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At least 343 records · Page 19Linked to original sources

PubMed2000

Delayed graft function influences renal function, but not survival.

BACKGROUND: In renal transplantation, the impact of delayed graft function (DGF) on prognosis is controversial. We analyzed the risk factors of DGF and its impact on graft function and prognosis. METHODS: Seven hundred thirty-four cadaveric renal transplants performed between 1983 and 1997 were analyzed. DGF was diagnosed when serum creatinine levels increased, remained unchanged, or decreased less than 10% per day in three consecutive days in the first week after transplantation. Creatinine clearances of more or less than 50 or 30 mL/min at one year were used as cut-off points for optimal and suboptimal graft function, respectively. The logistic regression model was used to identify independent risk factor related to DGF and renal function one year after transplantation. The Cox regression model was used to examine the influence of DGF on long-term graft survival. RESULTS: Multivariate analysis revealed the following risk factors for DGF: recipient pretransplantation mean arterial blood pressure of less than 100 mm Hg (OR = 2.08, 95% CI, 1.43 to 3.03), female donor to male recipient combination (OR = 1.55, 95% CI, 1.02 to 2.35), donor age of more than 50 years (OR = 2.21, 95% CI, 1.49 to 3.26), cold ischemia time of more than 28 hours (OR = 1.78, 95% CI, 1.19 to 2.63), and peak panel reactive antibodies of more than 50% (OR = 1.7, 95% CI, 1.15 to 2.55). The incidence of DGF was one of the independent risk factors for suboptimal graft function at one year (OR = 1.68, 95% CI, 1.14 to 2.48), together with donor age of more than 50 years (OR = 2.39, 95% CI, 1.61 to 3.57), female donor gender (OR = 1.99, 95% CI, 1.42 to 2.78), the occurrence of acute rejection episodes (OR = 2.66, 95% CI, 1.87 to 3.78), peak panel-reactive antibodies of more than 50% (OR = 1.67, 95% CI, 1.15 to 2.47), and sharing of 1 to 3 versus 4 to 8 cross-reactive antigens groups (OR = 1.65, 95% CI, 1.09 to 2. 49). Moreover, DGF was one of the two independent risk factors for acute rejection episodes, but it had no independent effect on graft survival. CONCLUSION: Several risk factors for DGF were identified, of which a low recipient pretransplant mean arterial blood pressure, the transplantation of kidneys from female donors to male recipients, and a prolonged cold ischemia time are potentially avoidable. Although DGF is one of the several risk factors of acute rejection and suboptimal function at one year, it is not independently associated with an increased rate of graft loss.

Acute Disease↗

PubMed2004

Tooth loss and caries prevalence in very old Swedish people: the relationship to cognitive function and functional ability.

OBJECTIVE: To analyse whether cognitive function and functional ability are related to oral health among community-dwelling older people over the age of 80 years. BACKGROUND: This cross-sectional study is based on the Kungsholmen Elders Oral Health Survey (KEOHS). The study included oral examinations carried out in two local clinics by standardised examiners and interviews using structured questionnaires. MATERIALS AND METHODS: Altogether 159 individuals were included in this study. Coronal caries and root caries were assessed using the National Institute of Dental and Craniofacial Research (NIDCR) diagnostic criteria. Cognitive function was assessed by the Mini-Mental State Examination (MMSE) index and functional ability was assessed by a global measure of self-reported changes. RESULTS: Older adults with a low MMSE score (< or = 23) tended to have a higher risk of coronal caries than those with higher scores. Participants with mild cognitive decline (MMSE = 24-26) and with a decrease in functional ability had a significantly higher risk of root caries. These associations changed little when adjusted by the covariates. In addition, people with a low MMSE (0-23) had a four times higher risk of not using dental services regularly. This result was unchanged after adjusting for the variables studied. CONCLUSIONS: This study revealed associations between the cognitive and functional status of the individual and aspects of oral health, that may contribute to a deeper understanding of the background of oral health status in older adults.

Activities of Daily Living↗

PubMed2002

Assessing functional status: exploring the relationship between the multiple sclerosis functional composite and driving.

