Showing papers by "University of Maryland, Baltimore published in 1991"
TL;DR: It is suggested that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis and contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung, colon, oesophagus and breast.
Abstract: Human hepatocellular carcinomas (HCC) from patients in Qidong, an area of high incidence in China, in which both hepatitis B virus and aflatoxin B1 are risk factors, were analysed for mutations in p53, a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G----T transversion in seven HCC DNA samples and the G----C transversion in the other HCC are consistent with mutations caused by aflatoxin B1 in mutagenesis experiments. No mutations were found in exons 5,6,8 or the remainder of exon 7. These results contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung, colon, oesophagus and breast; these are primarily scattered over four of the five evolutionarily conserved domains, which include codon 249 (refs 4-9). We suggest that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis.
1,390 citations
TL;DR: This chapter discusses the development of follicles in the mammalian ovary, a complex, functional miniature organ arises from the handful of cells that constitute a simple primordial follicle, a structure so small that it is invisible at the lower magnifications of a light microscope.
Abstract: Publisher Summary This chapter discusses the development of follicles in the mammalian ovary. The unresolved issues in follicular development are focused. Folliculogenesis culminates in the production of fully ripe, preovulatory follicles visible to the naked eye as large bulges on the surface of the ovary. Each ripe follicle contains thousands of highly differentiated cells. This complex, functional miniature organ arises from the handful of cells that constitute a simple primordial follicle, a structure so small that it is invisible at the lower magnifications of a light microscope. All regulatory influences can only permit or prevent cells from completing the full maturation process; they cannot change the course of differentiation. A plethora of modulating influences act as permissive inducers, impeding or propelling the committed follicular cells through the process of clonal expansion. As each follicle progresses through its program of limited clonal expansion and maturation, its cells proliferate more and more rapidly. With every passing generation, the proliferative potential of the granulosa and theca cells continues to diminish, while the state of maturation increases.
1,239 citations
TL;DR: The use of a novel suicide vector containing the pir-dependent R6K replicon and the sacB gene of Bacillus subtilis to construct an eae deletion mutant of EPEC is reported, establishing the utility of a new system for the construction of deletion mutations.
Abstract: The ability to attach to epithelial cells, efface the microvillus surface, and disrupt the underlying cytoskeleton is characteristic of enteropathogenic Escherichia coli (EPEC). Recently, eae, a gene necessary for this phenomenon, was described (A. E. Jerse, J. Yu, B. D. Tall, and J. B. Kaper, Proc. Natl. Acad. Sci. USA 87:7839-7843, 1990). We report the use of a novel suicide vector containing the pir-dependent R6K replicon and the sacB gene of Bacillus subtilis to construct an eae deletion mutant of EPEC. This system enables positive selection for the loss of vector sequences. The resulting mutant, CVD206, is indistinguishable from the wild-type strain except for the loss of a 94-kDa outer membrane protein and attaching and effacing ability. Both the 94-kDa outer membrane protein and attaching and effacing ability are restored upon reintroduction of the eae gene on a plasmid. These results confirm the role of the eae gene in the attaching and effacing activity of EPEC and establish the utility of a new system for the construction of deletion mutations.
1,095 citations
TL;DR: Direct evidence is reported for direct evidence that antigen-induced proliferation of B cells at another site, periarteriolar lymphocyte sheath-associated foci, was not associated with somatic hypermutation, and most represent cells of distinct B-cell clones which expanded locally, generating somatic antibody mutants at high rate.
Abstract: The generation and selection of somatic antibody mutants are key elements of acquired immunity, essential for the affinity maturation of antibody responses dependent on T cells. The mutants are generated through a mechanism that introduces point mutations at high rate into rearranged variable (V) region genes in the course of cell proliferation. Their appearance coincides with the generation of germinal centres, which are characterized by oligoclonal B-cell proliferation and have been suggested to be the microenvironment in which antibody mutants are generated. We report here direct evidence for this hypothesis. Rearranged V-region genes were amplified from the genomic DNA of cells picked from individual germinal centres. The sequence analysis of these genes revealed that most represent cells of distinct B-cell clones which expanded locally, generating somatic antibody mutants at high rate. By contrast, antigen-induced proliferation of B cells at another site, periarteriolar lymphocyte sheath-associated foci, was not associated with somatic hypermutation.
