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PubMed2005

Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurones: exclusion from the nucleus and accumulation in dendritic granules and spine heads.

Long-term synaptic change in the cortex and the hippocampus is believed to require the highly localized delivery and translation of mRNAs in the dendritic shafts and spines. The molecular interactions that underlie local signalling between synapses and mRNAs are still largely undefined. After purification from total brain extracts, the NMDA receptor is known to be associated with numerous proteins, including the multifunctional RNA-binding factor TLS (also called FUS). In non-neural tissue, TLS is a vital nuclear protein with roles in DNA repair, homologous recombination, transcriptional regulation and pre-mRNA processing. We have examined the distribution of TLS in hippocampal neurones, both in the adult brain and in mature primary cultures, using subcellular fractionation and immunofluorescence techniques. TLS immunoreactivity is largely excluded from the neuronal nucleus and is found in the cytosol and in somatodendritic particles. In some of these particles, TLS colocalizes with Sam68, a nuclear RNA-binding protein that we previously showed is incorporated into dendritic RNA granules. Some of the TLS clusters also colocalize with NMDA receptor clusters. Finally, TLS clusters are occasionally seen within spine heads. The apparent removal of TLS from the nucleus might result in specific patterns of mRNA transcription or splicing in hippocampal neurones. TLS may also contribute to steering, anchoring or regulating mRNAs at synaptic sites.

Actins↗

PubMed1997

Tumor lysis syndrome in small cell carcinoma and other solid tumors.

OBJECTIVE: To review the risk factors and clinical findings associated with tumor lysis syndrome (TLS) in patients with small cell carcinomas and other solid tumors. METHODS: Reports of TLS in the English-language literature were identified by searching MEDLINE and the bibliographies of relevant case reports, journal articles, and book chapters. All reports identified through these searches, including abstracts from national meetings, were reviewed and included in this analysis. Data regarding clinical and biochemical parameters relevant to the occurrence of TLS were extracted from each report. RESULTS: Of the 25 reported solid tumor patients who developed TLS, 7 had small cell carcinoma, 5 breast cancer, and 4 neuroblastoma. TLS was associated with a variety of treatment regimens, including chemotherapy, immunotherapy, hormonal therapy, radiation therapy, and surgery. Common risk factors for TLS in this population included pretreatment renal insufficiency, elevated serum lactate dehydrogenase (LDH), and hyperuricemia. Among the typical biochemical findings of TLS, acute renal insufficiency and hyperuricemia were identified in nearly all patients and hyperkalemia, hyperphosphatemia, hypocalcemia, and increased serum LDH were reported in over 75% of patients. In addition, seven patients, including the current case, presented with profound metabolic acidosis. Nine of 25 patients died during the acute episode of TLS. CONCLUSIONS: Although TLS occurs infrequently in patients with solid tumors, the risk factors and biochemical abnormalities associated with this potentially fatal complication of therapy must be recognized to allow for adequate monitoring and early initiation of appropriate therapeutic measures.

Aged↗

PubMed1999

Distinct roles for Rev1p and Rev7p during translesion synthesis in Saccharomyces cerevisiae.

Translesion synthesis (TLS) in Saccharomyces cerevisiae requires at least Rev1p and polymerase zeta (Pol zeta), a complex of the Rev3 polymerase and its accessory factor Rev7p. Although their precise role(s) are poorly characterized, in vitro studies suggest that each protein contributes to TLS in a manner dependent on the particular lesion and surrounding DNA sequence. In the present study, strand segregation analysis is used to attempt to identify the role(s) of the Rev1 and Rev7 proteins during TLS. This assay uses double-stranded plasmids containing a genetic marker opposite to a replication blocking lesion (N-2-acetylaminofluorene; AAF) to measure TLS quantitatively and qualitatively in vivo. The AAF adduct is localized within a repetitive sequence in a manner that allows the formation of misaligned primer-template replication intermediates. Elongation from a misaligned intermediate fixes a frameshift mutation (slipped TLS), while extension of the correctly aligned lesion terminus yields error-free (non-slipped) TLS. The results indicate that there is a strong requirement for Rev7p during Pol zeta-mediated TLS measured in vivo. Furthermore, Rev1p is needed only for non-slipped TLS; slipped TLS remains efficient in its absence, revealing a previously uncharacterized Rev1p activity similar to Escherichia coli UmuDC function. Specifically, this activity is required for elongation from a correctly aligned lesion terminus.

