tbuckley/cabot-search huggingface dataset:
705. A Practical Approach to siRNA-Based Treatment Design Using Bioluminescent Imaging and Mathematical Modeling
Authors: Derek W. Bartlett, Mark E. Davis
Journal: Molecular Therapy (2006)

Small interfering RNA (siRNA) molecules achieve sequence- specific gene silencing through a process known as RNA interference (RNAi). Compared to other nucleic acid-based therapeutics aimed at post-transcriptional gene silencing, such as antisense oligodeoxynucleotides, siRNA molecules achieve greater magnitude and duration of gene silencing at significantly lower doses. While the duration of gene knockdown by siRNA typically lasts around 1 week in rapidly dividing cells, recent reports of knockdown lasting for several weeks in nondividing cells indicate that dilution due to cell division may be a limiting factor in rapidly dividing cells. To determine if cell division directly impacts the duration of gene knockdown by siRNA, we chose to investigate the kinetics of siRNA-mediated gene silencing in luciferase-expressing cell lines with different observed doubling times using noninvasive bioluminescent imaging and a mathematical model of siRNA delivery and function. In vitro and in vivo, the duration of gene knockdown is inversely proportional to the rate of cell division. Consistent with previous reports, luciferase protein levels recover to pre-treatment values within less than 1 week in rapidly dividing cell lines, but take longer than 3 weeks to return to steady-state levels in nondividing fibroblasts. Similar results are observed in vivo, with knockdown lasting around 1 week in subcutaneous tumors in A/J mice and 3-4 weeks in the nondividing hepatocytes of BALB/c mice. These data indicate that dilution due to cell division, and not intracellular siRNA half-life, governs the duration of gene silencing under these conditions. Here, we will present our latest results describing the effects of cell doubling time, siRNA stability, and dosing schedule on siRNA- mediated gene silencing. Specifically, we will investigate whether the duration of knockdown using chemically modified siRNA molecules exhibits a similar dependence on cell doubling time. The implications of these findings will be highlighted using model calculations to determine the dosing schedule required to maintain persistent silencing of target proteins and to predict when maximum mRNA or protein knockdown will occur, an especially important factor when trying to observe a therapeutic effect resulting from protein knockdown. The approach of bioluminescent imaging combined with mathematical modeling provides insights into siRNA function that will hopefully be of practical use for both researchers and clinicians alike.
Alternative and Classical NF-κB Signaling Retain Autoreactive B Cells in the Splenic Marginal Zone and Result in Lupus-like Disease
Authors: Thomas Enzler, Giuseppina Bonizzi, Gregg J. Silverman, Dennis C. Otero, George F. Widhopf, Amy Anzelon-Mills, Robert C. Rickert, Michael Karin
Journal: Immunity (2006)
Reversal of Abnormal Platelet Aggregability and Change in Exercise Tolerance in Patients with Angina Pectoris Following Oral Propranolol
Authors: WILLIAM H. FRISHMAN, BABETTE WEKSLER, JAMES P. CHRISTODOULOU, CHARLES SMITHEN, THOMAS KILLIP
Journal: Circulation (1974)

Nineteen patients with severe but stable angina pectoris who had positive ECG response to exercise on a bicycle ergometer and 11 normal subjects were studied. Patients received placebo for six weeks and were then randomized into placebo (n = 9) and propranolol (n = 10) treatment groups. Threshold for platelet aggregation in response to adenosine diphosphate (ADP) was measured in fresh platelet rich plasma. Mean concentration of ADP necessary for a biphasic threshold aggregation response was 1.56 µM (geometric mean) in patients and 3.85 µM in normals ( P &lt; 0.01). Serial studies with placebo showed no significant change in ADP threshold. With propranolol, 80 mg/day, platelet aggregation in response to ADP was entirely normalized; 3.79 µM ADP produced maximal aggregation compared to 1.32 µM before therapy ( P &lt; 0.01). No additional changes were noted with propranolol, 160 mg/day. In the propranolol-treated patients (80 mg/day) who demonstrated reduction in ADP-induced platelet aggregation, total work during exercise increased by 128%, from 765 ± 125 (standard error of mean) kpm during the control period to 1,- 792 ± 285 kpm ( P &lt; 0.01). Thus patients with angina and abnormal exercise tolerance demonstrate increased platelet aggregability in vitro which is restored toward normal with propranolol in dosage sufficient to improve exercise tolerance.
Nucleotide degradation and functional impairment during cardioplegia: amelioration by inosine.
Authors: D F DeWitt, K E Jochim, D M Behrendt
Journal: Circulation (1983)