1,076 citations
Journal Article•
TL;DR: The data suggest that Th1- and Th2-associated lymphokines may be differentially sensitive to intracellular signals such as cAMP, and that PGE2 may play an important role in regulating the development of a response dominated by Th0 cells, with different signaling pathways.
Abstract: PGE2 is known to inhibit IL-2 and IFN-gamma production from Th cells and is widely viewed as a general immunosuppressant. However, PGE2 was found not to inhibit IL-4 production from Th2 clones, and IL-5 production from these clones was slightly enhanced. The same results were obtained with short term T cell lines, which indicates that the lack of inhibition of IL-4 and IL-5 production by PGE2 is a general phenomenon. PGE2 functions by increasing cAMP levels through activation of adenylate cyclase. Despite its failure to inhibit lymphokine release, PGE2 was capable of increasing cAMP levels in Th2 cells, and forskolin, a direct activator of adenylate cyclase, also did not inhibit IL-4 or IL-5 production. These data indicate that the failure of PGE2 to inhibit IL-4 and IL-5 production was not due to an inability of PGE2 to induce an increase in intracellular cAMP, and suggested instead that the expression of IL-4 and IL-5 in Th2 cells is insensitive to elevated cAMP levels. When Th0 clones were examined, PGE2 was again found to differentially affect IL-2 and IL-4 production in three of five clones tested. In two additional Th0 clones, both IL-2 and IL-4 production were inhibited. These data suggest that lymphokine production may be regulated on two different levels. First, Th1- and Th2-associated lymphokines may be differentially sensitive to intracellular signals such as cAMP. Second, T cell subsets may exist, including subsets of Th0 cells, with different signaling pathways. In addition, our data suggest that PGE2 may play an important role in regulating the development of a response dominated by Th1- or Th2-associated lymphokines.
838 citations
TL;DR: In this article, a human ouabain-like compound (OLC) was identified by mass spectroscopy as an endogenous substance from human plasma that binds with high affinity to the digitalis glycosides and their aglycones.
Abstract: The plasma membrane sodium-potassium pumps that regulate intracellular sodium in most animal cells have specific, high-affinity receptors for the digitalis glycosides and their aglycones. This has fostered speculation that there is an endogenous ligand. We have purified and structurally identified by mass spectroscopy an endogenous substance from human plasma that binds with high affinity to this receptor and that is indistinguishable from the cardenolide ouabain. This human ouabain-like compound (OLC) displaces [3H]ouabain from its receptor, inhibits Na,K-ATPase and ouabain-sensitive 86Rb+ uptake, and has cardiotonic actions quantitatively similar to commercial ouabain. Immunoreactive OLC was detected in the plasma of many mammals, and high concentrations were found in the adrenals. The circulating OLC may modulate intracellular Na+ and affect numerous Na+ gradient-dependent processes including intracellular Ca2+ and pH homeostasis in many tissues. Furthermore, altered circulating levels of OLC may be associated with the pathogenesis of certain forms of hypertension.
749 citations
TL;DR: It is suggested that foci may represent regions of predominantly interclonal competition for antigen among unmutated B cells, while germinal centers are sites of intraclonal clonal competition between mutated sister lymphocytes.
Abstract: After primary immunization with an immunogenic conjugate of (4-hydroxy-3-nitrophenyl)acetyl, two anatomically and phenotypically distinct populations of antibody-forming cells arise in the spleen. As early as 2 d after immunization, foci of antigen-binding B cells are observed along the periphery of the periarteriolar lymphoid sheaths. These foci expand, occupying as much as 1% of the splenic volume by day 8 of the response. Later, foci grow smaller and are virtually absent from the spleen by day 14. A second responding population, germinal center B cells, appear on day 8-10 and persist at least until day 16 post-immunization. Individual foci and germinal centers represent discrete pauciclonal populations that apparently undergo somatic evolution in the course of the primary response. We suggest that foci may represent regions of predominantly interclonal competition for antigen among unmutated B cells, while germinal centers are sites of intraclonal clonal competition between mutated sister lymphocytes.
736 citations
TL;DR: Using the lattice of single variable decomposition slices ordered by set inclusion, it is shown how a slice-based decomposition for programs can be formed and how to delineate the effects of a proposed change by isolating those effects in a single component of the decomposition.