DNA-Directed DNA Polymerase↗

PubMed2002

tRNA elements mediate the assembly of an icosahedral RNA virus.

tRNAs, the adapter molecules in protein synthesis, also serve as metabolic cofactors and as primers for viral RNA-directed DNA synthesis. The genomic and subgenomic RNAs of some plant viruses have a 3'-terminal tRNA-like structure (TLS) that can accept a specific amino acid and serve as a site for initiation of replication and as a simple telomere. We report a previously undescribed role for the TLS of brome mosaic virus (BMV), and potentially for cellular tRNA, in mediating the assembly of its icosahedral virions. BMV genomic RNAs and subgenomic RNA lacking the TLS failed to assemble into virions when incubated with purified BMV coat protein. Assembly was restored by addition of a 201-nt RNA containing the BMV TLS. TLSs from two other plant viruses as well as tRNAs from wheat germ and yeast were similarly active in the BMV virion assembly reaction, but ribosomal RNA and polyadenylate did not facilitate assembly. Surprisingly, virions assembled from TLS-less BMV RNA in the presence of tRNAs or TLS-containing short RNA did not incorporate the latter molecules. Consistent with a critical role for the BMV TLS in virion assembly, mutations in the BMV genomic RNAs that were designed to disrupt the folding of the TLS also abolished virion assembly. We discuss the likely roles of the TLS in early stages of virion assembly.

Base Sequence↗

PubMed2003

Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase.

To evaluate the clinical benefit of the prophylactic use of urate oxidase in children with non-Hodgkin's lymphoma (NHL), we analyzed the incidence and complications of tumor lysis syndrome (TLS) in children with B-cell acute lymphoblastic leukemia (B-ALL) or stage III/IV Burkitt's lymphoma and a lactate dehydrogenase (LDH) level > or =500 U/l before and after the introduction of a protocol amendment to use urate oxidase for the prophylaxis of TLS. Data from 1791 children with NHL enrolled in the two subsequent multicenter studies NHL-BFM 90 and 95 were evaluated. The presence of the side effects TLS, anuria, sepsis, and other complications during the first 2 weeks after admission were registered. Until March 1996, no urate oxidase was used (period 1). From November 1997 all children with B-ALL or stage III and IV B-NHL and LDH > or =500 U/l should receive urate oxidase prophylactically (period 3). In between (period 2), urate oxidase was given in a minority of hospitals therapeutically. Initial chemotherapy was identical. Altogether, 78 children (4.4%) developed a TLS. Patients with B-ALL had the highest risk to develop a TLS (26.4%) followed by B-ALL/Burkitt's lymphoma and a LDH > or =500 U/l (14.9%). In period 1, 16.1% and 9.2% of the latter children developed a TLS or anuria, respectively, compared to 12.3% and 6.2% in period 3 ( p=NS). The incidence of sepsis remained unchanged (5.0% vs 4.6%). In children with B-ALL the differences in the incidence of TLS and anuria between period 3 and period 1 were more pronounced, reaching significance for anuria (15.4% vs 3.8%, p=0.03). Our results suggest that patients with the highest risk to develop a TLS might benefit from the prophylactic use of urate oxidase.

Adolescent↗

PubMed2006

High-pressure studies of optical dephasing in polymer glasses.

The effect of high pressure on the optical dephasing of chromophores in organic polymers at low temperature is evaluated within the stochastic sudden jump two-level-system (TLS) model. The approximations within the "standard" TLS model cannot account for the observed pressure dependence of the pure dephasing rate without ad hoc assumptions about changes in the TLS density of states. However, the photon echo model of Geva and Skinner for disordered systems can be used to model pressure-dependent optical dephasing results for a variety of doped polymer systems without assuming changes in the TLS density of states. The relative importance of pressure-induced changes in TLS density, chromophore-TLS coupling, and TLS-phonon coupling is evaluated by fitting experimental high-pressure photon echo results to the TLS model.

