Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This is a study of Lesotho's proposal to United Nations agencies for financial assistance to build a medical school and a 600- bed referral teaching hospital. To qualify for such assistance, a feasibility study was prepared that included data from Lesotho's Ministries of Planning, Finance and Health on the following: 1) demography, including fertility; 2) health status and major health problems; 3) health facilities and health service utilization; 4) health manpower; and 5) health service organization, financing and cost. Lesotho's population was 1.37 million in 1981 growing at 2.3% per year. 13% of the population was urban, living in Maseru, the capital. Infant and child mortality rates are 116/1000 and 15.6/1000 while maternal mortality rates are 3.7/1000. The leading causes of death for children are malnutrition, acute respiratory and infectious diseases, gastrointestinal diseases and congenital anomalies. While adults are dying from tuberculosis, heart disease, injuries, burns and digestive diseases. Even though Lesotho's climate and high altitude insulate it from many diseases, there is concern over the high incidence of pulmonary tuberculosis, sexually transmitted diseases (STD's) and respiratory infections. In 1980 1/3 of the population has access to hospital care. Maseru had 40% of the hospital beds, yet only 4.4% of the population. In 1982 there were 1536 health workers employed by the Ministry of Health, of these 41 were doctors, 175 nurses and 132 nursing assistants. Instead of building a new medical school, Lesotho accepted renovating the existing general hospital, converting it into a national referral center, while introducing more specialties at 20% of the $US60 estimated for a new medical school. Recommendations to the government also included: 1) special programs aimed at reducing and controlling tuberculosis and STD's; 2) establishing and strengthening primary health care programs; and 3) decreasing long hospital stays. (author's modified).
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PMID:Getting the best value for money in health care. 261 Aug 47

The vast majority of pediatric RBC hypoplastic anemias are accounted for by red blood cell aplasia associated with chronic hemolysis, Diamond-Blackfan anemia, and transient erythroblastopenia of childhood. However, other causes of hypoplastic anemia occur in children, and some of these are similar to what is seen in adult RBC aplasia. For example, it has been reported that a 5-year-old girl with an aregenerative anemia had a thymoma and later developed pancytopenia. RBC aplasia also has been seen in children receiving anticonvulsant drug therapy, children recovering from severe protein malnutrition, children with hepatitis, and in children with leukemia during maintenance therapy. In addition, it is not uncommon for pediatric hematologists to observe children with RBC aplasia where there is no obvious diagnosis, although many are considered to be variants of Diamond-Blackfan anemia. Several important questions about RBC hypoplastic anemias in children need to be resolved; it is hoped that this will be accomplished in the next decade. Do RBC hypoplastic crises associated with hemolytic anemia occur with viral infections other than HPV? What is the cellular pathophysiology in DBA and TEC? Does the apparent heterogeneity of these disorders reflect limitations of laboratory techniques or are we looking at several different diseases? Is acute leukemia a real complication of Diamond-Blackfan anemia? Is TEC a completely benign entity or will we see other long-term problems in these children? Is the incidence of TEC actually increasing? Will TEC-like problems be seen in other aged children? As a case in point, we recently observed a 16-year-old girl who presented with pure RBC aplasia that required RBC transfusion support for 5 months; she also received prednisone therapy. After 7 months, however, this young lady had a spontaneous remission, and now 4 years later she is normal and free of any hematologic abnormalities. This was a most unusual event in our experience and, in view of the apparent increasing incidence of TEC in young children, we queried whether we were observing an adolescent equivalent of this disorder. During the next several years the answer to this and the other questions posed herein should be available.
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PMID:Diagnosis and management of red cell aplasia in children. 312 94

Cervical cancer is the most prevalent cancer of women in Ethiopia and sexually transmitted diseases are highly prevalent in the country. In order to establish a possible cause and effect relationship between sexually transmitted diseases and cervical cancer, likely etiological socio-economic factors for these two conditions have been analysed. While residence, income, age at first coitus, age, number of sexual partners, marital status/profession and duration of sexual life affect both conditions, there is a significant difference between the most important factors in the etiology of the separate conditions. Serological testing shows a high prevalence of gonorrhea, which was used as a marker of STD. Women with gonococcal antibodies had evidence of increased exposure to other STD; there was no such correlation for cervical cancer. Our results indicate that STD per se is unlikely to be a primary cause of CC in Ethiopia. It appears probable that the etiology of CC in Ethiopia is multifactorial. Early exposure of the immature cervical epithelium to STD, the trauma of repeated childbirth, and multiple sexual partners in women whose defence factors are impaired by chronic malnutrition, add up to a major medico-socio-economic factor. The evidence presented here suggests that CC in Ethiopia is not so much the result of a sexually transmitted disease, but a sociosexual disease.
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PMID:Is cervical cancer in Ethiopian women the result of a sexually transmitted disease? 835 10