Abstract: Program slicing is applied to the software maintenance problem by extending the notion of a program slice (that originally required both a variable and line number) to a decomposition slice, one that captures all computation on a given variable, i.e., is independent of line numbers. Using the lattice of single variable decomposition slices ordered by set inclusion, it is shown how a slice-based decomposition for programs can be formed. One can then delineate the effects of a proposed change by isolating those effects in a single component of the decomposition. This gives maintainers a straightforward technique for determining those statements and variables which may be modified in a component and those which may not. Using the decomposition, a set of principles to prohibit changes which will interfere with unmodified components is provided. These semantically consistent changes can then be merged back into the original program in linear time. >
706 citations
TL;DR: Level of positive and negative symptoms ascertained when patients received optimal neuroleptic treatment during the index hospitalization significantly predicted outcome levels of symptoms and functioning and time spent hospitalized during the follow-up period, suggesting that treatment response is a critical predictor variable for the course of illness in schizophrenics.
Abstract: We performed a longitudinal study of chronic schizophrenic patients who were hospitalized for research purposes at the National Institute of Mental Health (NIMH) Intramural Program in the 1970s and early 1980s We assessed present course, outcome and predictor data from the initial cohort of 58 young chronic schizophrenic patients who were followed up for 2 to 12 years following their NIMH index hospitalization At follow-up, the sample showed substantial functional impairment and levels of symptoms with only about 20% of the sample demonstrating a good outcome In addition, strong intercorrelation was noted among the symptom and functioning indexes at follow-up Moreover, neuropsychologic tests of frontal cortical functioning were significantly correlated with outcome levels of negative symptoms and social functioning but not with levels of positive symptoms During the period from the index hospitalization to the follow-up assessment, 78% of the sample suffered a relapse, 38% attempted suicide and 24% had episodes of major affective illness Furthermore, levels of positive and negative symptoms ascertained when patients received optimal neuroleptic treatment during the index hospitalization significantly predicted outcome levels of symptoms and functioning and time spent hospitalized during the follow-up period In contrast, levels of index positive and negative symptoms ascertained during the drug-free state did not predict outcome symptoms or functioning These data suggest that treatment response is a critical predictor variable We examined the implication of these data for the course of illness in schizophrenics
656 citations
TL;DR: In this paper, the authors examined culture supernatants of V. cholerae strains, both CT-positive and CT-negative, and found a toxin that increases the permeability of the small intestinal mucosa by affecting the structure of the intercellular tight junction, or zonula occludens.
Abstract: Attenuated Vibrio cholerae vaccine strains specifically mutated in genes encoding cholera toxin (CT) are still capable of causing mild to moderate diarrhea. Culture supernatants of V. cholerae strains, both CT-positive and CT-negative, were examined in Ussing chambers, and a toxin was found that increases the permeability of the small intestinal mucosa by affecting the structure of the intercellular tight junction, or zonula occludens. The activity of this toxin is reversible, heat-labile, sensitive to protease digestion, and found in culture supernatant fractions containing molecules between 10 and 30 kDa in size. Production of this factor (named ZOT for zonula occludens toxin) correlates with diarrheagenicity of V. cholerae strains in volunteers and may represent another virulence factor of infectious diarrhea that must be eliminated to achieve a safe and effective live oral vaccine against cholera.
512 citations
TL;DR: ATP-dependent calcium uptake by isolated sarcoplasmic reticulum vesicles is inhibited by concentrations of free thapsigargin as low as 10(-10) M, due to primary inhibition of the Ca(2+)-dependent ATPase which is coupled to active transport.
TL;DR: This review describes the little that is known about GABAA receptor subtypes and discusses approaches to establishing the subunit composition of subtypes, emphasizing possible molecular bases of receptor heterogeneity.
Abstract: GABAA receptors are GABA (gamma-aminobutyric acid)-gated chloride channels, which are major mediators of neuronal inhibition in the brain and are modulated by benzodiazepines, barbiturates, alcohol, and other important centrally acting drugs. Although previous pharmacological and biochemical data had suggested a degree of heterogeneity, recent cloning of at least 15 different receptor subunits, thought to be combined in groups of five, indicates that the brain may contain a truly astonishing variety of GABAA receptor subtypes. This review describes the little that is known about these subtypes, emphasizing possible molecular bases of receptor heterogeneity. We also discuss approaches to establishing the subunit composition of subtypes.
TL;DR: Expression of brain mRNA or cRNAs in Xenopus oocytes was used to determine what subunits of the GABAA receptor are required for modulation by barbiturates, benzodiazepines, and ethanol.
