tbuckley/cabot-search huggingface dataset:
Renal Protection in Diabetes
Authors: Paola Fioretto, Marino Bruseghin, Ilaria Berto, Pietro Gallina, Enzo Manzato, Michele Mussap
Journal: Journal of the American Society of Nephrology (2006)

Diabetes is the most common cause of ESRD in Western countries. This article describes the impact of glycemic control in the various stages of the disease and considers the impact of tight glycemic control on the development and progression of diabetic nephropathy (DN). The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetic Study have demonstrated in type 1 and type 2 diabetes that intensive glycemic control significantly reduces the risk for development of microalbuminuria. Although observational studies suggest an impact of glycemia also on the progression of DN, fewer data are available on the impact of improved metabolic control in secondary prevention. The long-term follow-up of the patients who participated in the Diabetes Control and Complications Trial (Epidemiology of Diabetes Interventions and Complications Study) demonstrated a sustained effect of previous tight glycemic control on both development and progression of DN. Finally, long-term normoglycemia, achieved by pancreas transplantation, is able not only to prevent the development of early diabetic glomerulopathy in kidney transplant recipients but also to halt progression and induce regression of the established diabetic renal lesions in nonuremic patients. Taken together, these studies strongly demonstrate that improvement in glucose control is the most important therapeutic approach in primary prevention. Tight glycemic control also is important in slowing progression of DN, and if blood glucose is normalized, then regression of DN can be achieved. Therefore, a target of glycated hemoglobin levels <7% should be recommended in all patients with diabetes.
Tachycardia-induced remodeling: atria and ventricles take a different route
Authors: A GOETTE
Journal: Cardiovascular Research (2004)

See article by Hanna et al. [7] (pages 236–244) in this issue. 

Myocardial remodeling is a common cardiac response to various pathological stimuli and may refer to changes in structure and function (structural remodeling) or electrophysiologic properties (electrical or ionic remodeling) [1–3]. Such disease-induced changes of tissue composition and architecture or function occur in both the atrium and/or the ventricle, and appear to progress steadily in a vicious cycle that, if not halted, eventually causes death of the patient [1]. Structural remodeling itself has a substantial influence on cardiac conduction properties [4]. In particular, the development of conduction inhomogeneities, including areas of slow conduction and conduction block, is associated with the occurrence of re-entrant arrhythmias in the atria and ventricles. Ventricular remodeling in the setting of volume or pressure overload contributes significantly to LV dilatation and dysfunction and, thereby, to the progression of heart failure, and is associated with increased morbidity and mortality [1,5]. Atrial remodeling and its relationship to atrial fibrillation (AF) have gained much interest during recent years since AF is the most common arrhythmia in clinical practice [2–4,6]. The high incidence of AF in the general population and the associated risk of stroke/heart failure make the identification of the underlying molecular and cellular mechanisms important goals towards alternate causal therapeutic concepts. … 

*Corresponding author. Tel.: +49-391-6713203; fax: +49-391-6713202. Email address: andreas.goette{at}medizin.uni-magdeburg.de
Immunologic and Hemodynamic Effects of “Low-Dose” Hydrocortisone in Septic Shock
Authors: Didier Keh, Thomas Boehnke, Steffen Weber-Cartens, Christina Schulz, Olaf Ahlers, Sven Bercker, Hans-Dieter Volk, Wolf-Dietrich Doecke, Konrad J. Falke, Herwig Gerlach
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Within the last few years, increasing evidence of relative adrenal insufficiency in septic shock evoked a reassessment of hydrocortisone therapy. To evaluate the effects of hydrocortisone on the balance between proinflammatory and antiinflammation, 40 patients with septic shock were randomized in a double-blind crossover study to receive either the first 100 mg of hydrocortisone as a loading dose and 10 mg per hour until Day 3 (n = 20) or placebo (n = 20), followed by the opposite medication until Day 6. Hydrocortisone infusion induced an increase of mean arterial pressure, systemic vascular resistance, and a decline of heart rate, cardiac index, and norepinephrine requirement. A reduction of plasma nitrite/nitrate indicated inhibition of nitric oxide formation and correlated with a reduction of vasopressor support. The inflammatory response (interleukin-6 and interleukin-8), endothelial (soluble E-selectin) and neutrophil activation (expression of CD11b, CD64), and antiinflammatory response (soluble tumor necrosis factor receptors I and II and interleukin-10) were attenuated. In peripheral blood monocytes, human leukocyte antigen-DR expression was only slightly depressed, whereas in vitro phagocytosis and the monocyte-activating cytokine interleukin-12 increased. Hydrocortisone withdrawal induced hemodynamic and immunologic rebound effects. In conclusion, hydrocortisone therapy restored hemodynamic stability and differentially modulated the immunologic response to stress in a way of antiinflammation rather than immunosuppression.
THE CLINICAL SCREENING OF PSYCHOPHARMACOTHERAPEUTIC AGENTS: A CONSIDERATION OF METHODOLOGY
Authors: JAMES H. EWING, KARL RICKELS, HAROLD H. MORRIS
Journal: American Journal of Psychiatry (1961)

