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PubMed2000

Spatially restricted factors cooperate with notch in the regulation of Enhancer of split genes.

Expression of the Drosophila Enhancer of split [E(spl)] genes, and their homologues in other species, is dependent on Notch activation. The seven E(spl) genes are clustered in a single complex and their functions overlap significantly; however, the individual genes have distinct patterns of expression. To investigate how this regulation is achieved and to find out whether there is shared or cross regulation between E(spl) genes, we have analysed the enhancer activity of sequences from the adjacent E(spl)mbeta, E(spl)mgamma and E(spl)mdelta genes and made comparisons to E(spl)m8. We find that although regulatory elements can be shared, most aspects of the expression of each individual gene are recapitulated by small (400-500 bp) evolutionarily conserved enhancers. Activated Notch or a Suppressor of Hairless-VP16 fusion are only sufficient to elicit transcription from the E(spl) enhancers in a subset of locations, indicating a requirement for other factors. In tissue culture cells, proneural proteins synergise with Suppressor of Hairless and Notch to promote expression from E(spl)mgamma and E(spl)m8, but this synergy is only observed in vivo with E(spl)m8. We conclude that additional factors besides the proneural proteins limit the response of E(spl)mgamma in vivo. In contrast to the other genes, E(spl)mbeta exhibits little response to proneural proteins and its high level of activity in the wing imaginal disc suggests that wing-specific factors cooperate with Notch to activate the E(spl)mbeta enhancer. These results demonstrate that Notch activity must be integrated with other transcriptional regulators and, since the activation of target genes is critical in determining the developmental consequences of Notch activity, provide a framework for understanding Notch function in different developmental contexts.

Animals↗
PubMed1999

Testicular endocrine function, seasonality and semen quality of the stallion.

To gain further information on gonadal function of the stallion, concentrations of testicular steroids in blood plasma (bpl) and seminal plasma (spl) and their distribution in the ejaculate were determined. Blood and semen samples from a total of 11 stallions were collected from November to July. Estrone (E1), estrone sulfate (E1S), estradiol-17beta (E2beta) and testosterone (T) were determined in bpl and spl, and in addition androstenedione (A), dehydroepiandrosterone (DHEA) and 5alpha-dihydrotestosterone (5alpha-DHT) were measured in spl. At certain points of time, aliquots of an ejaculate were centrifuged, washed and the distribution of E1, E1S, E2beta and T into seminal plasma and the sperm fraction was assessed. Hormone assay was by RIA, partly after prior separation by HPLC. Mean concentrations (X(g) x DF) were as follows: E2beta (bpl) 31.1 (1.16), (spl) 24.2 (1.42) pg ml(-1); E1 (bpl) 143.3 (1.21), (spl) 117.7 (1.53) pg ml(-1); E1S (bpl) 157.3 (1.44), (spl) 2.92 (1.42) ng ml(-1); T (bpl) 570.6 (1.43), (spl) 23.1 (1.68) pg ml(-1); A (spl) 17.9 (1.39) pg ml(-1); DHEH (spl) 12.4 (1.51) pg ml(-1); 5alpha-DHT (spl) 9.7 (1.29) pg ml(-1). Except for E2beta and A in seminal plasma, a seasonal pattern was established for all other steroids with lowest mean values occurring from November to April. From the semen parameters determined, only motility was correlated to season. There was a higher correlation among oestrogen in blp than in spl and the only correlation identified between oestrogenic and androgenic steroids was between T and E2beta in blp. In spl, T was correlated with A and 5alpha-DHT. T was the dominant free steroid in bpl while it was E1 in spl; T and E1S concentrations were about 23- and 54-fold lower in spl compared to bpl with E1S, however, showing the highest absolute values in both fluids. In the fractionated ejaculate an association of free oestrogens, particularly E2beta, with spermatozoa was observed.

Androgens↗
PubMedDate not supplied

Formation of glutathionyl-spironolactone disulfide by rat liver cytochromes P450 or hog liver flavin-containing monooxygenases: a functional probe of two-electron oxidations of the thiosteroid?