TL;DR: The amount of detectable Eae protein was increased in the presence of a high-molecular-weight plasmid which is associated with the ability to produce localized adherence to tissue culture cells, suggesting that the virulence plasmids of EPEC strain E2348/69 may have a regulatory role in the production of A/E activity.
Abstract: The production of a characteristic intestinal histopathology called attaching and effacing (A/E) lesions by enteropathogenic Escherichia coli (EPEC) is a major characteristic of EPEC pathogenesis. We previously identified a chromosomal gene (eae) of EPEC necessary for the production of A/E lesions on human tissue culture cells. Using antiserum raised to an Eae-PhoA fusion protein, we found that the eae gene encodes a 94-kDa membrane protein. This antiserum recognized a 94-kDa membrane protein in parent strain E2348/69 and a protein of similar size in E. coli HB101 carrying eae on a plasmid but did not recognize any proteins in E. coli HB101 carrying a plasmid with an internal deletion in the eae gene. Antigenically related proteins of ca. 94 kDa were detected in a collection of EPEC strains representing seven EPEC serogroups and in two EHEC strains of serotype O26:H11. Volunteer sera drawn 28 days after but not before ingestion of strain E2348/69 recognized the 94-kDa Eae protein as well as a 128-kDa Eae-PhoA fusion protein, suggesting that the Eae protein is likely to be a previously reported 94-kDa protein shown to be immunogenic in volunteers. The amount of detectable Eae protein was increased in the presence of a high-molecular-weight plasmid which is associated with the ability to produce localized adherence to tissue culture cells. These data suggest that the virulence plasmid of EPEC strain E2348/69 may have a regulatory role in the production of A/E activity.
TL;DR: In this paper, the authors evaluated the nonlinear dynamics of human cerebral maturation in terms of continuous versus discontinuous cognitive development and found that frontal regions exhibited different wave characteristics than posterior regions, similarly, left and right hemispheres exhibited differential developmental features.
Abstract: The issue of continuous versus discontinuous cognitive development was evaluated in terms of the nonlinear dynamics of human cerebral maturation. Convergent evidence from studies of the development of cerebral architecture, the development of EEG relative power, and the development of EEG coherence demonstrate oscillations and equilibrium processes that underlay cerebral maturation. Life‐span development was shown to be a “wave” process with spectral characteristics determined by anatomy. The frontal regions exhibited different wave characteristics than posterior regions, similarly, the left and right hemispheres exhibited differential developmental features. The establishment of corticocortical connections with different regions of the frontal lobes were shown to sequentially occur and to dominate postnatal cerebral development from birth to age 16.
TL;DR: The results imply that KATP-dependent action potential shortening is likely to occur if ATP concentration falls below normal levels, as may happen regionally, or globally, during myocardial ischemia.
Abstract: The role of ATP-sensitive potassium (KATP) channels in modulating the action potential and contraction of guinea pig ventricular myocytes was investigated. Under voltage clamp, the maximum whole-cell KATP channel conductance was estimated (195 +/- 10 nS, n = 6) by exposing the cells to complete metabolic blockade (2 mM cyanide in the presence of 10 mM 2-deoxy-glucose). In isolated inside-out membrane patches, the ATP dependence of KATP channel activity under relevant conditions was measured (half-maximal inhibition at 114 microM). Under current clamp (with intracellular ATP concentration = 5 mM), the effect of graded KATP channel activation on the action potential and the twitch was estimated by injection of a current (proportional to voltage) that simulated the KATP conductance. As this "conductance" was increased, the action potential was shortened, and contractile amplitude declined, as expected. From the results of these experiments, the quantitative dependence of the action potential duration on intracellular ATP concentration was estimated, without relying on a mathematical model of the cell membrane. The results imply that KATP-dependent action potential shortening is likely to occur if ATP concentration falls below normal levels (approximately 5 mM), as may happen regionally, or globally, during myocardial ischemia.
TL;DR: A multivariate model suggests that patients at the lowest risk for stroke recurrence have a low diastolic blood pressure, no history of stroke, nohistory of diabetes mellitus, and an infarct of unknown cause.