OBJECTIVE: To explore the relationship between the Multiple Sclerosis Functional Composite (MSFC), which is comprised of 3 clinical dimensions (arm and hand function, leg function and ambulation, cognition), and an everyday functional skill, driving performance. DESIGN: Cohort study. SETTING: Medical rehabilitation research organization. PARTICIPANTS: Twenty-nine individuals with documented multiple sclerosis (MS) and limited motor decrements. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Driving-related skills were measured by using the overall category rating from the Useful Field of View (UFOV) Test, its 3 subtests, the error and latency scores from the Neurocognitive Driving Test (NDT), subjective (self-report) and objective (Department of Motor Vehicles [DMV] reports) reported driving experience, and number of motor vehicle crashes. Within the group, differences were explored between participants rated as low risk versus moderate-high risk on the UFOV overall score and between participants who reported a change in driving habits after MS versus those who reported no change. RESULTS: The overall MSFC score correlated significantly with the UFOV overall score, the visual-information processing and selective attention subtests of the UFOV, the NDT latency score, as well as with the number of days a week the individual drove and the number of crashes reported by the DMV. An examination of the MSFC components revealed that the cognition component was significantly related to the UFOV overall score, all 3 subtests of the UFOV, and the NDT latency score. The arm and hand function component correlated significantly with NDT latency and the selective attention subtest of the UFOV. Individuals classified as low risk on the UFOV overall had more education, better MSFC scores, and lower NDT latency scores. Only the overall MSFC score distinguished those who reported a change in driving habits after onset of MS. CONCLUSIONS: Problems with everyday functional skills such as driving are accurately identified through the use of the overall MSFC and its components.

Adult↗

PubMed2005

Density-functional theory and Monte Carlo simulation for the surface structure and correlation functions of freely jointed Lennard-Jones polymeric fluids.

We present a nonlocal density-functional theory of polymeric fluids consisting of freely jointed Lennard-Jones chains with explicit consideration of the segment size, van der Waals attraction, and structural correlations due to chain connectivity. The excess Helmholtz energy functional is derived from a modified fundamental measure theory for the short-ranged repulsion and the first-order thermodynamic perturbation theory for chain connectivity. The contribution of the long-ranged attraction to the Helmholtz energy functional is taken into account using a quadratic density expansion with the direct correlation function obtained from the first-order mean-spherical approximation. The numerical performance of the density-functional theory is compared well with the simulation results from this work as well as those from the literature for the segment-level density profiles and correlation functions of Lennard-Jones chains in slit pores, near isolated nanoparticles, or in bulk.

Journal Article↗

PubMedDate not supplied

Carvedilol improves left ventricular function in heart failure patients with idiopathic dilated cardiomyopathy and a wide range of sympathetic nervous system function as measured by iodine 123 metaiodobenzylguanidine.

BACKGROUND: Carvedilol treatment reduces the mortality rate in patients with congestive heart failure. It is not known whether carvedilol treatment is effective in heart failure patients with substantial cardiac sympathetic nerve dysfunction. The goal of this study was to determine the effect of chronic carvedilol treatment in patients with cardiac sympathetic nerve dysfunction of varying severity. METHODS AND RESULTS: In 22 congestive heart failure patients with idiopathic cardiomyopathy, sympathetic nerve function was assessed before and after 7.2 +/- 2.7 months of carvedilol treatment with the use of iodine 123 metaiodobenzylguanidine (MIBG) imaging, radionuclide ventriculography, and transmyocardial norepinephrine sampling. Patients with relatively advanced impairment of cardiac sympathetic nerve function, as manifested by a baseline I-123 MIBG ratio lower than 1.40, had a statistically significant improvement in I-123 heart-mediastinum ratio with carvedilol treatment, from 1.26 +/- 0.12 to 1.39 +/- 0.20 (P =.004). Of 10 patients with a baseline I-123 MIBG ratio lower than 1.40, 9 had an increase in the heart-mediastinum ratio with carvedilol treatment. Left ventricular ejection fraction increased from 25.4% +/- 7.8% to 37.3% +/- 14.7% (P <.001), with no difference between patients with relatively advanced versus relatively preserved cardiac sympathetic nerve function. CONCLUSION: Most patients with congestive heart failure show a favorable response in left ventricular function to carvedilol treatment, regardless of the baseline level of cardiac sympathetic nervous system function, as assessed by neuronal imaging with I-123 MIBG. Patients with relatively advanced impairment of baseline I-123 MIBG uptake are most likely to show evidence of improved cardiac sympathetic nervous system function in response to carvedilol therapy.