The degradation of adenine nucleotide levels and impairment of functional recovery associated with exposure to hypothermic (20 degrees C) cardioplegia was studied in 84 isolated working rat hearts. After a 1-hour control period, hearts were exposed to 1 hour of cardioplegia that consisted of increasingly longer periods of cardioplegic solution (CPS) infusion (30 seconds and 10, 30 and 60 minutes), followed by increasingly shorter periods of global ischemia (591/2 minutes and 50, 30 and 0 minutes). Hearts were then reperfused for 1 hour with control perfusate, during which recovery of cardiac output was monitored. Additional hearts were freeze-clamped at various points in the protocols to determine adenine nucleotide levels (ATP, ADP, AMP and their sum TAN). Exposure to increasingly longer periods of CPS perfusion resulted in proportionally greater degradation of nucleotides and poorer recovery of cardiac output. Addition of inosine to the recovery perfusate as well as the CPS further improved nucleotide levels and recovery of cardiac output. These results suggest that washout of nucleotide degradation products in the CPS or reperfusion prevents their salvage for nucleotide resynthesis and impairs functional recovery from cardioplegia.
Experts warn public health reforms will lead to job losses and service fragmentation
Authors: M. Limb
Journal: BMJ (2011)

Leading public health experts voiced concerns at a conference over the coalition government’s plans to transform the way public health is delivered.

Warnings came from senior policy makers and service managers about insufficient funding for the reforms, potential service fragmentation, and loss to the system of skilled public health staff.

Some, however, highlighted opportunities under the new approach to integrate services more effectively and improve public health outcomes.

Around 90 people working in public health heard health secretary Andrew Lansley explain his reform plans at a conference organised by the Local Government Committee and the Health Service Journal on 19 January.

Mr Lansley defended the November 2010 public health white paper, Healthy Lives, Healthy People ( BMJ 2010; 341:c6938; doi: 10.1136/bmj.c6938), that underpins the Health and Social Care Bill published on 19 January ( BMJ 2010; 342:d418; doi: 10.1136/bmj.d418).

The changes will see responsibility for public health transferring to local government and leaving the remit of primary …
65 Clinical evaluation of a human monoclonal antibody against the envelope protein (E2) of HCV for prevention of HCV infection
Authors: S. Dagan, R. Eren, N. Graham, O. Nussbaum, D. Terkieltaub, N. Terrault, R. Tur-Kaspa, Y. Lurie, R. Safadi, Z. Akerman, E. Galun
Journal: Journal of Hepatology (2004)
Clonal lymphoproliferation following chronic active Epstein-Barr virus infection and hypersensitivity to mosquito bites
Authors: Shigehiko Ishihara, Shintaro Okada, Hiroshi Wakiguchi, Takanobu Kurashige, Kanji Hirai, Keisei Kawa-Ha
Journal: American Journal of Hematology (1997)

In order to elucidate the possibility of lymphoproliferation in cases of chronic active Epstein-Barr virus infection (CAEBV), to clarify the clonality and genotype of proliferating lymphocytes, and to search for the factors that induce lymphoproliferation, we studied 11 cases of CAEBV, using genetical and immunological techniques. Epstein-Barr virus (EBV) DNA in peripheral mononuclear cells was detected in eight cases by Southern blotting. Among those eight cases, monoclonal proliferation of EBV DNA-positive cells was observed in three cases and oligoclonal proliferation in three cases. In the cases of monoclonal proliferation, one case manifested T-cell lymphoproliferation and the rest natural killer (NK) cell lymphoproliferation. The anti-EBV antibody titers in the study did not have any relativity to lymphoproliferation. On the other hand, three of the four cases of NK cell lymphoproliferation and one of the two cases of T-cell lymphoproliferation exhibited hypersensitivity to mosquito bites (HMB) in their clinical histories, while none of the three nonlymphoproliferation cases did. These facts indicate that T-cell and NK cell lymphoproliferative diseases (LPDs) could be more closely associated with EBV infection than we had previously expected. Also, the anti-EBV antibody titers may not be the indicator of EBV-associated LPD, and HMB may be one of the factors that induce EBV-associated LPD.
Fetal complications of obstetric cholestasis.
Authors: R Reid, K J Ivey, R H Rencoret, B Storey
Journal: BMJ (1976)