Abstract: We prospectively studied stroke recurrence in 1,273 patients with ischemic stroke who were entered into the Stroke Data Bank. Median follow-up was 13 months. The 2-year cumulative recurrence rate among these patients was 14.1%. Age, sex, race, history of hypertension, atrial fibrillation, or transient ischemic attacks, and stroke location were not associated with a higher risk of stroke recurrence. Patients with an elevated blood pressure, an abnormal initial computed tomogram, or a history of diabetes mellitus were at a higher risk of stroke recurrence. In contrast, patients with an infarct of unknown cause were at a lower risk of stroke recurrence than patients with a defined stroke mechanism, such as lacune, embolism, or atherosclerosis. A multivariate model suggests that patients at the lowest risk for stroke recurrence have a low diastolic blood pressure, no history of stroke, no history of diabetes mellitus, and an infarct of unknown cause.
TL;DR: Aloe emodin inactivated all of the viruses tested except adenovirus and rhinovirus, showing that anthraquinones extracted from a variety of plants are directly virucidal to enveloped viruses.
Abstract: To determine the extent of antiviral activity present in a number of plant extracts, hot glycerin extracts were prepared from Rheum officinale, Aloe barbadensis, Rhamnus frangula, Rhamnus purshianus, and Cassia angustifolia and their virucidal effects were tested against herpes simplex virus type 1. All the plant extracts inactivated the virus. The active components in these plants were separated by thin-layer chromatography and identified as anthraquinones. A purified sample of aloe emodin was prepared from aloin, and its effects on the infectivity of herpes simplex virus type 1 and type 2, varicella-zoster virus, pseudorabies virus, influenza virus, adenovirus, and rhinovirus were tested by mixing virus with dilutions of aloe emodin for 15 min at 37 degrees C, immediately diluting the sample, and assaying the amount of infectious virus remaining in the sample. The results showed that aloe emodin inactivated all of the viruses tested except adenovirus and rhinovirus. Electron microscopic examination of anthraquinone-treated herpes simplex virus demonstrated that the envelopes were partially disrupted. These results show that anthraquinones extracted from a variety of plants are directly virucidal to enveloped viruses.
TL;DR: It is indicated that strain 17-2 produces a low molecular weight, partially heat-stable, protease-sensitive enterotoxin which appears to be plasmid associated, and genetically and immunologically distinct from E. coli STa.
Abstract: Enteroaggregative Escherichia coli (EAggEC) have been associated with persistent diarrhea in young children, but little is known about its pathogenesis. We assayed for enterotoxic activity in culture filtrates (CF) of EAggEC strains in Ussing chambers mounted with rabbit ileal mucosa. CF from strain 17-2, a prototype Chilean EAggEC strain, caused a greater rise in potential difference and short circuit current (SCC) than that seen in HB101 control, and this effect was abolished by protease pretreatment and partially stable after heat treatment. Ultrafiltration of 17-2 CF preparations localized the active moiety to the 2-5 kD Mr size range. CF from HB101 transformed with the 17-2 plasmid showed Ussing chamber activity. less than 10-kD CF fractions from five of six other EAggEC strains screened in Ussing chambers gave SCC responses of similar magnitude to 17-2. The 17-2 CF activity was not neutralized after pretreatment with polyclonal anti-STa antibody. Additionally, all of the seven EAggEC strains studied were nonreactive by heat-stable enterotoxin variant STa ELISA, were negative in the suckling mouse assay, and failed to hybridize with heat-stable enterotoxin variant STh and STp DNA probes. In summary, our data indicate that 17-2 produces a low molecular weight, partially heat-stable, protease-sensitive enterotoxin which appears to be plasmid associated, and genetically and immunologically distinct from E. coli STa. Preliminary screening suggests that this tox+ phenotype may be common among EAggEC.
TL;DR: It is shown analytically that the evolution equation can be reduced to the nonlinear Schrödinger equation if the variation length is much shorter than the soliton period.
Abstract: The effects of randomly varying birefringence on solitons are studied. It is shown analytically that the evolution equation can be reduced to the nonlinear Schrodinger equation if the variation length is much shorter than the soliton period. The soliton does not split at high values of the average birefringence, but it does undergo spreading and loss of polarization. A soliton with a temporally constant initial state of polarization is still largely polarized after 40z0 if the normalized birefringence is δ ≤ 1.3.
TL;DR: Obesity, excessive weight gain in young adulthood, and hypertension are risk factors for the development of gout.