3-Iodobenzylguanidine↗

PubMed2003

Hypergeometric generating functions for values of Dirichlet and other L functions.

Although there is vast literature on the values of L functions at nonpositive integers, the recent appearance of some of these values as the coefficients of specializations of knot invariants comes as a surprise. Using work of G. E. Andrews [(1981) Adv. Math. 41, 173-185; (1986) q-Series: Their Development and Application in Analysis, Combinatories, Physics, and Computer Algebra, Conference Board of the Mathematical Sciences Regional Conference Series in Mathematics 66 (Am. Math. Soc, Providence, RI); (1975) Problems and Prospects for Basic Hypergeometric Series: The Theory and Application of Special Functions (Academic, New York); and (1992) Illinois J. Math. 36, 251-274], we revisit this old subject and provide uniform and general results giving such generating functions as specializations of basic hypergeometric functions. For example, we obtain such generating functions for all nontrivial Dirichlet L functions.

Journal Article↗

PubMed1992

Structural and functional analysis of a replication enhancer: separation of the enhancer activity from origin function by mutational dissection of the replication origin gamma of plasmid R6K.

The plasmid R6K possesses three distinct origins of replication: alpha, beta, and gamma. The replication origin gamma of plasmid R6K performs a dual function: (i) as an origin itself and (ii) as an enhancer element required in cis for the activation at a distance of the other two replication origins alpha and beta. We have dissected the gamma origin/enhancer by site-directed mutagenesis and have reached the following conclusions. The origin function can be specifically inactivated without impairing the enhancer function by insertion and/or deletion mutations near the opposite ends of the origin gamma sequence. One such mutation deleted sequences that included the left DnaA site I. The second mutation involved insertion of linker sequences that resulted in a spatial alteration between the right DnaA site II and the VIIth pi binding iteron (tandemly repeated binding sites). Other mutations that either partly or completely deleted the A+T-rich sequence adjacent to, but not including, the pi binding iterons also abrogated enhancer and origin function and suggested that pi binding sites were necessary but not sufficient for enhancer activity. Finally, the functional analysis of a set of mutants of the gamma origin/enhancer suggested that a continuous stretch of 300 base pairs is necessary for origin gamma function and that the sequences that included the binding sites for pi, DnaA, and integration host factor proteins are required in the correct stereochemical alignment to impart origin activity.

Bacterial Proteins↗

PubMed1997

Structure-function relationships of omega-conotoxin GVIA. Synthesis, structure, calcium channel binding, and functional assay of alanine-substituted analogues.

The structure-function relationships of the N-type calcium channel blocker, omega-conotoxin GVIA (GVIA), have been elucidated by structural, binding and in vitro and in vivo functional studies of alanine-substituted analogues of the native molecule. Alanine was substituted at all non-bridging positions in the sequence. In most cases the structure of the analogues in aqueous solution was shown to be native-like by 1H NMR spectroscopy. Minor conformational changes observed in some cases were characterized by two-dimensional NMR. Replacement of Lys2 and Tyr13 with Ala caused reductions in potency of more than 2 orders of magnitude in three functional assays (sympathetic nerve stimulation of rat isolated vas deferens, right atrium and mesenteric artery) and a rat brain membrane binding assay. Replacement of several other residues with Ala (particularly Arg17, Tyr22 and Lys24) resulted in significant reductions in potency (<100-fold) in the functional assays, but not the binding assay. The potencies of the analogues were strongly correlated between the different functional assays but not between the functional assays and the binding assay. Thus, the physiologically relevant assays employed in this study have shown that the high affinity of GVIA for the N-type calcium channel is the result of interactions between the channel binding site and the toxin at more sites than the previously identified Lys2 and Tyr13.

Alanine↗

PubMed1998

Delineation of the functional site of alpha-dendrotoxin. The functional topographies of dendrotoxins are different but share a conserved core with those of other Kv1 potassium channel-blocking toxins.