Among 56 pregnancies complicated by obstetric cholestasis five intrauterine deaths and one neonatal death occurred between 33 and 39 weeks, and a further six infants required urgent delivery for intrapartum asphyxia. Eighteen spontaneous premature deliveries occurred. Five mothers required specific treatment for unexplained postpartum haemorrhage. Cholestasis of pregnancy is therefore not a condition benign to the fetus, and it may contribute to increased maternal morbidity.
Prothrombin-Time Methods
Authors: Herbert S. Sise
Journal: JAMA (1965)

<h3>To the Editor:—</h3> Oral anticoagulation remains a complicated subject involving many facets, but one variable could be made a constant if the one-stage prothrombin time were carried out by the standard technique outlined over 25 years ago, when I explicitly described the preparation of thromboplastin.<sup>1</sup>This test has not required any modification but is greatly in need of being better understood. It measures primarily the depression of factor VII. By a slight addition, namely, mixing 0.01 ml of aged normal serum with 0.09 ml of the plasma, the test becomes a quantitative measure of free prothrombin.<sup>2</sup>The more elaborate procedure of Owren and Aas, which is based on the concept of the original one-stage test, adds nothing basic to my serum-corrected prothrombin time. Neither method measures total prothrombin but merely the free prothrombin. It seems likely that what Moschos, Wong, and Sise in "Controlled Study of the Effective
Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart
Authors: Sukru Anil Dogan, Claire Pujol, Priyanka Maiti, Alexandra Kukat, Shuaiyu Wang, Steffen Hermans, Katharina Senft, Rolf Wibom, Elena I. Rugarli, Aleksandra Trifunovic
Journal: Cell Metabolism (2014)
Effect of a factor VIII concentrate on type IIB von willebrand's disease‐associated thrombocytopenia presenting during pregnancy in identical twin mothers
Authors: Masahiro Ieko, Shoki Sakurama, Akira Sagawa, Megumi Yoshikawa, Shoichi Nakagawa, Masahiro Satoh, Taro Yasukouchi
Journal: American Journal of Hematology (1990)

Marked thrombocytopenia developed during pregnancy in both identical twins mothers who had systemic lupus erythematosus (SLE) and also type IIB von Willebrand's disease (vWD). The proband's platelet count decreased in the third trimester of pregnancy. Large-dose gamma-globulin and prednisolone treatments were performed because of the suspicion of immune thrombocytopenic reaction associated with SLE. These treatments were not effective. Her platelet count returned to the normal range immediately after delivery. Postpartum examinations revealed the decreased ristocetin cofactor activity and the deficiency of large von Willebrand factor (vWF) multimers in preserved plasma samples from the third trimester. These abnormal findings improved after delivery. Investigation of family members revealed that the proband had inherited type IIB vWD from her mother. The other twin, who was also under treatment for SLE, became pregnant about 1 year after delivery in the proband and followed almost the same course as that observed in the proband. As bleeding tendency was observed a few days before delivery, a factor VIII concentrate (Haemate P) was administered to compete with her variant vWF. This concentrate could prevent the further decrease in her platelet count, thereby correcting the hemorrhagic tendency. It seems evident that factor VII concentrate would be effective in treating thrombocytopenia associated with type IIB vWD.
Complete Transposition of the Great Vessels
Authors: LARRY P. ELLIOTT, HENRY N. NEUFELD, RAY C. ANDERSON, PAUL ADAMS, JESSE E. EDWARDS
Journal: Circulation (1963)