Cytokine pathways are essential for the differentiation and function of lymphoid cells. The major T-cell growth factor is IL-2, which is produced by subsets of T lymphocytes in response to antigenic stimulation. The IL-2 receptor is expressed by T cells after antigenic stimulation, and when engaged by IL-2 induces proliferation, differentiation, and protection from apoptosis. Rare patients with severe combined immune deficiency (SCID) have been found to have mature T lymphocytes that do not produce IL-2, although no genetic abnormality has yet been defined for these patients. The fact that these patients and IL-2 knockout mice have the ability to generate mature T lymphocytes indicates that IL-2 is the major growth factor for mature T lymphocytes but not for immature thymocytes. X-linked SCID, the most common form of SCID, has a phenotype of thymic hypoplasia, peripheral T lymphopenia, the presence of B lymphocytes that do not undergo normal class switching, and usually the absence of natural killer (NK) cells. X-SCID is caused by mutations of a receptor subunit, which was originally described as the IL-2Rgamma. The phenotypic differences between X-SCID and IL-2-deficient SCID suggests that the IL-2Rgamma chain might be a component of other receptors needed for thymic development, B cell class-switching, and NK development. The IL-2Rgamma is now known to be a shared subunit between the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, which explains the complex X-SCID phenotype. Because of this shared usage, the IL-2Rgamma is known as the common gamma chain (gamma c). Each ligand induces dimerization of gamma c with the ligand-specific receptor subunit, eg, the IL-2Rbeta, resulting in signal transduction through the JAK-STAT (signal transducers and activators of transcription) pathway. The JAK3 tyrosine kinase is constitutively associated with the gamma c and is necessary for signaling through the gamma c-containing receptors. Deficiency of JAK3 gives rise to a SCID phenotype that closely resembles that of X-SCID, but is autosomally recessive in inheritance. It is likely that other specific immune deficiencies of the cytokine pathways exist, eg, IL-7Ralpha-deficient SCID. T cells with wild-type gamma c and JAK3 proteins have a profound selective advantage over cells that contain mutant proteins. The selective advantage allows these patients to be treated by bone marrow transplantation (BMT) without ablative chemotherapy, and is the reason that these forms of SCID are potential targets for early gene therapy efforts.
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PMID:X-linked SCID and other defects of cytokine pathways. 980 Dec 59

IGF-I is the best marker of GH secretory status but it also depends on the nutritional status and peripheral hormones such as insulin, glucocorticoids, thyroid hormones and gonadal steroids. Though monitoring IGF-I levels is the best way for evaluating appropriate GH replacement, the usefulness of IGF-I assay in the diagnosis of adult GH deficiency (GHD) is still matter of debate. To clarify this point in a large population of GHD adults (no. = 135, 61 women and 74 men; age, mean +/- SE: 43.8 +/- 1.4 yr, range 20-80 yr) we studied IGF-I levels, their reproducibility and association to peak GH response to GHRH + arginine (GHRH + ARG) test and insulin tolerance test (ITT). The results in GHD were compared with those in a large population of normal subjects (no. = 336, 233 women and 103 men, aged 20-80 yr). Mean IGF-I levels in GHD (77.8 +/- 4.9 micrograms/l) were clearly lower (p < 0.001) than those in normal subjects (170.2 +/- 4.7 micrograms/l). In Childhood Onset GHD (CO-GHD; no. = 40; age, mean +/- SE: 27.8 +/- 1.5 yr) IGF-I levels were lower than those in Adult Onset GHD (AO-GHD; no. = 95, age, mean +/- SE: 50.7 +/- 1.4 yr) (56.6 +/- 9.7 vs 87.1 +/- 5.4 micrograms/l, p < 0.0003). In both GHD and normal subjects IGF-I levels showed good, reproducibility (r = 0.92, p < 0.00001 and r = 0.62, p < 0.00001, respectively). In GHD, but not in normal subjects, IGF-I levels were positively associated to peak GH responses to GHRH + ARG (r = 0.57, p < 0.00001); on the other hand, the GH peak after ITT was not associated to IGF-I in GHD. In normal subjects, but not in GHD, IGF-I levels were negatively associated to age (r = -0.60, p < 0.00001). Considering individual IGF-I levels there was a clear overlap between GHD and normal subjects. However, this overlap was strongly dependent on age. In fact, in the third and fourth decade of life 83.6% of GHD had IGF-I levels below the 3rd centile of normal values; on the other hand, in the fifth-sixth decade and in ageing 47% and only 12% of GHD, respectively, had IGF-I levels low for age. In conclusion, our results demonstrate that IGF-I levels represent a reproducible marker of GH status and are reduced more in CO-GHD than in AO-GHD adults. An overlap exists between GHD and normal subjects, however this is small up to the 4th decade of life. Thus, though normal IGF-I levels do not rule out the existence of GHD, up to 40 yr low IGF-I levels strongly point to GHD if malnutrition and liver disease have been ruled out.
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PMID:Usefulness of IGF-I assay for the diagnosis of GH deficiency in adults. 980 91