We have previously reported that the diuretic thiosteroid spironolactone (SPL) inactivates rat liver microsomal cytochromes P450 [P450 (P450 3A and P450 2C11)] in a in a mechanism-based fashion, and we have identified two polar SPL metabolites (SPL-sulfinic acid and -sulfonic acid), formed in a partition ratio of approximately 20:1 in such rat liver microsomal incubations [Decker et al. (1989) Biochemistry 28, 5128-5136]. We proposed at the time that these metabolites were most likely derived from further enzymatic (or nonenzymatic) oxidations of the one-electron oxidation product [SPL-thiyl radical (SPL-S.)] and/or the two-electron-oxidized species [SPL-sulfenic acid (SPL-SOH)]. In those studies, glutathione (GSH) was found to attenuate both SPL-mediated P450 loss as well as polar metabolite formation by approximately 40%. We have now reexamined this in greater detail and report that it is due to GSH trapping of an electrophilic oxidized SPL species to form an adduct that we have isolated and unambiguously characterized by mass spectral analyses as the glutathionyl-SPL adduct (SPL-SSG). Moreover, we have found not only that rat liver microsomal formation of this adduct is enhanced at pH 9.0, the pH optimum for flavin-containing monooxygenase (FMO), but also that such adduct formation was indeed efficiently catalyzed by purified hog liver FMO. Because FMO oxidations of thiols are thought to entail a two-electron process to form the corresponding sulfenic acids, we infer that such a SPL-SSG adduct most likely reflects FMO-catalyzed oxidation of SPL to SPL-SOH, which on leaving the FMO active site is then trapped by GSH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Molecular dissection of mutations in the Bacillus subtilis spore photoproduct lyase gene which affect repair of spore DNA damage caused by UV radiation.

In response to UV irradiation, Bacillus subtilis spore DNA accumulates the unique thymine dimer 5-thyminyl-5,6-dihydrothymine, or spore photoproduct (SP). SP is broken down into monomers during spore germination by the product of the spl gene which has been proposed to encode the enzyme SP lyase. The wild-type spl gene was cloned by complementation of a mutation designated spl-1; the putative spl gene product is a 40-kDa protein whose deduced amino acid sequence contains regions homologous to DNA photolyases. During phenotypic characterization of spl subclones using transformation crosses between the cloned wild-type spl gene and an spl-1 mutant recipient, in addition to the expected transformant classes exhibiting UV-resistant (type I) and UV-sensitive (type III) spores, an additional recombinant class was observed (called type II), spores of which exhibited slower germination kinetics following UV irradiation. The results suggested that the spl-1 allele consisted of at least two separable mutations. The DNA region which could rescue the spl-1 allele was localized to a 511-bp region within the spl coding sequence; this region was amplified from the spl-1 mutant chromosome by PCR and sequenced. The region contained two amino acid substitutions, an Arg replacing Gly-168 (G168R) and an Asp replacing Gly-242 (G242D) in the deduced SP lyase sequence, as well as 18 silent mutations. PCR amplification of chromosomal DNA from a selected type II recombinant and sequence analysis of the amplification product confirmed that recombination had indeed occurred between codons 168 and 242 and further localized the point of crossover by using the 18 silent mutations as molecular markers throughout the region. By in vitro mutagenesis, alleles of spl containing all combinations of single and double amino acid substitutions were introduced into the cloned wild-type spl gene. When integrated into the B. subtilis chromosome at the amyE locus, it was observed that although both amino acid substitutions contribute to the spl-1 phenotype, the G168R mutation exerted a much greater effect than did the G242D mutation.

Alleles↗
PubMed1984

Greater splanchnic excitation of primate T1-T5 spinothalamic neurons.

Effects of electrical stimulation of the left greater splanchnic nerve (SPL) on T1-T5 spinothalamic (STT) neurons were determined. Eighty-five STT neurons were studied in 36 anesthetized monkeys (Macaca fascicularis). All neurons were excited by manipulation of their somatic receptive fields and by electrical stimulation of cardiopulmonary (CP) sympathetic afferent fibers. SPL stimulation excited 63 (74%) STT neurons. There was an increasing percentage of cells with SPL input at more caudal segments and in deeper laminae. Both SPL and CP sympathetic stimulation elicited early or both early and late responses. Latencies to cell activation were usually shorter for CP sympathetic stimulation than for SPL stimulation (5.4 +/- 0.8 versus 11.3 +/- 2.0 ms for early responses and 44.2 +/- 4.2 versus 111.0 +/- 6.6 ms for late responses). The maximum number of spikes per SPL or CP sympathetic stimulus was determined. In the T2 and T3 segments, early responses to CP sympathetic stimulation were significantly greater. However, at more caudal segments, responses to CP sympathetic input decreased while responses to SPL input increased until at T4 there was no difference in the two responses. In T5, responses to SPL input were greater. No differences in the magnitudes of late responses were observed in any of the segments. The response of six cells to SPL stimulation was inhibited by a train of conditioning stimuli applied to the left thoracic vagus nerve. Maximum inhibition occurred at a CT interval of 50 ms and test responses were significantly reduced at CT intervals as great as 200 ms. Bilateral vagotomy eliminated the inhibitory effect. Cutting the left sympathetic chain between the T5 and T6 rami communicantes eliminated 27% of the response to SPL stimulation. More caudal cuts reduced the response further until 71% of the response was abolished by a cut between T8 and T9. Lesions in the dorsolateral column of the spinal cord had little effect on the responses, while lesions of the lateral and ventrolateral columns reduced or abolished the responses. We conclude that SPL stimulation excites T1-T5 STT neurons by way of extraspinal and intraspinal pathways. SPL information is integrated with information from a variety of other visceral and somatic sources. SPL input to cells with somatic fields in the chest region may explain the clinical phenomenon of chest pain associated with abdominal disorders.