Journal Article↗

PubMed2002

Fulminant tumour lysis syndrome in acute myelogenous leukaemia with inv(16)(p13;q22).

Tumour lysis syndrome (TLS) is caused by rapid breakdown of malignant cells resulting in electrolyte disturbances and acute renal failure. TLS has rarely been described in patients with acute myelogenous leukaemia (AML). Between November 1997 and July 2001, 114 consecutive adult AML patients aged <60 yr received induction chemotherapy consisting of cytosine arabinoside 1.5 g m(-2) q 12 h x 12 doses and daunorubicin 45 mg m(-2) d(-1) x 3 doses. During induction chemotherapy (CT), seven patients (6.1%, 95% CI 2.5-12.2) developed fulminant TLS, resulting in acute renal failure; five of these seven patients had inversion of chromosome 16 [inv(16)(p13;q22)], and one patient had a biological equivalent [t(16,16)(p13;q22)]. Four of the TLS patients underwent leukapheresis for a presenting white blood cell (WBC) count > 100 x 10(9) L(-1) prior to commencing chemotherapy, and six patients subsequently required haemodialysis for a median of 2 (range 1-8) wk. One TLS patient died of intracerebral hemorrhage on day 10 and another patient of multiorgan failure on day 17. Of the other five patients, all entered a complete remission (CR) and recovered normal renal function. Four patients remain in continuous CR [median follow-up 20 (range 12-25) months]. One patient relapsed at 12 months and again developed TLS on re-induction. In univariate analysis, TLS patients were more likely to have an elevated presentation and pre-chemotherapy WBC counts, elevated serum creatinine, and uric acid levels at presentation, as well as an inv(16). In multivariate analysis, only serum creatinine and inv(16) remained statistically significant (P < 0.001 for each). Patients with an inv(16) are a unique AML subgroup at high risk for fulminant TLS.

Adolescent↗

PubMed2000

The processing of a Benzo(a)pyrene adduct into a frameshift or a base substitution mutation requires a different set of genes in Escherichia coli.

Replication through a single DNA lesion may give rise to a panel of translesion synthesis (TLS) events, which comprise error-free TLS, base substitutions and frameshift mutations. In order to determine the genetic control of the various TLS events induced by a single lesion, we have chosen the major N2-dG adduct of (+)-anti-Benzo(a)pyrene diol epoxide [(+)-anti-BPDE] adduct located within a short run of guanines as a model lesion. Within this sequence context, in addition to the major event, i.e. error-free TLS, the adduct also induces base substitutions (mostly G --> T transversions) and -1 frameshift mutations. The pathway leading to G --> T base substitution mutagenesis appears to be SOS independent, suggesting that TLS is most probably performed by the replicative Pol III holoenzyme itself. In contrast, both error-free and frameshift TLS pathways are dependent upon SOS-encoded functions that belong to the pool of inducible DNA polymerases specialized in TLS (translesional DNA polymerases), namely umuDC (Pol V) and dinB (Pol IV). It is likely that, given the diversity of conformations that can be adopted by lesion-containing replication intermediates, cells use one or several translesional DNA polymerases to achieve TLS.

Bacterial Proteins↗

PubMed1996

Cellular strategies for accommodating replication-hindering adducts in DNA: control by the SOS response in Escherichia coli.