This paper presents data on the increase of plasma interleukin-10 (IL-10) levels and rapid loss of CD4+ T cells among HIV-infected individuals in southern India. A cohort of 35 HIV-positive individuals were evaluated and classified into 3 categories based on the US Centers for Disease Control (CDC) clinical classification: 9 asymptomatic, 11 symptomatic with a non-AIDS defining illness, and 15 AIDS cases. Results revealed that asymptomatic individuals experienced rapid declines in CD4 counts (280 cells/mcl/year), which is 3 times lower than the rate of HIV-positive asymptomatic subjects in developed countries. It has been estimated that progression to AIDS would occur within 2 years for the average Indian patient. On the other hand, symptomatic patients were observed to have a stable CD4 count during the 6 months of study, which could be attributable to anti-tuberculosis treatment and trimethoprim-sulfamethoxazole. The shifts in serum IL-10 levels and CD4 counts were lower for a statistically significant correlation (p = 0.1). Several factors were identified that may have caused the differing rates of disease progression, which include infectious agents and malnutrition. Among the patients, the mean period from AIDS diagnosis to death was 5 months, which is similar to reports of rapid progression in India.
Int J STD AIDS 2000 Jan
PMID:Increase in plasma IL-10 levels and rapid loss of CD4+ T cells among HIV-infected individuals in south India. 1066 1

Nutrition is an important regulator of growth hormone (GH) action. Nutritional deprivation causes a GH resistance involving post-receptor alterations in the signaling pathway, but the responsible mechanisms remain unknown. Herein, suppressors of cytokine signaling proteins (SOCS) were investigated as potential agents in GH-resistance induced by malnutrition which inhibits activation of Janus kinase 2/signal transductor and activator of transcription 5 (JAK2/STAT5) pathway. Growth hormone receptor (GHR), IGF-I and SOCS3 mRNA expression was measured in the liver of rats fed with a low protein diet and with GH stimulation. Protein diet restriction significantly diminished GHR mRNA and receptor binding sites (p < 0.05), but caused a highly increased SOCS3 gene expression. In diet-restricted rats, GH administration increased GHR and IGF-I mRNA; however, GHR reached basal levels observed in animals feeding with a high protein diet. The malnourished group increased SOCS3 gene transcription in response to GH administration. These results suggested that a reduced hepatic sensitivity to GH was associated with SOCS3 over-expression. In addition, ubiquitous distribution of SOCS3 and CIS suggests a role for SOCS proteins as tissue specific modulators of cytokine sensitivity.
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PMID:[Role of the cytokine-3 signaling suppressor protein (SOCS 3) in growth hormone resistance induced by malnutrition]. 1458 33