Animals↗
PubMed1991

Two genetically and molecularly distinct functions involved in early neurogenesis reside within the Enhancer of split locus of Drosophila melanogaster.

Molecular correlation of the genetic aspects of the function of the neurogenic gene Enhancer of split [E(spl)] has previously been hampered by the densely transcribed nature of the chromosomal region within which it resides. We present data indicating that two distinct molecular species contribute to E(spl) function. Analysis of new E(spl) alleles has allowed us to define two complementing functions within the locus. Subsequent phenotypic analysis of different E(spl) deficiencies combined with P element-transformed constructs has demonstrated that these two functions correspond to: (1) a family of helix-loop-helix (HLH) protein-encoding genes and (2) the single copy gene E(spl) m9/10, whose product shares homology with G-protein beta subunits. The zygotically active E(spl) HLH genes can, at least partially, substitute for one another's functions and their total copy number determines the activity of the locus. E(spl) m9/10 acts synergistically with the E(spl) HLH genes and other neurogenic genes in the process of neurogenesis. The maternal component of E(spl) m9/10 has the most pronounced effect in neurogenesis, while its zygotic component is predominantly required during postembryonic development. The lethality of trans-heterozygotes of null E(spl) deficiency alleles with a strong Delta point mutation is a result of the concomitant reduction in activity of both E(spl) HLH and m9/10 functions. Immunocytochemical localization of the E(spl) m9/10 protein has revealed that it is a ubiquitously distributed nuclear component in embryonic, larval and imaginal tissues.

Alleles↗
PubMed1999

Testosterone increases the number of substance P-like immunoreactive neurons in a specific sub-division of the lateral hypothalamus of the weakly electric, brown ghost knifefish, Apteronotus leptorhynchus.

During spawning, male and female brown ghost knife fish modulate their electric organ discharge to produce discrete courtship signals known as chirps. However, non-spawning fish show clear sex differences in chirp responsiveness to electrosensory stimuli; males consistently chirp, whereas females do not. This behavioral dimorphism is paralleled by sex differences in substance P-like immunoreactivity (SPl-ir) in the prepacemaker nucleus (PPn) which regulates chirping. The PPn is densely innervated by SPl-ir fibers in males, but not in females. However, we have shown that both female chirping behavior and the expression of SPl-ir in the PPn are enhanced following adult testosterone treatment [J.G. Dulka, L. Maler, W. Ellis, Androgen-induced changes in electrocommunicatory behavior are correlated with changes in substance P-like immunoreactivity in the brain of the electric fish, Apteronotus leptorhynchus, J. Neurosci. 15 (1995) 1879-1890]. Thus, testosterone-induced changes in SPl-ir input to the PPn may modulate female chirping during spawning. Recent evidence suggests that SPl-ir projections to the PPn may originate from SPl-ir neurons in the lateral hypothalamus (Hl). If so, one might expect to see a greater number of SPl-ir neurons in the Hl of testosterone-implanted females compared to Blank-implanted controls. In making this comparison, we found that both groups of females had similar numbers of SPl-ir neurons in the anterior Hl, but that testosterone-implanted females had significantly (p<0.01) more SPl-ir neurons in a distinct part of the posterior Hl. This sub-population of testosterone-sensitive, SPl-ir neurons may contribute to the regulation of chirping, since an increase in their number is positively correlated with the appearance of SPl-ir fibers in the PPn [J.G. Dulka, L. Maler, W. Ellis, Androgen-induced changes in electrocommunicatory behavior are correlated with changes in substance P-like immunoreactivity in the brain of the electric fish, Apteronotus leptorhynchus, J. Neurosci. 15 (1995) 1879-1890].

Animals↗
PubMed2006

Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer.