The replication of double-stranded plasmids containing a single adduct was analyzed in vivo by means of a sequence heterology that marks the two DNA strands. The single adduct was located within the sequence heterology, making it possible to distinguish trans-lesion synthesis (TLS) events from damage avoidance events in which replication did not proceed through the lesion. When the SOS system of the host bacteria is not induced, the C8-guanine adduct formed by the carcinogen N-2-acetylaminofluorene (AAF) yields less than 1% of TLS events, showing that replication does not readily proceed through the lesion. In contrast, the deacetylated adduct N-(deoxyguanosin-8-yl)-2-aminofluorene yields approximately 70% of TLS events under both SOS-induced and uninduced conditions. These results for TLS in vivo are in good agreement with the observation that AAF blocks DNA replication in vitro, whereas aminofluorene does so only weakly. Induction of the SOS response causes an increase in TLS events through the AAF adduct (approximately 13%). The increase in TLS is accompanied by a proportional increase in the frequency of AAF-induced frameshift mutations. However, the polymerase frameshift error rate per TLS event was essentially constant throughout the SOS response. In an SOS-induced delta umuD/C strain, both US events and mutagenesis are totally abolished even though there is no decrease in plasmid survival. Error-free replication evidently proceeds efficiently by means of the damage avoidance pathway. We conclude that SOS mutagenesis results from increased TLS rather than from an increased frameshift error rate of the polymerase.

2-Acetylaminofluorene↗

PubMed1999

Induction of a secreted protein by the myxoid liposarcoma oncogene.

The TLS-CHOP oncoprotein, found in the majority of human myxoid liposarcomas, consists of a fusion between the transcription factor CHOP/GADD153 and the N terminus of an RNA-binding protein TLS/FUS. Clinical correlation and in vitro transformation assays indicate that the N terminus of TLS plays an important role in oncogenesis by TLS-CHOP. Until now, however, the only activity attributed to the oncoprotein is that of inhibiting the binding of transcription factors of the C/EBP class to certain adipogenic target genes, a function that TLS-CHOP shares with the nononcogenic CHOP protein. Here we report the isolation of a gene, DOL54, that is activated in primary fibroblasts by the expression of TLS-CHOP. DOL54 is expressed in the neoplastic component of human myxoid liposarcomas and increases the tumorigenicity of cells injected in nude mice. Activation of DOL54 requires an intact DNA-binding and dimerization domain in TLS-CHOP, a suitable cellular dimerization partner, and depends on the TLS N terminus. Normal adipocytic differentiation is associated with an early and transient expression of DOL54, and the gene encodes a secreted protein that is tightly associated with the cell surface or extracellular matrix. TLS-CHOP thus leads to the unscheduled expression of a gene that is normally associated with adipocytic differentiation.

Animals↗

PubMed2004

Tumour lysis syndrome: new therapeutic strategies and classification.

Tumour lysis syndrome (TLS) describes the metabolic derangements that occur with tumour breakdown following the initiation of cytotoxic therapy. TLS results from the rapid destruction of malignant cells and the abrupt release of intracellular ions, nucleic acids, proteins and their metabolites into the extracellular space. These metabolites can overwhelm the body's normal homeostatic mechanisms and cause hyperuricaemia, hyperkalaemia, hyperphosphaetemia, hypocalcaemia and uraemia. TLS can lead to acute renal failure and can be life-threatening. Early recognition of patients at risk and initiation of therapy for TLS is essential. There is a high incidence of TLS in tumours with high proliferative rates and tumour burden such as acute lymphoblastic leukaemia and Burkitt's lymphoma. The mainstays of TLS prophylaxis and treatment include aggressive hydration and diuresis, control of hyperuricaemia with allopurinol prophylaxis and rasburicase treatment, and vigilant monitoring of electrolyte abnormalities. Urine alkalinization remains controversial. Unfortunately, there have been few comprehensive reviews on this important subject. In this review, we describe the incidence, pathophysiological mechanisms of TLS and risk factors for its development. We summarise recent advances in the management of TLS and provide a new classification system and recommendations for prophylaxis and/or treatment based on this classification scheme.

Allopurinol↗

PubMed1993

Temporary threshold and loudness shifts: frequency patterns and correlations.