Regulation of survival, expansion, and differentiation of erythroid progenitors requires the well-controlled activity of signaling pathways induced by erythropoietin (Epo) and stem cell factor (SCF). In addition to qualitative regulation of signaling pathways, quantitative control may be essential to control appropriate cell numbers in peripheral blood. We demonstrate that Bruton's tyrosine kinase (Btk) is able to associate with the Epo receptor (EpoR) and Jak2, and is a substrate of Jak2. Deficiency of Btk results in reduced and delayed phosphorylation of the EpoR, Jak2, and downstream signaling molecules such as Stat5 and PLCgamma1 as well as in decreased responsiveness to Epo. As a result, expansion of erythroid progenitors lacking Btk is impaired at limiting concentrations of Epo and SCF. In addition, we show that SCF induces Btk to interact with TNF-related apoptosis-inducing ligand (TRAIL)-receptor 1 and that lack of Btk results in increased sensitivity to TRAIL-induced apoptosis. Together, our results indicate that Btk is a novel, quantitative regulator of Epo/SCF-dependent expansion and survival in erythropoiesis.
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PMID:Btk is required for an efficient response to erythropoietin and for SCF-controlled protection against TRAIL in erythroid progenitors. 1500 95

Leptin regulates energy homeostasis primarily by binding and activating its long form receptor (LRb). Deficiency of either leptin or LRb causes morbid obesity. Leptin stimulates LRb-associated JAK2, thus initiating multiple pathways including the Stat3 and phosphatidylinositol (PI) 3-kinase pathways that mediate leptin biological actions. Here we report that SH2-B, a JAK2-interacting protein, promotes activation of the PI 3-kinase pathway by recruiting insulin receptor substrate 1 (IRS1) and IRS2 in response to leptin. SH2-B directly bound, via its PH and SH2 domain, to both IRS1 and IRS2 both in vitro and in intact cells and mediated formation of a JAK2/SH2-B/IRS1 or IRS2 tertiary complex. Consequently, SH2-B dramatically enhanced leptin-stimulated tyrosine phosphorylation of IRS1 and IRS2 in HEK293 cells stably expressing LRb, thus promoting association of IRS1 and IRS2 with the p85 regulatory subunit of PI 3-kinase and phosphorylation and activation of Akt. SH2-B mutants with lower affinity for IRS1 and IRS2 exhibited reduced ability to promote association of JAK2 with IRS1, tyrosine phosphorylation of IRS1, and association of IRS1 with p85 in response to leptin. Moreover, deletion of the SH2-B gene impaired leptin-stimulated tyrosine phosphorylation of endogenous IRS1 in mouse embryonic fibroblasts (MEF), which was reversed by reintroduction of SH2-B. Similarly, SH2-B promoted growth hormone-stimulated tyrosine phosphorylation of IRS1 in both HEK293 and MEF cells. Our data suggest that SH2-B is a novel mediator of the PI 3-kinase pathway in response to leptin or other hormones and cytokines that activate JAK2.
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PMID:SH2-B promotes insulin receptor substrate 1 (IRS1)- and IRS2-mediated activation of the phosphatidylinositol 3-kinase pathway in response to leptin. 1531 8

This study examines the effects of malnutrition on IL-6 signaling pathways of rats fed 2% vs. 20% casein diets for 14 days. Effects of malnutrition on the abundance and IL-6-stimulated phosphorylation of signaling proteins in the JAK-STAT and MAP kinase pathways were examined in the liver. Changes of the acute-phase response as reflected by serum alpha(1)-acid glycoprotein (AG), TNF-alpha (TNF), and IL-1beta (IL-1) were compared in the two dietary groups at 0, 4, 8, 16, and 24 h after IL-6 administration. Under basal conditions, the abundance of the IL-6 receptor, gp130, JAK1, STAT1, and STAT3 proteins and levels of phosphorylation of ERK1/2 and p38 were significantly increased in the liver in the 2% casein group compared with the 20% casein group. With IL-6 stimulation, the increased phosphorylation per unit of protein of these signaling proteins was not different in the liver between the two groups. Before IL-6 stimulation, serum levels of TNF, IL-1, IL-6, and AG were significantly higher in the 2% casein group than in the 20% casein group. After bolus injection of IL-6, changes in IL-1 and AG were similar in the two dietary groups, although a slight decline in AG level was noted after 8 h of IL-6 administration in the 2% protein group. These data demonstrate that protein malnutrition produces changes in inflammation-related proteins characteristic of a low-grade systemic inflammatory response and, thus, can serve as an inflammatory stimulus. The capacity for response to IL-6 is preserved, suggesting adaptive preservation of acute-phase responsiveness during malnutrition.
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PMID:Effects of protein malnutrition on IL-6-mediated signaling in the liver and the systemic acute-phase response in rats. 1537 Dec 80


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