Sphingolipid metabolites such as sphingosine-1-phosphate (S1P) and ceramide modulate apoptosis during development and in response to stress. In general, ceramide promotes apoptosis, whereas S1P stimulates cell proliferation and protects against apoptosis. S1P is irreversibly degraded by the enzyme S1P lyase (SPL). In this study, we show a crucial role for SPL in mediating cellular responses to stress. SPL expression in HEK293 cells potentiated apoptosis in response to stressful stimuli including DNA damage. This effect seemed to be independent of ceramide generation but required SPL enzymatic activity and the actions of p38 MAP kinase, p53, p53-inducible death domain protein (PIDD), and caspase-2 as shown by molecular and chemical inhibition of each of these targets. Further, SPL expression led to constitutive activation of p38. Endogenous SPL expression was induced by DNA damage in WT cells, whereas SPL knockdown diminished apoptotic responses. Importantly, SPL expression was significantly down-regulated in human colon cancer tissues in comparison with normal adjacent tissues, as determined by quantitative real-time PCR (Q-PCR) and immunohistochemical analysis. Down-regulation of S1P phosphatases was also observed, suggesting that colon cancer cells manifest a block in S1P catabolism. In addition, SPL expression and activity were down-regulated in adenomatous lesions of the Min mouse model of intestinal tumorigenesis. Taken together, these results indicate that endogenous SPL may play a physiological role in stress-induced apoptosis and provide an example of altered SPL expression in a human tumor. Our findings suggest that genetic or epigenetic changes affecting intestinal S1P metabolism may correlate with and potentially contribute to carcinogenesis.

Aldehyde-Lyases↗
PubMed2003

An investigation of input level range for the nucleus 24 cochlear implant system: speech perception performance, program preference, and loudness comfort ratings.

OBJECTIVE: Cochlear implant recipients often have limited access to lower level speech sounds. In this study we evaluated the effects of varying the input range characteristics of the Nucleus 24 cochlear implant system on recognition of vowels, consonants, and sentences in noise and on listening in everyday life. DESIGN: Twelve subjects participated in the study that was divided into two parts. In Part 1 subjects used speech processor (Nucleus 24 SPrint trade mark ) programs adjusted for three input sensitivity settings: a standard or default microphone sensitivity setting (MS 8), a setting that increased the input sensitivity by 10.5 dB (MS 15), and the same setting that increased input sensitivity but also incorporated the automatic sensitivity control (ASC; i.e., MS 15A) that is designed to reduce the loudness of noise. The default instantaneous input dynamic range (IIDR) of 30 dB was used in these programs (i.e., base level of 4; BL 4). Subjects were tested using each sensitivity program with vowels and consonants presented at very low to casual conversational levels of 40 dB SPL and 55 dB SPL, respectively. They were also tested with sentences presented at a raised level of 65 dB SPL in multi-talker babble at individually determined signal to noise ratios. In addition, subjects were given experience outside of the laboratory for several weeks. They were asked to complete a questionnaire where they compared the programs in different listening situations as well as the loudness of environmental sounds, and state the setting they preferred overall. In Part 2 of the study, subjects used two programs. The first program was their preferred sensitivity program from Part 1 that had an IIDR of 30 dB (BL 4). Seven subjects used MS 8 and four used MS 15, and one used the noise reduction program MS 15A. The second program used the same microphone sensitivity but had the IIDR extended by an additional 8 to 10 dB (BL 1/0). These two programs were evaluated similarly in the speech laboratory and with take-home experience as in Part 1. RESULTS PART 1: Increasing the microphone input sensitivity by 10.5 dB (from MS 8 to MS 15) significantly improved the perception of vowels and consonants at 40 and 55 dB SPL. The group mean improvement in vowel scores was 25 percentage points at 40 dB SPL and 4 percentage points at 55 dB SPL. The group mean improvement for consonants was 23 percentage points at 40 dB SPL and 11 percentage points at 55 dB SPL. Increased input sensitivity did not significantly reduce the perception of sentences presented at 65 dB SPL in babble despite the fact that speech peaks were then within the compressed range above the SPrint processor's automatic gain control (AGC) knee-point. Although there was a demonstrable advantage for perception of low-level speech with the higher input sensitivity (MS 15 and 15A), seven of the 12 subjects preferred MS 8, four preferred MS 15 or 15A, and one had no preference overall. Approximately half the subjects preferred MS 8 across the 18 listening situations, whereas an average of two subjects preferred MS 15 or 15A. The increased microphone sensitivity of MS 15 substantially increased the loudness of environmental sounds. However, use of the ASC noise reduction setting with MS 15 reduced the loudness of environmental sounds to equal or below that for MS 8. RESULTS PART 2: The increased instantaneous input range gave some improvement (8 to 9 percentage points for the 40 dB SPL presentation level) in the perception of consonants. There was no statistically significant increase in vowel scores. Mean scores for sentences presented at 65 dB SPL in babble were significantly lower (5 percentage points) for the increased IIDR setting. Subjects had no preference for the increased IIDR over the default. The IIDR setting had no effect on the loudness of environmental sounds. CONCLUSIONS: Given the fact that individuals differ in threshold (T) and comfort (C) levels for electrical stimulation, and preferred microphone sensitivity, volume control, and noise-reduction settings, it is essential for the clinicid recipient to determine what combination is best for the individual over several sessions. The results of this study clearly show the advantage of using higher microphone sensitivity settings than the default MS 8 to provide better speech recognition for low-level stimuli. However, it was also necessary to adjust other parameters such as map C levels, automatic sensitivity control and base level, to optimize loudness comfort in the diversity of listening situations an individual encounters in everyday life.