Two experiments studied the frequency pattern of TLS (temporary loudness shift) as a function of the level and frequency of the fatiguing sound. In experiment 1, the fatiguing tones were intermittent 375-, 1500-, or 3000-Hz tones (10 s on/10 s off) at 75, 80, 85, 90, or 95 dB SPL. The TLS patterns were established for a continuous, 60-phon test tone at different frequencies presented simultaneously with the intermittent fatiguing tone. In experiment 2, a 1000-Hz exposure tone with an intermittency of 10 s on/20 s off was used with a continuous 60-dB test tone at different frequencies. In both experiments, the total exposure duration was 60 s; TLS was measured 5 s after the exposure ended. For the lowest two exposure levels, the TLS pattern had one peak centered on the exposure frequency. As the exposure level increased, a two-peak pattern became evident, with the second peak at higher test frequencies. This finding could be interpreted as psychoacoustical evidence for the double (passive and active) mode of displacement of the basilar membrane. In experiment 2, a TTS (temporary threshold shift) measurement after exposure to a 45-min, 1000-Hz tone at 90 dB was added to the TLS sessions. The correlations between maximum TTS after a 45-min exposure and the TLS obtained after a 60-s exposure were calculated for each of the exposure levels and test frequencies used in TLS measurements. The correlation reached as high as 0.9 for TLSs measured at 1120 Hz after a 90-dB exposure; it was smaller but significant for TLSs at the exposure frequency. Despite these correlations, differences in the overall patterns of TTS and TLS suggest that they stem from two different mechanisms.

Acoustic Stimulation↗

PubMed2004

tRNA-like structure regulates translation of Brome mosaic virus RNA.

For various groups of plant viruses, the genomic RNAs end with a tRNA-like structure (TLS) instead of the 3' poly(A) tail of common mRNAs. The actual function of these TLSs has long been enigmatic. Recently, however, it became clear that for turnip yellow mosaic virus, a tymovirus, the valylated TLS(TYMV) of the single genomic RNA functions as a bait for host ribosomes and directs them to the internal initiation site of translation (with N-terminal valine) of the second open reading frame for the polyprotein. This discovery prompted us to investigate whether the much larger TLSs of a different genus of viruses have a comparable function in translation. Brome mosaic virus (BMV), a bromovirus, has a tripartite RNA genome with a subgenomic RNA4 for coat protein expression. All four RNAs carry a highly conserved and bulky 3' TLS(BMV) (about 200 nucleotides) with determinants for tyrosylation. We discovered TLS(BMV)-catalyzed self-tyrosylation of the tyrosyl-tRNA synthetase but could not clearly detect tyrosine incorporation into any virus-encoded protein. We established that BMV proteins do not need TLS(BMV) tyrosylation for their initiation. However, disruption of the TLSs strongly reduced the translation of genomic RNA1, RNA2, and less strongly, RNA3, whereas coat protein expression from RNA4 remained unaffected. This aberrant translation could be partially restored by providing the TLS(BMV) in trans. Intriguingly, a subdomain of the TLS(BMV) could even almost fully restore translation to the original pattern. We discuss here a model with a central and dominant role for the TLS(BMV) during the BMV infection cycle.

Base Sequence↗

PubMed2005

Incidence and pathogenesis of tumor lysis syndrome.

Tumor lysis syndrome (TLS) is a constellation of metabolic disturbances that may be observed in patients with malignancies. Clinically significant TLS can occur spontaneously, but most often is seen 48-72 h after initiation of cancer treatment. The metabolic abnormalities observed in patients with TLS include hyperkalemia, hyperuricemia, and hyperphosphatemia, which leads to secondary hypocalcemia. The precise incidence of TLS is not defined, risk factors being represented by large tumor burden, neoplasms with either high growth fraction or high sensitivity to chemotherapy, and by pre-existing impairment of renal function. Neither racial, nor sex predilection exists. The pathogenesis of TLS is related to the rapid tumor cell turnover or destruction, which may result in release of intracellular ions and metabolic byproducts into the systemic circulation. Acute renal failure (ARF) may frequently complicate TLS and is mainly due to renal tubule precipitation of uric acid, calcium phosphate, or hypoxanthine. Hemodynamic changes reducing glomerular flow due to still undefined mediators are also involved in TLS pathophysiology. Pre-existing volume depletion or renal dysfunction may worsen metabolic derangements and ARF. A good comprehension of TLS pathophysiology has provided the basis for an effective and rational treatment of this complication, adversely affecting the outcome of cancer patients.