Abstract: Objective. —To identify potentially modifiable risk factors for the development of gout. Design. —Longitudinal cohort study (The Johns Hopkins Precursors Study). Participants. —Of 1337 eligible medical students, 1271 (95%) received a standardized medical examination and questionnaire during medical school. The participants were predominantly male (91%), white (97%), and young (median age, 22 years) at cohort entry. Outcome Measure. —The development of gout. Results. —Sixty cases of gout (47 primary and 13 secondary) were identified among 1216 men; none occurred among 121 women ( P =.01). The cumulative incidence of all gout was 8.6% among men (95% confidence interval, 5.9% to 11.3%). Body mass index at age 35 years ( P =.01), excessive weight gain (>1.88 kg/m 2 ) between cohort entry and age 35 years ( P =.007), and development of hypertension ( P =.004) were significant risk factors for all gout in univariate analysis. Multivariate Cox proportional hazards models confirmed the association of body mass index at age 35 years (relative risk [RR] = 1.12; P =.02), excessive weight gain (RR = 2.07; P =.02), and hypertension (RR = 3.26; P =.002) as risk factors for all gout. Hypertension, however, was not a significant risk factor for primary gout. Conclusions. —Obesity, excessive weight gain in young adulthood, and hypertension are risk factors for the development of gout. Prevention of obesity and hypertension may decrease the incidence of and morbidity from gout; studies of weight reduction in the primary and secondary prevention of gout are indicated. ( JAMA . 1991;266:3004-3007)
TL;DR: Follow-up data suggest that the illness tends to reach a plateau of psychopathology early in the course, with as many patients tending to improve in the long-term as those who tend to show further deterioration.
Abstract: Two- and five-year follow-up observations of the International Pilot Study of Schizophrenia's Washington cohort provided data bearing on several controversial issues regarding the course of schizophrenia. Forty schizophrenic patients have now been observed 11 years after their index admission. Social, occupational, hospital utilization, and symptom areas of functioning continue to be only modestly correlated with one another and do not become increasingly uniform over time. Initial prognostic variables continue to be more predictive of long-term outcome than are cross-sectional symptom manifestations. Restricted affect at the initial evaluation had been a predictor of 5-year outcome, but it was not a significant predictor of outcome at 11 years. While serious long-term consequences of illness are observed, the follow-up data suggest that the illness tends to reach a plateau of psychopathology early in the course, with as many patients tending to improve in the long-term as those who tend to show further deterioration.
TL;DR: Laparoscopic guided cholecystectomy appears to offer a number of advantages in patient care as well as a significant reduction in health care expenses for gallbladder disease.
Abstract: Cholecystectomy remains the most effective form of therapy for patients with symptomatic cholelithiasis. An alternative method of gallbladder removal, laparoscopic guided cholecystectomy, was attempted in 100 patients. Five patients required conversion of the laparoscopic procedure to an open laparotomy for the following reasons: discovery of a pancreatic malignancy in one patient, extensive adhesions in one, presence of an aberrant accessory right hepatic duct in one, common hepatic duct injury in one, and avulsion of the cystic duct in one. Both ductal injuries occurred during the early phase of the clinical program. In those patients undergoing laparoscopic cholecystectomy, 93 were discharged within 24 hours of surgery and 94 returned to normal activity within 1 week. Laparoscopic guided cholecystectomy appears to offer a number of advantages in patient care as well as a significant reduction in health care expenses for gallbladder disease. Appropriate training in laparoscopic surgery is necessary in order to avoid operative complications.
TL;DR: The Ca2+ pump-inhibitory sesquiterpene lactone, thapsigargin, is shown to distinguish these two Ca 2+ pools and identify a third Ca2- pumping pool unresponsive to InsP3 or GTP.
Westat1, NewYork–Presbyterian Hospital2, North Shore-LIJ Health System3, Yeshiva University4, Metropolitan Hospital Center5, New York Medical College6, Harlem Hospital Center7, State University of New York System8, Mount Sinai St. Luke's and Mount Sinai Roosevelt9, New York University10, University of Connecticut11, Boston University12, University of Maryland, Baltimore13, Children's National Medical Center14, Emory University15, Children's Memorial Hospital16, University of Illinois at Chicago17, Boston Children's Hospital18, Children's Hospital Oakland Research Institute19, University of Puerto Rico20, Bayer21
TL;DR: In symptomatic HIV-infected children the prophylactic use of intravenous immune globulin, is safe, and it significantly increases the time free from serious bacterial infections for those entering treatment with CD4+ lymphocyte counts greater than or equal to 0.2 x 10(9) per liter.
