5. The scl-/- embryos were pale, edematous, and markedly growth retarded after embryonic day 8.75. Histological studies showed complete absence of recognizable hematopoiesis in the yolk sac of these embryos. Early organogenesis appeared to be otherwise normal. Culture of yolk sac cells of wild-type, heterozygous, and homozygous littermates confirmed the absence of hematopoietic cells in scl-/- yolk sacs. Reverse transcription PCR was used to examine the transcripts of several genes implicated in early hematopoiesis. Transcripts of GATA-1 and PU.1 transcription factors were absent from RNA from scl-/- yolk sacs and embryos. These results implicate scl as a crucial regulator of early hematopoiesis.

Animals↗
PubMed1995

Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5.

The murine homeo box gene Nkx2-5 is expressed in precardiac mesoderm and in the myocardium of embryonic and fetal hearts. Targeted interruption of Nkx2-5 resulted in abnormal heart morphogenesis, growth retardation and embryonic lethality at approximately 9-10 days postcoitum (p.c.). Heart tube formation occurred normally in mutant embryos, but looping morphogenesis, a critical determinant of heart form, was not initiated at the linear heart tube stage (8.25-8.5 days p.c.). Commitment to the cardiac muscle lineage, expression of most myofilament genes and myofibrillogenesis were not compromised. However, the myosin light-chain 2V gene (MLC2V) was not expressed in mutant hearts nor in mutant ES cell-derived cardiocytes. MLC2V expression normally occurs only in ventricular cells and is the earliest known molecular marker of ventricular differentiation. The regional expression in mutant hearts of two other ventricular markers, myosin heavy-chain beta and cyclin D2, indicated that not all ventricle-specific gene expression is dependent on Nkx2-5. The data demonstrate that Nkx2-5 is essential for normal heart morphogenesis, myogenesis, and function. Furthermore, this gene is a component of a genetic pathway required for myogenic specialization of the ventricles.

Animals↗
PubMed1995

Extracellular matrix and adhesive molecules in the early development of the gut and its innervation in normal and spotting lethal rat embryos.

The distribution of fibronectin (FN), laminin (LM), J1/tenascin, chondroitin sulphate proteoglycan (CSPG), neural cell adhesion molecule (NCAM), neurofilament (NF) and the HNK-1 epitope were studied immunohistochemically in the developing mid- and hindgut of E12.5-E16.5 rat embryos. Over this period the gut wall changed from a uniform mesenchyme to an annular organisation. FN and LM remained widely distributed, but J1/tenascin became concentrated in mesenchyme outside the nascent circular muscle layer, and CSPG declined in, and NCAM increased in, the circular layer. Protease and fixation treatments suggested that CSPG could mask other molecules such as LM. This re-organisation proceeded bidirectionally, as a rostrocaudal wave which was met in the colon by a caudorostral wave. The caecum, however, was conspiciously delayed in all maturation events and also showed mesenchymal and serosal epithelial labelling for the cell-adhesion-related HNK-1 epitope, which was absent elsewhere. This period also covered the appearance of enteric neurons, recognised by HNK-1 and NF antibodies. Cells labelled by these antibodies appeared in a unidirectional rostrocaudal wave, from the duodenum at E12.5 to the rectum at E16.5. This wave was not in exact synchrony with the wave of intestinal maturation, but lagged behind so that neuronal cells first appeared in increasingly mature micro-environment at progressively more caudal levels. These cells initially were positioned imprecisely about mid-way across the gut mesenchyme layer and were not clearly related spatiotemporally to any of the above molecules. Slightly later, however, this neural region was broadly defined by relatively low levels of both CSPG and J1/tenascin. The final position of the myenteric neurons was very precise, and was related to a thin J1/tenascin layer and to a step in NCAM labelling intensity. Litters of pups, of which 25% would be expected to be spotting lethal homozygous embryos which develop total colonic and caecal aganglionosis, showed no difference in any of the molecules studied, but in 4 embryos out of 12, the progress of the rostrocaudal wave of neuron appearance was distinctly slowed even in the duodenum and proximal small intestine, regions well outside the final aganglionic zone. The observations suggest that this Hirschsprung's-disease-like regionalised defect is a result of a generalised abnormality which does not involve gross changes in extracellular matrix and NCAM expression.

Animals↗
PubMed1993

Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants.

We have isolated two murine homeobox genes, Nkx-2.5 and Nkx-2.6, that are new members of a sp sub-family of homeobox genes related to Drosophila NK2, NK3 and NK4/msh-2. In this paper, we focus on the Nkx-2.5 gene and its expression pattern during post-implantation development. Nkx-2.5 transcripts are first detected at early headfold stages in myocardiogenic progenitor cells. Expression preceeds the onset of myogenic differentiation, and continues in cardiomyocytes of embryonic, foetal and adult hearts. Transcripts are also detected in future pharyngeal endoderm, the tissue believed to produce the heart inducer. Expression in endoderm is only found laterally, where it is in direct apposition to promyocardium, suggesting an interaction between the two tissues. After foregut closure, Nkx-2.5 expression in endoderm is limited to the pharyngeal floor, dorsal to the developing heart tube. The thyroid primordium, a derivative of the pharyngeal floor, continues to express Nkx-2.5 after transcript levels diminish in the rest of the pharynx. Nkx-2.5 transcripts are also detected in lingual muscle, spleen and stomach. The expression data implicate Nkx-2.5 in commitment to and/or differentiation of the myocardial lineage. The data further demonstrate that cardiogenic progenitors can be distinguished at a molecular level by late gastrulation. Nkx-2.5 expression will therefore be a valuable marker in the analysis of mesoderm development and an early entry point for dissection of the molecular basis of myogenesis in the heart.