1. The methodology of the initial patient screening of psychopharmacological agents is a relatively neglected but important area for discussion and improvement. 2. The main functions of this activity are to uncover safely and efficiently a wide variety of leads about desirable and undesirable pharmacological and psychiatric actions. This requires balance and compromise between the practice of the clinical art of pharmacotherapy and the use of procedures of good scientific control. 3. There are advantages in conducting such investigations on a research and teaching-oriented, active and eclectic treatment, inpatient service, using small numbers of acutely ill psychotic patients under intensive observation for periods up to 2 to 3 months. Subtle drug effects can be seen, and such a milieu calls forth a wide range of adjustmental behavior for study. 4. Multiple observers of different professional backgrounds and training, using a variety of rating scales and checklists to evaluate independently the same phenomena, enhance objectivity, diminish bias and help to circumvent individual blind spots. 5. There are special problems of selection of subjects since one is interested in observing the effects of drugs upon a large spectrum of psychopathological factors while insuring safety. 6. In the experimental design the testing of a new drug against a carefully selected active referent agent and inert placebo, and the use of intrapatient and interpatient comparisons are feasible and to be recommended. Although starting with flexible adjustment of dose, a rigid dosage schedule and true crossover design can be employed to advantage safely in the later stages of many studies. 7. Along with the collection of data by open experiment, provision can be made for employing double-blind technique. 8. There is a special need in preliminary drug testing for systematic handling of individual case data during each investigation in order to uncover and exploit leads, insure safety and to allow for the report of certain kinds of summary data to drug firms and to other investigators. 9. The detailed post-experiment report of individual case data allows others to seek significant correlations other than those of interest to the investigator himself. 10. This particular kind of research can be effectively incorporated into a larger research program.
The Fragile Histidine Triad Gene: A Molecular Link Between Cigarette Smoking and Cervical Cancer
Authors: Christine H. Holschneider, Rae Lynn Baldwin, Kiran Tumber, Chisa Aoyama, Beth Y. Karlan
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Smoking is an epidemiologic risk factor for cervical cancer. The fragile histidine triad (FHIT) gene is a tumor suppressor gene that is altered in 80% of tobacco-associated lung cancers. We hypothesized that reduced FHIT protein expression, homozygous deletions (HD) or hemizygous deletions (HemiD) and microsatellite alterations (MA) at the FHIT/FRA3B locus occur more commonly in cervical cancers of smokers than nonsmokers. Experimental Design: Archival tissues of 58 patients with stage IA1 to IB2 squamous cell carcinoma of the cervix were identified. FHIT protein expression was studied with immunohistochemistry. Laser capture microdissection was used to isolate tumor and normal DNA. HD/HemiD of FHIT exons 4 and 5 were analyzed by monoplex real-time PCR. MA at FHIT/FRA3B were studied with multiplex nested PCR with three fluorescently labeled microsatellite markers (D3S1300, D3S1312, and D3S1480). Results: Eighteen of 26 tumors from smokers (69%) and 13 of 32 nonsmokers (41%; P &amp;lt; 0.05) showed loss of FHIT protein expression. Thirty-seven stage IB tumors yielded sufficient DNA for analyses. HD or HemiD of both exons tested occurred in 8 of 17 smokers (47%) and 2 of 20 nonsmokers (10%; P &amp;lt; 0.05). MA at more than two sites were found in 11 of 17 tumors of smokers (65%) and 6 of 20 nonsmokers (30%; P &amp;lt; 0.05). Mean composite genomic FHIT alteration scores were significantly higher for tumors of smokers versus nonsmokers (0.67 versus 0.40; P &amp;lt; 0.02). Conclusion: Loss of FHIT expression, HD, HemiD, and MA at the FHIT/FRA3B locus occur significantly more commonly in cervical cancers of smokers. These findings suggest that the tumor suppressor gene FHIT may represent a molecular target in cigarette smoking–associated cervical carcinogenesis.
Prevalence of Amblyopia and Strabismus in White and African American Children Aged 6 through 71 MonthsThe Baltimore Pediatric Eye Disease Study
Authors: David S. Friedman, Michael X. Repka, Joanne Katz, Lydia Giordano, Josephine Ibironke, Patricia Hawse, James M. Tielsch
Journal: Ophthalmology (2009)
Excellent Prognosis in a Subset of Patients with Ewing Sarcoma Identified at Diagnosis by CD56 Using Flow Cytometry
Authors: Shifra Ash, Drorit Luria, Ian J. Cohen, Yacov Goshen, Helen Toledano, Josephine Issakov, Isaac Yaniv, Smadar Avigad
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Ewing sarcoma (ES) is considered a systemic disease with the majority of patients harboring micrometastases at diagnosis. Multiparameter flow cytometry (MPFC) was used to detect ES cells in bone marrow (BM) of ES patients at diagnosis and to evaluate the prognostic significance of CD56 expression in BM samples. Experimental Design: BM samples from 46 ES patients, 6 tumor aspirates, 2 ES cell lines, and 10 control BM samples were analyzed by MPFC. ES cells were identified by the combination of CD45−/CD90+/CD99+. CD56 was evaluated on these cells by a cutoff of 22%. Results: BM samples obtained from all patients at diagnosis were found to be positive for micrometastatic tumor cells assessed by CD99+/CD90+/CD45− expression. A total of 60% of the BM samples harbored high CD56 expression. There was a highly significant correlation between CD56 expression and progression-free survival (PFS; 69% in low/negative expression versus 30% in high expression groups, P = 0.024). In patients with localized nonpelvic disease, those expressing low/negative CD56 had 100% PFS versus 40% in the high expressing group (P = 0.02). By Cox regression analysis, CD56 was found to be an independent prognostic marker with an 11-fold increased risk for relapse in patients with localized disease (P = 0.006). Conclusion: All samples contained cells that are positive for the CD99+/CD90+/CD45− combination at diagnosis, indicating that ES is a systemic disease. CD56 expression could be used to reveal ES patients with excellent prognosis or patients predisposed to relapse, thus improving treatment stratification and implementation of personalized therapy. Clin Cancer Res; 17(9); 2900–7. ©2011 AACR.
The Ligand-binding Domain of CD22 Is Needed for Inhibition of the B Cell Receptor Signal, as Demonstrated by a Novel Human CD22-specific Inhibitor Compound
Authors: Soerge Kelm, Judith Gerlach, Reinhard Brossmer, Claus-Peter Danzer, Lars Nitschke
Journal: The Journal of Experimental Medicine (2002)