Acute Kidney Injury↗

PubMed1998

Total least-squares reconstruction with wavelets for optical tomography.

In a previous paper [Zhu et al., J. Opt. Soc. Am. A 14, 799 (1997)] an iterative algorithm for obtaining the total least-squares (TLS) solution of a linear system based on the Rayleigh quotient formulation was presented. Here we derive what to our knowledge are the first statistical properties of this solution. It is shown that the Rayleigh-quotient-form TLS (RQF-TLS) estimator is equivalent to the maximum-likelihood estimator when noise terms in both data and operator elements are independent and identically distributed Gaussian. A perturbation analysis of the RQF-TLS solution is derived, and from it the mean square error of the RQF-TLS solution is obtained in closed form, which is valid at small noise levels. We then present a wavelet-based multiresolution scheme for obtaining the TLS solution. This method was employed with a multigrid algorithm to solve the linear perturbation equation encountered in optical tomography. Results from numerical simulations show that this method requires substantially less computation than the previously reported one-grid TLS algorithm. The method also allows one to identify regions of interest quickly from a coarse-level reconstruction and restrict the reconstruction in the following fine resolutions to those regions. Finally, the method is less sensitive to noise than the one-grid TLS and multigrid least-squares algorithms.

Algorithms↗

PubMed2002

[Pediatric trauma life support and cardiopulmonary resuscitation].

Accidents are the most frequent cause of mortality among children older than one year. Thus, the need to proceed to cardiopulmonary resuscitation (CPR) during the early phases of trauma life support (TLS) is always a possibility. Trauma is a special situation in CPR: expected problems (i.e., hemorrhage, pneumo-hemothorax, hypothermia, and difficult intubation and vascular access), specific therapeutic actions (i.e., helmet retrieval and cervical spine immobilization), and exceptions to standard CPR guidelines (i.e., contraindication for the head tilt-chin lift manoeuvre) can arise. Therefore, TLS and CPR interventions must be appropriately integrated. TLS is considered a method (much like CPR). It combines organization and leadership with competent, structured and timely actions. Appropriate intervention within the first few moments ("platinum half-hour" and " golden hour") and first day ("silver day") is essential. As in CPR, two modalities can be distinguished: basic TLS (on the scene, without technical resources) and advanced TLS (with resources). The acronym PAA summarizes basic TLS: Protect-Alert-Aid. The advanced TLS sequence includes the following: primary survey and initial stabilization, secondary survey, triage, transport, and definitive care. The main objective of the primary survey and initial stabilization phase is the identification and treatment of injuries with immediate potential to cause death. CPR in the context of TLS should be adapted to the special features of trauma. Particular attention should be paid to the cervical spine. While not specific for trauma care, the early and generous administration of oxygen should be emphasized.

Cardiopulmonary Resuscitation↗

PubMed1996

Partially differentiated ex vivo expanded cells accelerate hematologic recovery in myeloablated mice transplanted with highly enriched long-term repopulating stem cells.