Abstract: BACKGROUND
Serious recurrent bacterial infections are a major cause of morbidity and mortality in children infected with the human immunodeficiency virus (HIV). Because intravenous immune globulin has been shown to prevent bacterial infection in patients with primary immunodeficiency and in uncontrolled studies of HIV-infected children, we undertook a multicenter study of its safety and efficacy in children with symptomatic HIV infection.
METHODS
In a double-blind trial, 372 HIV-infected children (mean age, 40 months) with clinical or immunologic evidence of HIV disease were randomly assigned to receive either intravenous immune globulin (400 mg per kilogram of body weight) or placebo (0.1 percent albumin) every 28 days. The children were stratified into two groups according to CD4+ lymphocyte count at entry into the study and the clinical classification of the Centers for Disease Control. The median length of follow-up was 17 months.
RESULTS
For children in either group with CD4+ counts greater than or equal to 0.2 x 10(9) per liter (greater than or equal to 200 per cubic millimeter) at entry, treatment with intravenous immune globulin significantly increased the time free from serious infection; estimated infection-free rates after 24 months were 67 percent for children receiving immune globulin as compared with 48 percent for those receiving placebo (P = 0.01). In addition, immune globulin was associated with an overall reduction in the number of both serious and minor bacterial infections (relative risk, 0.68; P = 0.01) and in the number of hospitalizations for acute care (relative risk, 0.65; P = 0.03). No such benefits were seen for children with CD4+ counts below 0.2 x 10(9) per liter at entry. For group 1 overall, there was a trend toward a difference in serious bacterial infection between immune globulin and placebo (24-month infection-free survival, 31 percent for intravenous immune globulin vs. 25 percent for placebo; P = 0.10). For group 2, the estimates of survival without serious infection were 73 percent with intravenous immune globulin as compared with 53 percent with placebo (P = 0.04). There was no effect of treatment on mortality for any group or CD4+ count at entry. Adverse reactions, noted for less than 1 percent of infusions, were minor.
CONCLUSIONS
In symptomatic HIV-infected children the prophylactic use of intravenous immune globulin, is safe, and it significantly increases the time free from serious bacterial infections for those entering treatment with CD4+ lymphocyte counts greater than or equal to 0.2 x 10(9) per liter.
TL;DR: A novel mechanism for the regulation of the GABAA receptor by protein phosphorylation is suggested, as two forms of the γ2‐subunit are generated by alternative splicing, as demonstrated by cloning and partial sequencing of the corresponding gene.
Abstract: gamma-Aminobutyric acidA (GABAA) receptors are multisubunit ligand-gated ion channels which mediate neuronal inhibition by GABA and are composed of at least four subunit types (alpha, beta, gamma, and delta). The gamma 2-subunit appears to be essential for benzodiazepine modulation of GABAA receptor function. In cloning murine gamma 2-subunits, we isolated cDNAs encoding forms of the subunit that differ by the insertion of eight amino acids. LLRMFSFK, in the major intracellular loop between proposed transmembrane domains M3 and M4. The two forms of the gamma 2-subunit are generated by alternative splicing, as demonstrated by cloning and partial sequencing of the corresponding gene. The eight-amino-acid insertion encodes a potential consensus serine phosphorylation site for protein kinase C. These results suggest a novel mechanism for the regulation of the GABAA receptor by protein phosphorylation.
TL;DR: Differences in behavior between PDL cells and gingival fibroblasts may prove important in designing appropriate clinical therapies directed at stimulating periodontal regeneration.
Abstract: A primary objective in the treatment of periodontal diseases is the regeneration of the mineralized and soft connective tissue components of the attachment apparatus. Current theories suggest the cells of the periodontium have the capacity, when appropriately triggered, to actively participate in restoring connective tissues, including mineralized tissues. To evaluate further the role of such cells in periodontal homeostasis, periodontal ligament (PDL) cells and gingival fibroblasts (GF) were cultured and examined for alkaline phosphatase levels and for the ability to produce mineralized nodules in culture. These are two characteristics of osteoblast-like cells in vitro. The levels of alkaline phosphatase produced by these cells were determined by a modified kinetic assay and the ability of these cells to produce mineral-like nodules in vitro was evaluated by Von Kossa staining and light and electron microscopy. PDL cells had significantly higher levels of alkaline phosphatase when compared with gingival fibroblasts obtained from the same patient and the same passage, in vitro. Furthermore PDL cells, but not GF, were capable of producing mineral-like nodules in vitro. These results indicate differences in behavior between PDL cells and GF; such differences may prove important in designing appropriate clinical therapies directed at stimulating periodontal regeneration.