This paper is based on a study of specimens of the heart that were obtained in 60 cases of complete transposition of the great vessels. The external relationship of the aorta and pulmonary trunk usually differed from the classic description of the aorta lying directly anterior to the pulmonary trunk (type III). This relationship was present in only two of the 60 cases. In 39 cases, the relationship of the great vessels was oblique (type I). In 19 of the 60 cases, the relationship of the great vessels was side-to-side (type II). There were two main patterns of origin of the coronary arteries. One had a tendency to be associated with the oblique (type I) relationship of the great vessels, which was most common; the other had a tendency to be associated with the side-to-side (type II) relationship of the great vessels, which was the second most common type. A ventricular septal defect was present in 22 (37 per cent) of the 60 cases. The anatomic characteristics of these defects were the same as occur in cases of an isolated defect in the ventricular septum. It was of particular interest that a left ventricular-right atrial communication was observed in three cases. Miscellaneous conditions observed include congenital obstruction of the aortic arch (eight cases), a right aortic arch in association with a ventricular septal defect and pulmonary stenosis (two cases), and juxtaposition of the atrial appendages (two cases). The atrioventricular valves resembled the homolateral valves of normal hearts. An Ebstein-like malformation of the mitral valve was present in one case.
Aspirin, NSAIDs, and Risk of Prostate Cancer: Results from the REDUCE Study
Authors: Adriana C. Vidal, Lauren E. Howard, Daniel M. Moreira, Ramiro Castro-Santamaria, Gerald L. Andriole, Stephen J. Freedland
Journal: Clinical Cancer Research (2014)

A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy.We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason ≥ 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent ≥1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins, hypertension, diabetes, and cardiovascular disease.Overall, 3,169 men (50%) were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR = 0.85, P = 0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR = 0.81, P = 0.015). Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though all ORs were <1 (all P ≥ 0.08). Therefore, we created a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR = 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR = 0.90, P = 0.15). Results were similar in placebo and dutasteride arms.Among men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted.
Transfection of Inducible Nitric Oxide Synthase Gene Causes Apoptosis in Vascular Smooth Muscle Cells
Authors: Masatora Iwashina, Masayoshi Shichiri, Fumiaki Marumo, Yukio Hirata
Journal: Circulation (1998)

Background —Excess production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in a variety of physiological processes including vascular remodeling. To elucidate whether endogenous NO generated by iNOS is involved in the programmed cell death (apoptosis) of the vasculature, iNOS cDNA– expressing construct was transfected into rat and human vascular smooth muscle cells (VSMCs) by lipofection. Methods and Results —VSMCs transiently transfected with iNOS cDNA functionally expressed 130 kd iNOS protein with full catalytic activity to generate massive NO in proportion to the doses of cDNA used; its enzymatic activity as well as NO production was completely blocked by an NOS inhibitor, N G -monomethyl- l -arginine (LNMMA). Overexpression of iNOS led to a marked inhibition of DNA synthesis as well as induction of apoptosis in VSMCs. Evidence for apoptotic cell death was provided by internucleosomal DNA fragmentation by agarose gel electrophoresis, positive staining for TdT-mediated dUTP biotin nick end-labeling, and appearance of hypodiploid cells by flow cytometry analysis. Apoptosis after transfection with iNOS cDNA was abrogated by LNMMA. Transfection of iNOS cDNA caused accumulation of the tumor suppressor gene p53 but not of bcl-2 , which was also blocked by LNMMA. Conclusions —These results demonstrate that massive generation of endogenous NO derived from iNOS overexpression leads to a marked apoptosis in VSMCs, thus suggesting an important role of NO as a proapoptotic factor for VSMCs in the process of vascular remodeling.
Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens.
Authors: P Scott, P Natovitz, R L Coffman, E Pearce, A Sher
Journal: The Journal of Experimental Medicine (1988)

BALB/c mice can be protected against a normally fatal Leishmania major infection by immunization with a partially purified, soluble subfraction of the parasite (fraction 9). In this study, we demonstrate that a T cell line established against fraction 9, designated line 9, transfers protection equivalent to that obtained by active immunization. In contrast, T cell lines (lines 1 and 9.2) responsive to a nonprotective soluble fraction (fraction 1) not only failed to protect BALB/c mice against L. major, but exacerbated the infection. Most importantly, in addition to differing in their antigen specificity, protective and exacerbative T cells lines could be distinguished on the basis of the lymphokines produced, a characteristic previously used to separate murine Th cells into two subsets, designated Th1 and Th2. We found that the protective cell line, line 9, displayed the Th1 property of secreting IL-2 and IFN-gamma, while the exacerbating lines secreted IL-4 and IL-5, a characteristic of Th2 cells. Our results demonstrate that Th1 and Th2 cells may have dramatically different effects on the outcome of an infection, and suggest that susceptibility and resistance in experimental leishmaniasis may depend upon a balance between the Th subsets induced.
Carcinoma in pleomorphic adenomas.
Authors: D H Patey
Journal: BMJ (1971)