We identified the residues that are important for the binding of alpha-dendrotoxin (alphaDTX) to Kv1 potassium channels on rat brain synaptosomal membranes, using a mutational approach based on site-directed mutagenesis and chemical synthesis. Twenty-six of its 59 residues were individually substituted by alanine. Substitutions of Lys5 and Leu9 decreased affinity more than 1000-fold, and substitutions of Arg3, Arg4, Leu6, and Ile8 by 5-30-fold. Substitution of Lys5 by norleucine or ornithine also greatly altered the binding properties of alphaDTX. All of these analogs displayed similar circular dichroism spectra as compared with the wild-type alphaDTX, indicating that none of these substitutions affect the overall conformation of the toxin. Substitutions of Ser38 and Arg46 also reduced the affinity of the toxin but, in addition, modified its dichroic properties, suggesting that these two residues play a structural role. The other residues were excluded from the recognition site because their substitutions caused no significant affinity change. Thus, the functional site of alphaDTX includes six major binding residues, all located in its N-terminal region, with Lys5 and Leu9 being the most important. Comparison of the functional site of alphaDTX with that of DTX-K, another dendrotoxin (Smith, L. A., Reid, P. F., Wang, F. C., Parcej, D. N., Schmidt, J. J., Olson, M. A., and Dolly, J. O. (1997) Biochemistry 36, 7690-7696), reveals that they only share the predominant lysine and probably a leucine residue; the additional functional residues differ from one toxin to the other. Comparison of the functional site of alphaDTX with those of structurally unrelated potassium channel-blocking toxins from venomous invertebrates revealed the common presence of a protruding key lysine with a close important hydrophobic residue (Leu, Tyr, or Phe) and few additional residues. Therefore, irrespective of their phylogenetic origin, all of these toxins may have undergone a functional convergence. The functional site of alphaDTX is topographically unrelated to the "antiprotease site" of the structurally analogous bovine pancreatic trypsin inhibitor.

Amino Acid Sequence↗

PubMed2000

Structural and functional differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenetative disease.

Tau, MAP2, and MAP4 are members of a microtubule-associated protein (MAP) family that are each expressed as "3-repeat" and "4-repeat" isoforms. These isoforms arise from tightly controlled tissue-specific and/or developmentally regulated alternative splicing of a 31-amino acid long "inter-repeat:repeat module," raising the possibility that different MAP isoforms may possess some distinct functional capabilities. Consistent with this hypothesis, regulatory mutations in the human tau gene that disrupt the normal balance between 3-repeat and 4-repeat tau isoform expression lead to a collection of neurodegenerative diseases known as FTDP-17 (fronto-temporal dementias and Parkinsonism linked to chromosome 17), which are characterized by the formation of pathological tau filaments and neuronal cell death. Unfortunately, very little is known regarding structural and functional differences between the isoforms. In our previous analyses, we focused on 4-repeat tau structure and function. Here, we investigate 3-repeat tau, generating a series of truncations, amino acid substitutions, and internal deletions and examining the functional consequences. 3-Repeat tau possesses a "core microtubule binding domain" composed of its first two repeats and the intervening inter-repeat. This observation is in marked contrast to the widely held notion that tau possesses multiple independent tubulin-binding sites aligned in sequence along the length of the protein. In addition, we observed that the carboxyl-terminal sequences downstream of the repeat region make a strong but indirect contribution to microtubule binding activity in 3-repeat tau, which is in contrast to the negligible effect of these same sequences in 4-repeat tau. Taken together with previous work, these data suggest that 3-repeat and 4-repeat tau assume complex and distinct structures that are regulated differentially, which in turn suggests that they may possess isoform-specific functional capabilities. The relevance of isoform-specific structure and function to normal tau action and the onset of neurodegenerative disease are discussed.

Alternative Splicing↗

PubMed2002

kappa-Hefutoxin1, a novel toxin from the scorpion Heterometrus fulvipes with unique structure and function. Importance of the functional diad in potassium channel selectivity.