TL;DR: It is suggested that emptying of Ca2+ from intracellular thapsigargin-sensitive Ca(2+)-pumping pools induces profound alteration of cell proliferation.
TL;DR: A cohort of 360 children in Santa Julia, a low socioeconomic area in Santiago, Chile, from November 1986 through April 1989 with twice weekly household visits for diarrheal disease was followed, finding Santa Julia an appropriate site for assessing the efficacy and effectiveness of measures to reduce Shigella infections.
Abstract: To prepare a field site for evaluating preventive interventions against endemic shigellosis, the authors followed prospectively a cohort of 360 children (90 each of children aged 0-11, 12-23, 24-35, and 36-47 months) in Santa Julia, a low socioeconomic area in Santiago, Chile, from November 1986 through April 1989 with twice weekly household visits for diarrheal disease; infants replaced children who reached 60 months of age. Coprocultures on 2 consecutive days from children with diarrhea and from age-matched controls within the cohort were cultured for Shigella. Bacteriologic surveillance was also maintained in the health center and children's hospital serving Santa Julia. In this community, where all households had access to potable water (68% inside) and all but 3% had access to a toilet, but where there was marked crowding, the overall incidence of diarrheal disease in the cohort was low (2.26 episodes/12 child months of observation in children aged 0-11 months and 2.09 in those aged 12-23 months), yet Shigella infections were common. Shigella accounted for 10% of diarrheal episodes in the cohort (vs. 3.2% isolation rate in controls, p less than 0.0001). The incidence of shigellosis in children aged 12-47 months was 0.16 cases per 12 child months of observation; in the first 5 years of life, a child had a 67% chance of experiencing shigellosis. Shigella sonnei, Shigella flexneri 2a, and S. flexneri 6 caused greater than 79% of the infections. Shigella occurred more often in hospitalized cases of diarrhea than in age-matched cases detected in the health center or by household surveillance (p less than 0.0001). An initial episode of Shigella diarrhea did not diminish overall the risk of subsequent shigellosis but did confer 72% protection (p = 0.05) against illness due to the homologous serotype. The high rate of both S. sonnei and S. flexneri shigellosis in a population with a low background rate of diarrhea makes Santa Julia an appropriate site for assessing the efficacy and effectiveness of measures to reduce Shigella infections.
TL;DR: Laroscopic cholecystectomy appears to offer significant advantages to patient recovery, and these data suggest that it can be performed with an efficacy, morbidity rate, and mortality rate similar to those of open choleCystectomy.
Abstract: Three hundred seventy-five consecutive patients underwent laparoscopic cholecystectomy from September 1989 to January 1991. Three hundred forty-one (91%) presented on an elective basis, and the remaining 34 patients (9%) were admitted for acute cholecystitis (24), gallstone pancreatitis (9), and cholangitis (1). Of the 375 patients, 20 were converted to laparotomy and cholecystectomy, for an overall success rate of 95% for patients undergoing laparoscopic cholecystectomy. Three hundred nineteen patients (90%) were discharged within 24 hours of surgery. Operative cholangiography was completed in 141 patients, showing choledocholithiasis in five (managed by postoperative endoscopic retrograde cholangiopancreatography [ERCP] in 4, common bile duct exploration [CBDE] in 1). Two retained stones (0.9%) were detected in 214 patients not undergoing cholangiography. Three patients (0.8%) were reoperated on because of perioperative complications. Overall morbidity for patients undergoing laparoscopic cholecystectomy was 3.5%. Major complications (0.6%) included a single common hepatic duct injury and a delayed cystic duct leak at 10 days. Minor complications occurred in 11 patients (2.9%). The single perioperative death (0.3%) was due to a myocardial infarction on postoperative day 3, after an otherwise uncomplicated laparoscopic procedure. Laparoscopic cholecystectomy appears to offer significant advantages to patient recovery, and these data suggest that it can be performed with an efficacy, morbidity rate, and mortality rate similar to those of open cholecystectomy.