Auditory Threshold↗
PubMed2004

Recognition of speech presented at soft to loud levels by adult cochlear implant recipients of three cochlear implant systems.

OBJECTIVE: The purpose of this study was to conduct a large-scale investigation with adult recipients of the Clarion, Med-El, and Nucleus cochlear implant systems to (1) determine average scores and ranges of performance for word and sentence stimuli presented at three intensity levels (70, 60, and 50 dB SPL); (2) provide information on the variability of scores for each subject by obtaining test-retest measures for all test conditions; and (3) further evaluate the potential use of lower speech presentation levels (i.e., 60 and/or 50 dB SPL) in cochlear implant candidacy assessment. DESIGN: Seventy-eight adult cochlear implant recipients, 26 with each of the three cochlear implant systems, participated in the study. To ensure that the data collected reflect the range of performance of adult recipients using recent technology for the three implant systems (Clarion HiFocus I or II, Med-El Combi 40+, Nucleus 24M or 24R), a composite range and distribution of consonant-nucleus-consonant (CNC) monosyllabic word scores was determined. Subjects using each device were selected to closely represent this range and distribution of CNC performance. During test sessions, subjects were administered the Hearing in Noise Test (HINT) sentence test and the CNC word test at three presentation levels (70, 60, and 50 dB SPL). HINT sentences also were administered at 60 dB SPL with a signal-to-noise ratio (SNR) of +8 dB. Warble tones were used to determine sound-field threshold levels from 250 to 4000 Hz. Test-retest measures were obtained for each of the speech recognition tests as well as for warble-tone sound-field thresholds. RESULTS: Cochlear implant recipients using the Clarion, Med-El, or Nucleus devices performed on average equally as well at 60 compared with 70 dB SPL when listening for words and sentences. Additionally, subjects had substantial open-set speech perception performance at the softer level of 50 dB SPL for the same stimuli; however, subjects' ability to understand speech was poorer when listening in noise to signals of greater intensity (60 dB SPL + 8 SNR) than when listening to signals presented at a soft presentation level (50 dB SPL) in quiet. A significant correlation was found between sound-field thresholds and speech recognition scores for presentation levels below 70 dB SPL. The results demonstrated a high test-retest reliability with cochlear implant users for these presentation levels and stimuli. Average sound-field thresholds were between 24 and 29 dB HL for frequencies of 250 to 4000 Hz, and results across sessions were essentially the same. CONCLUSIONS: Speech perception measures used with cochlear implant candidates and recipients should reflect the listening challenges that individuals encounter in natural communication situations. These data provide the basis for recommending new candidacy criteria based on speech recognition tests presented at 60 and/or 50 dB SPL, intensity levels that reflect real-life listening, rather than 70 dB SPL.

Adult↗
PubMed2001

Molecular characterization of a novel Staphylococcus aureus serine protease operon.

The present study identified and characterized a unique operon (spl) encoding six serine protease-like proteins. In addition, native Spl proteins were isolated and characterized. Typical of most exoproteins, the spl gene products contain putative 35- or 36-amino-acid signal peptides. The Spl proteins share 44 to 95% amino acid sequence identity with each other and 33 to 36% sequence identity with V8 protease. They also contain amino acids found in catalytic triads of enzymes in the trypsin-like serine protease family, and SplB and SplC were shown to degrade casein. The spl operon is transcribed on a 5.5-kb transcript, but several nonrandom degradation products of this transcript were also identified. Similar to other S. aureus exoprotein genes, the spl operon is maximally expressed during the transition into stationary phase and is positively controlled by the Agr virulence factor regulator. The Sar regulatory system did not affect spl operon expression. PCR analysis revealed the presence of the spl operon in 64% of the S. aureus isolates tested, although one spl operon-negative isolate was shown to contain at least two of the spl genes. Finally, intraperitoneal injection of an spl operon deletion mutant revealed no major differences in virulence compared to the parental strain.