Amino Acid Sequence↗
PubMed1992

Age-related changes in oral sensation.

Oral sensation (including two-point discrimination, oral stereognosis, vibrotactile detection, somesthetic sensitivity, proprioception, and thermal sensitivity) was studied in 60 healthy adults in five age categories: 20 to 34, 35 to 49, 50 to 64, 65 to 79, and 80 years and above. Thermal and somesthetic sensitivity as well as proprioception did not change with age. Ability to differentiate tactile and vibratory sensation on the lip decreased after age 80 (P less than .01), but vibration detection on the soft palate did not change. Stereognostic ability remained good up to age 80, and then declined for four of the nine shapes tested (P less than .01). Two-point discrimination deteriorated on the upper lip (P less than .01), on the cheeks (P less than .02), and on the lower lip (P less than .06). Two-point discrimination on the tongue and palate did not change. It was noted that oral sensation remained good with aging, showing only a slight decline in function after age 80.

Adult↗
PubMed1990

Post-choledochoenterostomy 'sump syndrome'.

The 'sump syndrome' is an uncommon, late complication of a side-to-side choledochoenterostomy. Five patients with this syndrome were encountered over a 5-year period. Pain or cholangitis was the clinical presentation in four patients, whereas one patient presented with secondary septic arthritis and a hepatic abscess. Liver function tests were mildly abnormal in each patient. All patients had a stomal size of less than 1 cm as assessed by forward- or side-viewing endoscopy. Endoscopic retrograde cholangiography revealed either stones or debris in the distal common bile ducts of all patients. Four patients had a surgical clearance of their duct with concurrent closure of the choledochoduodenostomy in three patients and the creation of a Rouxen-Y end-to-side choledochojejunostomy in the fourth patient. The other patient had an endoscopic sphincterotomy performed. After 1-4 years of follow-up, four patients have had a total resolution of symptoms. The other patient with follow-up for 4 years has had one episode of cholangitis which resolved rapidly with antibiotic treatment. The pathogenesis and clinical spectrum of the sump syndrome are reviewed and current management strategies are discussed.

Abdominal Pain↗
PubMed1989

Hierarchy of cytotoxic T cell clones. I. Reversal of resistance to lysis and killing between anti-hapten cytotoxic T cells.

Cells from clones of anti-hapten cytotoxic T lymphocytes (CTL) can act as both effector cells and, when treated with the specific hapten, as target cells. Individual clones can kill haptenated cells only from other clones that are less efficient killers. Clones specific for both fluorescein and trinitrophenol could be ordered in a single hierarchy in which resistance to lysis correlated with lytic efficiency. When the killing efficiency was reduced with phorbol myristate acetate (PMA) or the colchicine analogue, Colcemid, the degree of resistance to lysis was also reduced. The use of PMA-treated fluoresceinated targets greatly enhanced intraclonal killing and similarly lead to a repositioning of clones within the hierarchy of normal cells. By the haptenation of appropriate clones, efficient CTL could kill cells from other clones in a direction apparently opposite to recognition. The results demonstrate that effects other than antigen recognition of the target cell may result in variations in the nature of T cell immune responses.

Animals↗
PubMed1989

Hierarchy of cytotoxic T cell clones. II. Intraclonal triggering of lysis by hapten-specific CTL.

Cells from clones of anti-hapten murine cytotoxic T lymphocytes (CTL) can act as both target and effector cells, but will not lyse members of the same clone. The effect of haptenation on the cytolytic activity of anti-fluorescein (FL) and anti-trinitrophenol (TNP) CTL clones was examined. Treatment of anti-FL clones with fluorescein isothiocyanate or anti-TNP clones with trinitrobenzene sulphonic acid induces these clones to kill in an antigen-independent fashion. Targets killed by the haptenated CTL included syngeneic and allogeneic B lymphocyte blast cells, P815, YAC-1 and in one case human GM 4072 tumor cells. The importance of CD8 and T cell receptor (TCR) occupancy is demonstrated by the ability to block autotriggering by antibody directed against Ly 2 and the TCR. The results demonstrate that effects other than antigen recognition of the target play a role in the final outcome of effector-target cell interactions and provide a mechanism which could lead to autodestruction and immunosuppression particularly in some types of viral infection.

Animals↗
PubMed1987

Hypertrophy of radial and ulnar arteries following denervation of the chicken wing.

Denervation of radial and ulnar arteries in the growing and adult domestic fowl was achieved by unilateral sectioning of the brachial plexus. Eight weeks later the denervated arteries and those of the contralateral wing were examined with light- and electron microscopy to determine the effect of denervation on arterial structure. In growing fowls, the area of the media in radial and ulnar arteries was increased by 29% and 25%, respectively, after denervation. The number of smooth muscle layers was also significantly increased by 16% (radial) and 14% (ulnar), but no significant variation was seen in the wall/lumen ratio of either growing artery. In adult fowls, the area of the media was increased by 93% (radial) and 32% (ulnar) following denervation and the number of smooth muscle cell layers increased by 39% (radial) and 11% (ulnar). There was also an increased wall/lumen ratio of 64% (radial) and 92% (ulnar). These results indicate that hyperplasia of smooth muscle has occurred in response to denervation. Flow-cytometric DNA analysis of growing arteries also indicates that the increase in muscle-cell volume is a result of cell division (not polyploidy) since no significant differences were found between the control and denervated arteries in any stages of the cell cycle.

Animals↗