An important and exciting challenge in the postgenomic era is to understand the functions of newly discovered proteins based on their structures. The main thrust is to find the common structural motifs that contribute to specific functions. Using this premise, here we report the purification, solution NMR, and functional characterization of a novel class of weak potassium channel toxins from the venom of the scorpion Heterometrus fulvipes. These toxins, kappa-hefutoxin1 and kappa-hefutoxin2, exhibit no homology to any known toxins. NMR studies indicate that kappa-hefutoxin1 adopts a unique three-dimensional fold of two parallel helices linked by two disulfide bridges without any beta-sheets. Based on the presence of the functional diad (Tyr(5)/Lys(19)) at a distance (6.0 +/- 1.0 A) comparable with other potassium channel toxins, we hypothesized its function as a potassium channel toxin. kappa-Hefutoxin 1 not only blocks the voltage-gated K(+)-channels, Kv1.3 and Kv1.2, but also slows the activation kinetics of Kv1.3 currents, a novel feature of kappa-hefutoxin 1, unlike other scorpion toxins, which are considered solely pore blockers. Alanine mutants (Y5A, K19A, and Y5A/K19A) failed to block the channels, indicating the importance of the functional diad.

Amino Acid Sequence↗

PubMed2004

Functional identification of three receptor activator of NF-kappa B cytoplasmic motifs mediating osteoclast differentiation and function.

Receptor activator of NF-kappa B ligand (RANKL) and its receptor activator of NF-kappa B (RANK) play pivotal roles in osteoclast differentiation and function. However, the structural determinants of the RANK that mediate osteoclast formation and function have not been definitively identified. To address this issue, we developed a chimeric receptor approach that permits a structure/function study of the RANK cytoplasmic domain in osteoclasts. Using this approach, we examined the role of six RANK putative tumor necrosis factor receptor-associated factor-binding motifs (PTM) (PTM1, ILLMT-REE(286-293); PTM2, PSQPS(349-353); PTM3, PFQEP(369-373); PTM4, VYVSQTSQE(537-545); PTM5, PVQEET(559-564); and PTM6, PVQEQG(604-609)) in osteoclast formation and function. Our data revealed that the RANK cytoplasmic domain possesses three functional motifs (PFQEP(369-373), PVQEET(559-564), and PVQEQG(604-609)) capable of mediating osteoclast formation and function. Moreover, we demonstrated that these motifs play distinct roles in activating intracellular signaling. PFQEP(369-373) initiates NF-kappa B, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 signaling pathways and PVQEET(559-564) activates NF-kappa B and p38 pathways in osteoclasts, whereas PVQEQG(604-609) is only capable of activating NF-kappa B pathway. Significantly, the revelation of these functional RANK cytoplasmic motifs has not only laid a foundation for further delineating RANK signaling pathways in osteoclasts, but, more importantly, these RANK motifs themselves represent potential therapeutic targets for bone disorders such as osteoporosis.

Amino Acid Sequence↗

PubMed1997

Correlation of functional independence measure (FIM) and SPECT Iofetamine (I-123) as a predictor of functional return in stroke.

Function following stroke is often measured using the Functional Independence Measure (FIM). Independence occurs when the patient achieves certain levels of functions. SPECT imaging assesses the regional cerebral blood flow (rCBF). Is it possible to correlate the FIM scores with SPECT imaging and predict functional return? We evaluated total of 69 stroke patients with SPECT imaging using Iofetamine (I-123). Patients were scanned within 14-21 days post-stroke. CT scans were evaluated and correlated with the SPECT images. This information was compared with the admission and discharge FIM scores. The rCBF reperfusion changes and region of stroke were evaluated and correlated with discharge functional status. The right parietal areas demonstrated a strong correlation with SPECT and FIM changes as predictors of return of functional living status (p-value = 0.0438). The right parietal area demonstrated an improvement in ambulation (p-value = 0.0578); the right brain correlated with overall improvement in FIM scores and change in SPECT imaging (p-value = 0.0833); the left brain did not exhibit significant values. Our conclusion was that there were trends seen with the predictive value of stroke recovery using SPECT imaging. The current sample number was not large enough to provide an adequate study, especially for the left brain; a larger study is needed. This information could be useful to help determine patient placement for rehabilitation.

Activities of Daily Living↗

PubMed1999

Parameters of odontostomatognathic disability: guidelines for evaluation of impaired simple and complex human functions involving the odontostomatognathic functional system.