The ability of an infusion of ex vivo expanded hematopoietic cells to ameliorate cytopenia following transplantation of hematopoietic stem cells (HSCs) is controversial. To address this issue, we measured the recovery of circulating leukocytes, erythrocytes, and platelets in lethally irradiated mice transplanted with 10(3) enriched HSCs, with or without their expanded equivalent (EE) generated after 7 days of culture in interleukin-3 (IL-3), IL-6, granulocyte colony-stimulating factor and Steel Factor. Two HSC populations differing in their content of short-term repopulating progenitors were evaluated. Thy-1loLIN-Sca-1+ (TLS) bone marrow (BM) is enriched in colony-forming cells (CFCs), day 8 and day 12 spleen colony-forming units (CFU-S) (435 +/- 19, 170 +/- 30, and 740 +/- 70 per 10(3) cells, respectively), and stem cells with competitive long-term repopulating potential (> or = 1 per 43 cells). Thy-1loSca-1+H-2Khl cells (TSHFU) isolated from BM 1 day after treatment of donor mice with 5-fluorouracil (5-FU) are also highly enriched in competitive repopulating units (CRU, > or = 1 per 55 cells), but are depleted of CFCs, day 8 and day 12 CFU-S (171 +/- 8, 0 and 15 +/- 4 per 10(3) cells, respectively). Recipients of 10(3) TLS cells transiently recovered leukocytes to > or = 2,000/microL in 12 days, but sustained engraftment required 25 days. Platelets recovered to > or = 200,000/microL in 15 days, and erythrocytes never decreased below 50% of normal. Mice transplanted with 10(3) TSHFU cells recovered leukocytes in 15 days, and platelets and erythrocytes in 18 days. Recipients of unseparated normal or 5-FU-treated BM cells (containing 10(3) TLS or TSHFU cells) recovered safe levels of blood cells in 9 to 12 days, suggesting that unseparated marrow contains early engrafting cells that were depleted by sorting. Upon ex vivo expansion, total cells, CFCs and day 12 CFU-S were amplified 2,062-,83- and 13-fold, respectively, from TLS cells; and 1,279-, 259- and 708-fold, respectively, from TSHFU cells. Expanded cells could regenerate the majority of lymphocytes and granulocytes in primary (17 weeks) and secondary (26 weeks) hosts and were only moderately impaired compared to fresh HSCs. The EE of TSHFU cells was more potent than that of TLS cells, suggesting that more highly enriched HSCs are more desirable starting populations for this application. When mice were transplanted with 10(3) TSHFU cells and their EE, the duration of thrombocytopenia was shortened from 18 to 12 days, and anemia was abolished. Leukocytes were also elevated on days 9 to 12, although sustained recovery was not accelerated. Anemia was also abrogated in recipients of 10(3) TLS cells and their EE. Early platelet counts were slightly higher than with TLS cells alone, but leukocyte recovery was not improved. These data confirm that TLS cells contribute to early and sustained hematopoiesis, and demonstrate a benefit of ex vivo expanded cells in accelerating engraftment of more primitive TSHFU stem cells depleted of progenitors.

Animals↗

PubMed1987

Thoracolumbosacral laminectomy in achondroplasia: long-term results in 22 patients.

Neurologic problems caused by vertebral stenosis in the thoracolumbosacral (TLS) region are common in achondroplasia. Surgical decompression by means of laminectomy is recommended often, but its long-term results have not been assessed. We reviewed the clinical history of 22 achondroplastic patients who had at least one TLS laminectomy performed before 1981. Symptoms predated the first TLS laminectomy by a mean of 2.3 years (range 0.1-17 years). Preoperatively, 91% of patients had motor function impairment, 86% had sensory dysfunction, 86% had neurogenic claudication, 77% had radicular pain, 59% had symptomatic bladder dysfunction, and 32% had fecal incontinence. Only upper motor neurons were affected in 45%, only lower motor neurons in 27%, and both in 27%. Follow-up after the first TLS laminectomy averaged 8 years. Of the 20 patients who initially improved neurologically, 12 had functional improvement for more than 5 years. However, 11 of these 12 subsequently regressed and 10 had additional laminectomies. Long-term neurologic and functional improvement was associated with both a short duration of symptoms preoperatively and absence of cervical stenosis. Because of hypertrophic scarring, 9 patients developed compression at the site of the initial TLS laminectomy and required re-operation 6.4 years (range 1-11 years) later. We conclude that TLS laminectomy is an effective treatment for spinal stenosis if performed early in the course of the neurologic syndrome. However, some patients have, or later develop, compression adjacent to the myelographic site of stenosis, and some develop hypertrophic scarring at the site of initial decompression. We therefore suggest that the first TLS laminectomy extend (1) 3 levels cephalad to the myelographic block, (2) at least to S2, and (3) laterally at least to the facets.

Achondroplasia↗