Amino Acid Sequence↗
PubMed1990

Distinct accessory cell requirements define two types of rat T cell hybridomas specific for unique determinants in the encephalitogenic 68-86 region of myelin basic protein.

Six clonotypically unique T cell hybridomas from Lewis rats were used to study accessory cell activities required for class II MHC restricted T cell responses to the 68-86 encephalitogenic sequence of myelin basic protein (MBP). T cell hybrids which were cultured with GP68-86 68-86 sequence of guinea pig MBP (GPMBP) and naive splenocytes (SPL) were induced to produce IL-2 as measured by the CTLL indicator cell line. The hybrids were categorized into two subsets (designated THYB-1 and THYB-2), because two distinct subset-specific pathways of communication between accessory cells and T cells were involved in GPMBP-induced IL-2 production. These pathways were distinguished by the following six observations. First, when the duration of a pulse of SPL with GPMBP was lengthened from 1 to 4 h, these SPL lost their ability to induce IL-2 production by THYB-2 hybrids yet nevertheless retained full stimulatory activity for THYB-1 hybrids. Second, paraformaldehyde fixation of GPMBP-pulsed SPL abrogated an activity necessary for Ag-induced IL-2 production by THYB-2 hybrids. These fixed SPL were nevertheless able to stimulate THYB-1 hybrids, albeit to a lesser extent than viable unfixed SPL. Third, the addition of either cycloheximide, cytochalasin B, or 2-deoxyglucose to an Ag pulse of SPL with GPMBP dramatically inhibited the subsequent responses of THYB-2 hybrids yet had little or no effect upon the reactivity of THYB-1 hybrids. Fourth, thymocytes lacked necessary activities for GPMBP evoked IL-2 production by THYB-2 hybrids yet strongly promoted THYB-1 hybrid responses. Fifth, exposure of SPL to as little as 500 rad of gamma-irradiation markedly attenuated THYB-2 hybrid response to GPMBP but did not affect THYB-1 responses. Sixth, anti-GPMBP responses by THYB-2 hybrids were observed only in the presence of both radioresistant adherent SPL and a distinct population of radiosensitive nonadherent SPL. Conversely, THYB-1 hybrids exhibited full reactivity to GPMBP in the presence of adherent radioresistant SPL. Together, these observations reveal that two distinct accessory cell-T cell pathways mediate immune recognition of the 68-86 encephalitogenic region of MBP. Furthermore, these results indicate that subsets of Th cells can be defined by the accessory cell type-specific interactions that are necessary for Ag-mediated responses.

Animals↗
PubMed1991

Impact of splenectomy on survival following gastrectomy for adenocarcinoma.

From 1972 to 1985, 161 palliative and 99 curative gastrectomies were performed, including splenectomy (SPL), in 49 and 42 patients, respectively. The relative contribution of tumor histology and location of primary tumor within the stomach to median survival times in months (MST) was examined by chi-square analysis for patients who had SPL and those who did not. MST for the 40 patients treated by curative gastrectomy and SPL was 33 months compared with 43.5 months in the 56 patients treated by curative gastrectomy without SPL (P = .24). Three postoperative deaths were excluded from this analysis. Neither tumor location nor the histological type had a statistically significant impact on MST within these two groups. SPL was not found to have statistically significant impact on survival following curative gastrectomy. In 46 patients treated by palliative gastrectomy with SPL the MST was 10.5 months compared with 15.5 months in 110 patients who were treated by palliative gastrectomy without SPL (P = .007). Five postoperative deaths and three patients in which primary tumor location could not be accurately determined were excluded from this analysis. The MST of 23 patients treated by SPL who had poor or undifferentiated histology was 8 months, compared with 15 months in 73 patients with similar histology not treated by SPL (P = .02). There was no statistically significant difference in MST between palliative gastrectomy patients who had well or moderately differentiated histology treated with (n = 23) and without (n = 37) SPL (P = .11). The impact of SPL on MST following palliative gastrectomy was not significantly influenced by tumor location in the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1998

Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast.