This paper explores the current status and the future of efforts to establish parameters of disability for the odontostomatognathic functional system ("the teeth, mouth, jaws and related structures as they subserve the functions of mastication, deglutition, digestion, speech, facial expression, respiration, sexual activity, appearance and posture"). Illness, disorders, disease or injuries involving this functional system include a broad spectrum of problems that affect the dental and paradental structures. The dentist is the primary healthcare provider (HP) in the diagnosis, treatment and impairment/disability/handicap status (IDH) decisions. The authors point out that the first stage of establishing parameters of odontostomatognathic disability was accomplished with recognition in the AMA Guides to Evaluation of Permanent Impairment of the temporomandibular joint and the masticatory musculature. The second stage will be the AMA Guides publishing of an objective rating system for functional impairment of the temporomandibular joint and the masticatory musculature. Prior to the third stage of actually establishing parameters of odontostomatognathic disability, the authors suggest that multiple objectives must be accomplished, including: 1. a change in current healthcare terminology; 2. an agreement on the organization of human physiological systems; 3. medical community acceptance of the integrated structures and functions of the odontostomatognathic functional system; and 4. an appreciation of both Level I (joint and muscle dysfunction) and Level II (complex odontostomatognathic dysfunction including problems with mastication, deglutition, digestion, speech, facial expression, respiration, sexual activity, appearance and posture). The authors conclude that once these objectives are met, parameters of odontostomatognathic disability can be established.

American Medical Association↗

PubMed2004

Function and disability in late life: comparison of the Late-Life Function and Disability Instrument to the Short-Form-36 and the London Handicap Scale.

PURPOSE: We evaluated the Late-Life Function and Disability Instrument's (LLFDI) concurrent validity, comprehensiveness and precision by comparing it with the Short-Form-36 physical functioning (PF-10) and the London Handicap Scale (LHS). METHODS: We administered the LLFDI, PF-10 and LHS to 75 community-dwelling adults (> 60 years of age). We used Pearson correlation coefficients to examine concurrent validity and Rasch analysis to compare the item hierarchies, content ranges and precision of the PF-10 and LLFDI function domains, and the LHS and the LLFDI disability domains. RESULTS: LLFDI Function (lower extremity scales) and PF-10 scores were highly correlated (r = 0.74 - 0.86, p > 0.001); moderate correlations were found between the LHS and the LLFDI Disability limitation (r = 0.66, p < 0.0001) and Disability frequency (r = 0.47, p < 0.001) scores. The LLFDI had a wider range of content coverage, less ceiling effects and better relative precision across the spectrum of function and disability than the PF-10 and the LHS. The LHS had slightly more content range and precision in the lower end of the disability scale than the LLFDI. CONCLUSIONS: The LLFDI is a more comprehensive and precise instrument compared to the PF-10 and LHS for assessing function and disability in community-dwelling older adults.

Activities of Daily Living↗

PubMed1970

Studies on thymus function. I. Cooperative effect of thymic function and lymphohemopoietic cells in restoration of neonatally thymectomized mice.

Immunological restoration of 45-day old, neonatally thymectomized C3Hf mice by treatment with humoral thymic function (thymoma grafts, thymus or thymoma in diffusion chambers) ranges from 0 to 12% and is difficult to acheive. When small numbers (5-20 x 10(6)) of young adult lymphohemopoietic cells, ineffective by themselves, are given in association with humoral thymic function, a cooperative effect is observed and restoration ranges from 30 to 60%. With a particular cell dosage (20 x 10(6)), effectivity for cooperation with thymic function was the following in decreasing order: spleen, lymph nodes, thoracic duct cells, bone marrow, blood leukocytes, thymus, and Peyer's patch cells. Comparable results were obtained using spleen, thymus, and hemopoietic liver from newborn donors in association with thymic function. For similar cell dosages, newborn thymus cells were more effective than adult thymus in their cooperative effect with thymic function. Dispersed thymus cells in association with young adult bone marrow or newborn hemopoietic liver cells showed no synergism for the cooperative effect with thymic function in the present model. Using hemiallogeneic cells (F(1) hybrid into parent) it was possible to show that restoration was mediated by proliferative expansion of the injected cells. This was indicated by specific tolerance to tissues of the other parental strain and by cellular chimerism, especially of lymphoid tissues, as indicated by chromosome markers and absence of significant numbers of immunocompetent cells of host origin. A population of paritally differentiated cells of hemopoietic origin, termed postthymic, sensitive to humoral activity of the thymus and present in the lymphohemopoietic tissues of adult and newborn mice is postulated to explain our results. These cells are postthymic and thymus dependent in the sense that they already received thymic influence, probably through traffic, and are incapable of self-renewal in absence of the thymus. Sensitivity to humoral activity of the thymus is characterized by proliferative expansion and/or a differentiative process eventually leading to larger numbers of competent cells.