CD22 is a B cell-specific transmembrane protein of the Siglec family. It binds specifically to alpha2,6-linked sialic acid (Sia) residues, which are also present on glycoproteins on the B cell surface. CD22 acts as a negative regulator in B cell receptor-mediated signaling by recruitment of Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 to its intracellular tail. To analyze how ligand-binding of CD22 influences its intracellular signaling domain, we designed synthetic sialosides as inhibitors for the lectin domain of CD22. One of these compounds inhibited binding of human CD22-Fc to target cells over 200-fold better than Sia and was highly selective for human CD22. When Daudi cells or primary B cells were stimulated with anti-immunoglobulin (Ig)M in presence of this sialoside inhibitor, a higher Ca(2+) response was observed, similar to CD22-deficient B cells. Accordingly, a lower tyrosine-phosphorylation of CD22 and SHP-1 recruitment was demonstrated in presence of the sialoside. Thus, by interfering with ligand binding of CD22 on the B cell surface, we have shown for the first time that the lectin domain of CD22 has a direct, positive influence on its intracellular inhibitory domain. Also, we have developed a novel low molecular weight compound which can enhance the response of human B cells.
Acidic Extracellular pH Promotes Experimental Metastasis of Human Melanoma Cells in Athymic Nude Mice
Authors: Einar K. Rofstad, Berit Mathiesen, Kristil Kindem, Kanthi Galappathi
Journal: Cancer Research (2006)