fibrosing alveolitis"8 with the addition of giant cells.In immune disease stimulation and later failure of affected endocrines may be a by-product of the antibody response.Preliminary studies by me of three thyroid patients showed reversal of hyperthyroidism on 15 mg daily of prednisone.The first case, with sarcoid hyperthyroidism, remains euthyroid three months after prednisone was withdrawn.Massive doses of steroids are not always necessary to "block" the thyroid overaction.Hyperthyroidism complicated by temporary myasthenia is rare, but early in- vestigation is important because it may be caused by sarcoidosis.Steroid treatment of myasthenia gravis may be more effective if started sooner.-Iam, etc.,
c-Maf plays a crucial role for the definitive erythropoiesis that accompanies erythroblastic island formation in the fetal liver
Authors: Manabu Kusakabe, Kazuteru Hasegawa, Michito Hamada, Megumi Nakamura, Takayuki Ohsumi, Hirona Suzuki, Tran Thi Nhu Mai, Takashi Kudo, Kazuhiko Uchida, Haruhiko Ninomiya, Shigeru Chiba, Satoru Takahashi
Journal: Blood (2011)
THE RAGE FOR RAPID OPERATING AND THE IMPORTANCE OF SAVING TIME IN SURGICAL OPERATIONS.
Authors: JOHN S. MILLER
Journal: JAMA (1900)

The question of time consumed in surgical operations is an important one. In the pre-anesthesia days time meant much to the unfortunate victim, whose vitality or resisting power was already reduced by nauseating and depressing drugs, such as infusion of tobacco, opium, etc., given with a view to benumbing the sensibility of the patient, who was frequently held by a corps of powerful assistants, or fastened to the operating-table by straight-jackets, straps or other devices. Dexterity and speed on the part of the surgeon then were indeed desirable factors to the shrieking and suffering patient. The introduction of anesthesia lessened the necessity for speed, and also removed the disturbing elements which may have interfered with the accurate fulfilment of delicate operations. Anesthesia, when properly induced, produces a tranquility in the patient, operator, and assistants, which is highly essential for the proper and successful progress of the operation. In this, however,
PHOTO-CONTACT DERMATITIS FROM SOAP
Authors: JOHN N. BURRY, G. F. DONALD
Journal: British Journal of Dermatology (1968)

SUMMARY.— Tribromosalicylanilide (T.B.S.) has been used as an antiseptic in soap in Australia since May 1964. Cases of photosensitivity from soap have been recognized since April 1967. Seven cases comprising I persistent light reaction to T.B.S., 5 transient light reactions to T.B.S. and 1 transient light reaction to hexachlorophane are described. All cases were photo-patch tested to T.B.S., multifungin, fenticlor, bithionol and hexachlorophane, using natural sunlight as the source of ultra-violet energy. Cross-sensitivity between all the test chemicals was proven. No differences could be demonstrated between the patch test responses to three grades of T.B.S. used for patch testing, and all cases primarily sensitized to T.B.S. cross-reacted with multifungin. The nature of the persistent light reaction and the mechanism of its production are discussed.
A Case of Puerperal Septicaemia: Treatment by Antistreptococcus Serum: Recovery
Authors: H. Gervis
Journal: BMJ (1900)

MEDICAL JOURwAl12. The transverse cut across the uterus allowing of easy uetroversion of fundus and facility of applying ligatures to vessels.3. The removal of the whole of the floor of Douglas's pouch.4. The incision in the posterior fornix being made as far back as possible; the resulting scar admitting of no " play" ibetween the bony pelvis and the neck of the bladder.A CASE OF PUERPERAL SEPTIC2EMIA: TREAT-MENT BY ANTISTREPTOCOCCUS SERUM: RECOVERY.