Sphingosine-1-phosphate (S-1-P) has been shown to participate in the proliferative signal transduction pathways of mammalian cells. Sphingosine-1-phosphate lyase (SPL) catalyzes the breakdown of S-1-P. Using the C. elegans SPL nucleotide sequence, we identified a mouse EST as a putative candidate for the homologous gene encoding this enzyme. Sequencing of the mouse EST revealed an open reading frame of 1707 nucleotides. This putative mouse SPL gene is 62% similar and 39% identical to the C. elegans SPL gene and 59% homologous and 39.6% identical to the yeast SPL gene. Expression of the mouse SPL gene in a yeast strain-delta bst1, which carries a deletion of the SPL gene and is hypersensitive to sphingosine, restored a sphingosine-resistant phenotype, suggesting this mouse gene can functionally complement the yeast defect when expressed. In vitro enzyme assay using extracts from these sphingosine-resistant transformants confirmed the SPL activities encoded by this mouse cDNA clone. Northern analysis indicated the mouse SPL gene is expressed at various levels in different tissues. Chromosomal localization mapped this SPL gene to Chromosome 10 at 32 cM. Here, we report the identification of the first mammalian sphingosine phosphate lyase gene.

Aldehyde-Lyases↗
PubMed2006

Differentiated hemodynamic changes controlled by splanchnic nerve.

The splanchnic (SPL) nerve is a postganglionic sympathetic nerve involved in the tonic regulation of the cardiovascular system. Electrical stimulation of this nerve produces mesenteric vasoconstriction and it has been assumed that vasodilatory responses are dependent on inhibition of the vasoconstrictor tone. Several different central stimuli have been shown to dilate the hindquarter vascular bed and constrict the mesenteric vascular bed. To determine whether vasodilatory and vasoconstrictor effects in different vascular beds are elicited by activation of different sympathetic nerves, we investigated the hemodynamic changes in hindquarter, mesenteric and renal vascular beds evoked by electrical stimulation of the SPL nerve. Stimulation of the intact or sectioned SPL nerve in chloralose-anesthetized, artificially ventilated rats evoked increases in the hindquarter vascular conductance and simultaneously decreased the mesenteric and renal vascular conductance. Intravenous (i.v.) administration of L-NAME prior to stimulation of the proximal end of the sectioned SPL nerve abolished the increase in hindquarter conductance, suggesting the involvement of nitric oxide in this response. In assessing the hemodynamic effects of tonic activity on the SPL nerves, no significant changes were observed after unilateral section of the SPL nerve, but bilateral section of the SPL nerves decreased hindquarter conductance and did not significantly change the mesenteric conductance simultaneously. No consistent response was observed in the renal vascular bed after unilateral and subsequent contralateral section of the SPL nerves. These findings demonstrate that electrical stimulation of the SPL nerve produces mesenteric vasoconstriction and simultaneous hindquarter vasodilatation, which is mediated by nitric oxide. Moreover, the present data suggest that SPL nerves may provide a tonic vasodilatory tone in the hindquarter vascular bed and simultaneously a vasoconstrictor tone in another, undetermined vascular bed.

Analysis of Variance↗
PubMed2026

Stretched penile length in boys with hypospadias: Population-based analysis using validated nomogram.

BACKGROUND: Hypospadias affects 1 in 200-300 male births. Parents are often concerned about penile adequacy beyond the urethral defect itself, yet few studies have systematically compared stretched penile length (SPL) in hypospadias against population-based reference standards. OBJECTIVE: To evaluate SPL distribution patterns in boys with Types I and II hypospadias and compare them with established normative data. METHODS: The authors studied 876 consecutive boys aged 1-14 years with unoperated Types I (distal) and II (mid-shaft) hypospadias. Two observers independently measured SPL using the validated SPLINT technique. The SPL measurements were compared against age-matched normative data from 1276 Indian children. Exact binomial probability tests were used for percentile distributions, chi-square tests for subtype comparisons and t-tests for mean deviations. RESULTS: The cohort included 479 Type I and 397 Type II cases. SPL distribution showed a marked leftward shift: 71% fell below the 50th percentile (expected 50%, p < 0.001) and 41.5% below the 25th percentile. Lower percentiles were overrepresented, 20.7% were below the 10th percentile and 20.8% in the 10th-25th range. Upper percentiles were depleted: only 7.4% in the 75th-90th range and 1.7% above the 90th percentile (all p < 0.001). Mean SPL was reduced by 6.8% (95% CI: -8.18 to -5.42%) in Type I and 7.5% (95% CI: -9.05 to -5.92%) in Type II. The two subtypes showed no significant distributional difference (&#x3c7;2 = 6.22, p = 0.18), suggesting that meatal position does not predict SPL reduction. CONCLUSIONS: Boys with distal and mid-shaft hypospadias show clinically meaningful SPL reduction that follows a continuous distribution rather than an all-or-none pattern. SPL reduction appears independent of meatal position. These findings support routine SPL assessment using population-specific references and can guide preoperative counselling.