Abstract Extracellular pH (pHe) is lower in many tumors than in the corresponding normal tissue. The significance of acidic pHe in the development of metastatic disease was investigated in the present work. Human melanoma cells (A-07, D-12, and T-22) were cultured in vitro at pHe 6.8 or 7.4 (control) before being inoculated into the tail vein of BALB/c nu/nu mice for formation of experimental pulmonary metastases. Cell invasiveness was studied in vitro by using Matrigel invasion chambers and angiogenesis was studied in vivo by using an intradermal assay. Protein secretion was measured by ELISA and immunocapture assays. Cells cultured at acidic pHe showed increased secretion of proteinases and proangiogenic factors, enhanced invasive and angiogenic potential, and enhanced potential to develop experimental metastases. Acidity-induced metastasis was inhibited by treatment with the general matrix metalloproteinase (MMP) inhibitor GM6001, the general cysteine proteinase inhibitor E-64, or blocking antibody against vascular endothelial growth factor-A (VEGF-A) or interleukin-8 (IL-8). Our study indicates that acidic pHe promotes experimental pulmonary metastasis in A-07, D-12, and T-22 human melanoma cells by a common mechanism involving acidity-induced up-regulation of the proteolytic enzymes MMP-2, MMP-9, cathepsin B, and cathepsin L and acidity-induced up-regulation of the proangiogenic factors VEGF-A and IL-8. One consequence of this observation is that treatment strategies involving deliberate tumor acidification to improve the efficacy of chemotherapy, photodynamic therapy, and hyperthermia should be avoided. Moreover, the possibility that the pHe of the primary tumor may be an important prognostic parameter for melanoma patients merits clinical investigation. (Cancer Res 2006; 66(13): 6699-707)
Impact of Race on the Severity of Acute Episodes of Asthma and Adrenergic Responsiveness
Authors: Amr El-Ekiaby, Lori Brianas, Mary E. Skowronski, Albert J. Coreno, Gayle Galan, Frank J. Kaeberlein, Roy E. Seitz, Karen D. Villaba, Howard Dickey-White, E. R. McFadden
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: African Americans acutely ill with asthma come to emergency departments more frequently and are admitted to hospital more often than whites but the reasons are unclear.Objectives: To determine whether such phenomena represent racial differences in attack severity or limited effectiveness of β2-agonist therapy.Methods and Main Results: We contrasted clinical features, airflow limitation, and albuterol responsiveness in adults acutely ill with asthma, 155 of whom where African American and 140 white, as they presented to eight emergency departments. Assessments were standardized across institutions using a care path, and admission and discharge decisions were made according to predetermined criteria. The degree of obstruction was measured by peak expiratory flow rates. The clinical features of both groups were similar. The African Americans, however, had lower flow rates (p = 0.002), and more of them experienced severe or potentially life threatening episodes (p < 0.001). Albuterol was equally efficacious in both populations and there were no differences in the post-treatment flow rates achieved irrespective of the initial attack intensity. There were no racial differences in admission/discharge ratios.Conclusions: Our data indicate that African Americans with asthma tend to present with somewhat more intense attacks than whites, but they respond equally well to routine treatment. Similarly, there were no racial disparities in hospitalizations when standard criteria are employed.
A surface receptor specific for human IgA on group B streptococci possessing the Ibc protein antigen.
Authors: G J Russell-Jones, E C Gotschlich, M S Blake
Journal: The Journal of Experimental Medicine (1984)

A number of group B streptococcal strains of various serotypes, Ia, Ib, Ic, II, and III were examined for their ability to bind human IgG and IgA. No strains of group B streptococci were found to bind IgG, but many strains possessing the Ibc protein antigen(s) were found to bind a significant amount of IgA. The extent of IgA binding correlated with the amount of a 130,000 mol wt, detergent-extractable protein, and reactivity with the Ic typing sera. Using nitrocellulose blots, it was found that the 130,000 mol wt protein bound human IgA. A method was developed to purify the protein while retaining its ability to bind human IgA. Using solid phase radioimmunoassays, it was determined that the protein bound to the Fc region of monomeric or polymeric IgA and that it failed to bind IgM or any IgG isotype.
STUDIES ON BACTERIAL NUTRITION
Authors: Theodor Thjötta
Journal: The Journal of Experimental Medicine (1921)