Animals↗

PubMed1970

Studies on thymus function. II. Cooperative effect of newborn and embryonic hemopoietic liver cells with thymus function.

Significant immunological restoration of 45-day old, neonatally thymectomized C3Hf mice was obtained by the cooperation of syngeneic newborn or embryonic hemopoietic liver cells with thymic function. Thymic function or cells alone are almost ineffective or restore approximately 10% of the animals. Newborn liver cells are effective in association with thymus grafts or humoral thymic function (thymoma grafts and thymus or thymomas in diffusion chambers). Embryonic liver cells are ineffective, even in large numbers, when associated with humoral thymic function. On the other hand, embryonic liver cells are effective in the cooperative effect only in association with viable thymus grafts, preferably syngeneic, whether the grafts were placed subcutaneously, intraperitoneally, or under the kidney capsule. Dispersed viable thymic cells are ineffective in association with embryonic liver cells. Cells capable of cooperating with humoral thymic function start to appear to embryonic liver by day 19-21 of gestation and are detectable until day 5-6 postbirth. Embryonic hemopoietic liver cells from 12 to 18 days of gestation contain cells capable of cooperation only with viable free thymus grafts and not with humoral thymic function. A prethymic cell population of partially differentiated cells of hemopoietic origin, insensitive to humoral activity of the thymus but requiring thymic stroma and traffic through the thymus is postulated to explain our results. This population of prethymic cells can become postthymic through this process and eventually develop into competent cells. Postthymic cells are characterized by their sensitivity to humoral activity of the thymus and by their wide distribution in the lymphohemopoietic tissues of newborn and young adult mice.

Animals↗

PubMed1982

In vitro effects of 4-hydroperoxycyclophosphamide on human immunoregulatory T subset function. I. Selective effects on lymphocyte function in T-B cell collaboration.

The alkylating agent cyclophosphamide may suppress or enhance immune responses in vivo but is inactive in vitro unless metabolized by microsomal enzyme activation. 4-hydroperoxycyclophosphamide (4-HC) is a synthetic compound that is spontaneously converted in aqueous solution to the active metabolites. In this report, we examined the in vitro sensitivity of functional human T cell subsets to 4-HC in a polyclonal B cell differentiation assay and in the generation of mitogen-induced suppressor cells for effector B cell function. Con A-induced T suppression of B cell differentiation is completely abrogated by a 1-h pretreatment of T cells at very low concentrations of between 10(-2) and 20 nmol/ml, whereas inducer T cell function is sensitive only to concentrations in greater than 40 nmol/ml. The effects of 4-HC on suppressor T cells appear to occur at concentrations that do not result in DNA cross-linking or decreased blastogenesis. Con A-induced T suppressors are generated from within the OKT4+, OKT8- subset and are sensitive to low-dose 4-HC only before activation, whereas differentiated suppressor cells are resistant to concentrations in greater than 80 nmol/ml. Low-dose 4-HC pretreatment of the B cell population results in abrogation of immunoglobulin secretion when treated B cells are cocultured with unfractionated T cells, however, this effect is completely reversible if pretreated B cells are cocultured with T cells devoid of suppressor activity. These results demonstrate that human presuppressor cells for B-effector function differentiate in response to Con A from the OKT4+, OKT8- subset and are exquisitely sensitive to low concentrations of CYP whereas mature suppressor and inducer functions are resistant to all but very high concentrations in vitro. The differential sensitivity of functional T and B cell subsets to 4-HC in vitro can be a very useful probe in dissecting immunoregulatory interactions with man.

B-Lymphocytes↗