Humans↗
PubMed1996

Acylation of pulmonary surfactant protein-C is required for its optimal surface active interactions with phospholipids.

This study investigates the importance of thioester-linked acyl groups in lung surfactant protein C (SP-C) in facilitating interactions with phospholipids that yield functionally important surface active behaviors. Native SP-C, palmitoylated at cysteine residues at positions 5 and 6, was isolated from bovine lung surfactant by liquid chromatography. Deacylated SP-C (dSP-C), unchanged in composition and sequence from SP-C but having a decreased alpha-helical content in films with dipalmitoyl phosphatidylcholine (DPPC) of 52 versus 70%, was obtained by treatment with 0.1 M sodium carbonate buffer at pH 10. Surface activity was studied for SP-C and dSP-C combined with column-purified phospholipids (PPL) from calf lung surfactant or with synthetic phospholipids (DPPC or a synthetic phospholipid mixture (SPL) containing 50:35:15, DPPC:egg phosphatidylcholine:egg phosphatidylglycerol). Interfacial measurements included surface pressure time adsorption isotherms for dispersed surfactants with diffusion minimized, dynamic surface pressure area isotherms and respreading for films in the Wilhelmy balance, and overall surface tension lowering at physiologic cycling rate in oscillating bubble experiments. Dispersions of PPL:SP-C and SPL:SP-C rapidly adsorbed to high equilibrium surface pressures of 47-48 mN/m, significantly better than corresponding dispersions containing dSP-C. The adsorption of PPL:dSP-C was essentially unchanged from that of PPL alone, and the adsorption of SPL:dSP-C was improved only slightly over SPL alone. In Wilhelmy balance studies, dynamic respreading was significantly improved over phospholipids alone in films of SP-C plus PPL, SPL, or DPPC. Respreading was improved less markedly by dSP-C in corresponding films with SPL or DPPC and not at all in films with PPL. Maximum surface pressures were also higher in cycled films of SP-C versus dSP-C combined with PPL or SPL. In bubble experiments (37 degrees C, 20 cycles/min), dispersions of PPL:SP-C and SPL:SP-C reached low minimum surface tensions of <1 and 5 mN/m, respectively, whereas PPL:dSP-C and SPL:dSP-C only reached minima of approximately 20 mN/m as did PPL and SPL alone. Acylation in SP-C is crucial for its interactions with phospholipids over the full spectrum of adsorption and dynamic surface behaviors important for lung surfactant.

Acylation↗
PubMed2002

Comparative study and effects of macrophage colony-stimulating factor (M-CSF) administration on NK1.1+ cells in mouse spleen and bone marrow.

We conducted a comparative study of NK1.1+ cells in spleen and bone marrow and the effects of administration of M-CSF on them. Administration of M-CSF to mice increased the number of NK1.1+ cells in spleen but not in bone marrow. The NK1.1+ cells in spleen (Spl-NK1.1) and bone marrow (BM-NK1.1) were purified by magnetic cell sorter. Their cell surface markers and functions were then examined. The percentage of Mac-1 antigen-positive cells (and F4/80 antigen-positive cells) was higher among BM-NK1.1 than Spl-NK1.1. Moreover, the administration of M-CSF increased the number of Mac-1 and F4/80 antigen-positive cells in both Spl-Nk1.1 and BM-NK1.1. The functions (cytolytic activity and IFN-gamma production) of Spl-NK1.1 and BM-NK1.1 were the same and were enhanced by the administration of M-CSF. But Spl-NK1.1 produced more IFN-gamma than BM-NK1.1 when M-CSF was administered. BM-NK1.1 showed a greater proliferative response to IL-2 than Spl-NK1.1. Administration of M-CSF augmented this response. BM-NK1.1 proliferated in response to IL-4 and IL-15, but Spl-NK1.1 responded only slightly. However, administration of M-CSF stimulated Spl-NK1.1 to respond to these cytokines. Both Spl-NK1.1 and BM-NK1.1 showed only a weak response to M-CSF in vitro. But the expression of c-fms antigen (M-CSFR) increased after the M-CSF injections in vivo. These results suggested that there are phenotypical and functional differences between Spl-NK1.1 and BM-NK1.1. The administration of M-CSF led to an accumulation of NK1.1+ cells which were mobilized from bone marrow in spleen.

Animals↗