From the data presented in the foregoing experiments it is evident that Bacillus influenzae will grow in a fluid medium consisting of plain broth to which have been added small amounts of emulsions or extracts of mucoid bacilli or of Bacillus proteus. The bacterial extracts may be made by simple boiling of the bacillary emulsions in broth or saline solution and centrifuging out the bacterial bodies; they may be filtered without losing their growth-inducing property. Cultures of Bacillus influenzae in bacterial extract broth, if not too small doses of the extracts were employed, always showed heavier growth than the control cultures in blood broth, and growth occurred at a considerably earlier period than in blood broth. In many instances growth could be seen after 3 to 4 hours, and a bacterial whirl was always visible after 6 hours incubation. When the nature of the culture used for seeding is not stated, this was 0.1 cc. of the supernatant fluid of a blood broth culture. All cultures were made in fluid medium; solid medium is much more difficult to use in connection with the extracts. In explanation of the remarkable growth of Bacillus influenzae in this blood-free medium, the idea is proposed that the growth-stimulating effect of the bacterial extracts is due possibly to substances of the same nature as the so called vitamines. Further investigations on this principle of bacterial nutrition will appear in subsequent papers, together with a more thorough study of the sources and character of the growth-inducing substances.
An Alternate Pathway for T Cell Development Supported by the Bone Marrow Microenvironment: Recapitulation of Thymic Maturation
Authors: Marcos E. García-Ojeda, Sussan Dejbakhsh-Jones, Irving L. Weissman, Samuel Strober
Journal: The Journal of Experimental Medicine (1998)

In the principal pathway of α/β T cell maturation, T cell precursors from the bone marrow migrate to the thymus and proceed through several well-characterized developmental stages into mature CD4+ and CD8+ T cells. This study demonstrates an alternative pathway in which the bone marrow microenvironment also supports the differentiation of T cell precursors into CD4+ and CD8+ T cells. The marrow pathway recapitulates developmental stages of thymic maturation including a CD4+CD8+ intermediary cell and positive and negative selection, and is strongly inhibited by the presence of mature T cells. The contribution of the marrow pathway in vivo requires further study in mice with normal and deficient thymic or immune function.
Deferoxamine inhibition of malaria is independent of host iron status.
Authors: C Hershko, T E Peto
Journal: The Journal of Experimental Medicine (1988)

The mechanism whereby deferoxamine (DF) inhibits the growth of malaria parasites was studied in rats infected with Plasmodium berghei. Peak parasitemia was 32.6% (day 14) in untreated controls and 0.15% (day 7) in rats receiving 0.33 mg/g in 8 hourly DF injections, subcutaneously. DF inhibition of parasite growth was achieved without any reduction in transferrin saturation or hemoglobin synthesis and with only a partial (56%) depletion of hepatic iron stores. Dietary iron depletion resulted in anemia (hematocrit 25 vs. 46%), microcytosis (MCV 54 vs. 60 fl), and reduced transferrin saturation (17 vs. 96%) without any effect on infection (peak parasitemia 30 vs. 36%). Similarly, parenteral iron loading with ferric citrate over 10 d (75 mg iron/kg) failed to aggravate infection. In a search for evidence of direct interaction between DF and parasitized erythrocytes, gel filtration and ultrafiltration was performed on hemolysates obtained from in vivo 59Fe-labeled parasitized erythrocytes. This showed that 1.1-1.9% of the intracellular radioiron was located in a chelatable, labile iron pool. Incubation of intact cells with 0-500 microM DF resulted in a proportional increase in intracellular iron chelation, and the chelation of all available labile intracellular iron was completed within 6 h. These observations indicate that the severity of P. berghei infection in rats and its in vivo suppression by DF are independent of host iron status and suggest that DF inhibition of malaria involves intracellular chelation of a labile iron pool in parasitized erythrocytes.
Raising more than just hope for cancer treatment
Authors: Ruth Williams
Journal: The Journal of Experimental Medicine (2006)

![Graphic][1] 

Tumor size in mice is reduced by Viagra treatments (right). Bedroom performance-boosting Viagra also boosts the immune system's battle against cancer, report Serafini et al on page 

[2691][2].

In cancer patients, though the body generates tumor-specific antibodies,