Differences in Treatment Response in Bronchial Epithelial Cells from Idiopathic Pulmonary Fibrosis (IPF) Patients: A First Step towards Personalized Medicine?

Idiopathic pulmonary fibrosis (IPF) has a detrimental prognosis despite antifibrotic therapies to which individual responses vary. IPF pathology is associated with oxidative stress, inflammation and increased activation of SRC family kinases (SFK). This pilot study evaluates individual responses to pirfenidone, nintedanib and SFK inhibitor saracatinib, markers of redox homeostasis, fibrosis and inflammation, in IPF-derived human bronchial epithelial (HBE) cells. Differentiated HBE cells from patients with and without IPF were analyzed for potential alterations in redox and profibrotic genes and pro-inflammatory cytokine secretion. Additionally, the effects of pirfenidone, nintedanib and saracatinib on these markers were determined. HBE cells were differentiated into a bronchial epithelium containing ciliated epithelial, basal, goblet and club cells. NOX4 expression was increased in IPF-derived HBE cells but differed on an individual level. In patients with higher NOX4 expression, pirfenidone induced antioxidant gene expression. All drugs significantly decreased NOX4 expression. IL-6 (p = 0.09) and IL-8 secretion (p = 0.014) were increased in IPF-derived HBE cells and significantly reduced by saracatinib. Finally, saracatinib significantly decreased TGF-ß gene expression. Our results indicate that treatment responsiveness varies between IPF patients in relation to their oxidative and inflammatory status. Interestingly, saracatinib tends to be more effective in IPF than standard antifibrotic drugs.

Endobronchial ultrasound-guided lymph node biopsy with transbronchial needle forceps: a pilot study.

One limitation of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the size of the available needles, frequently yielding only cells for cytological examination. The aim of this pilot study was to evaluate the efficacy and safety of newly developed needle forceps to obtain tissue for the histological diagnosis of enlarged mediastinal lymph nodes. Patients with enlarged, positron emission tomography (PET)-positive lymph nodes were included. The transbronchial needle forceps (TBNF), a sampling instrument combining the characteristics of a needle (bevelled tip for penetrating through the bronchial wall) with forceps (two serrated jaws for grasping tissue) was used through the working channel of the EBUS-TBNA scope. Efficacy and safety was assessed. 50 patients (36 males and 14 females; mean age 51 yrs) with enlarged or PET-positive lymph nodes were included in this pilot study. In 48 (96%) patients penetration of the bronchial wall was possible and in 45 patients tissue for histological diagnosis was obtained. In three patients TBNF provided inadequate material. For patients in whom the material was adequate for a histological examination, a specific diagnosis was established in 43 (86%) out of 50 patients (nonsmall cell lung cancer: n=24; small cell lung cancer: n=7; sarcoidosis: n=4; Hodgkin's lymphoma: n=4; tuberculosis: n=2; and non-Hodgkin's lymphoma: n=2).No clinically significant procedure-related complications were encountered. This study demonstrated that EBUS-TBNF is a safe procedure and provides diagnostic histological specimens of mediastinal lymph nodes.

Non-conventional hemostatic risk factors for coronary heart disease in individuals with spinal cord injury.

STUDY DESIGN: Review. OBJECTIVES: In subjects with spinal cord injury (SCI), there is strong evidence for platelet hyperactivity, which may stimulate atherosclerosis and coronary heart disease (CHD). The literature was reviewed. BACKGROUND: Individuals with SCI develop premature CHD. In addition to the conventional risk factors associated with CHD, there are pathologic hematological factors involved in atherogenesis that are similar to those that have been demonstrated in individuals with diabetes, and these hematological factors might affect individuals with SCI. One such hematological factor, platelet aggregation, is essential for the development of CHD, which results from thrombus formation in the coronary vasculature. Prostacyclin (PGI(2)) is a potent inhibitor of platelet aggregation and is thought to have a beneficial role in inhibiting atherogenesis; therefore, it is possible that individuals with SCI have impaired PGI(2) receptor function. METHODS: We reviewed the literature by conducting a search using PubMed (1970-2007). RESULTS: Acute thrombosis is emerging as an important factor in the etiology of CHD and therefore could mediate the risk of CHD in persons with SCI, in addition to previously known risk factors such as hyperlipidemia, hypertension, hyperlipidemia, diabetes mellitus and hyperinsulinemia. Because PGI(2) may retard atherogenesis through its inhibitory effects on platelet function, we discuss the effects of PGI(2) on platelets in persons with SCI in this review. CONCLUSIONS: Subjects with chronic SCI develop abnormal platelet function, resulting in the production of atherogenic and thrombogenic factors for the following reasons: (1) the PGI(2) and insulin receptors on their platelets are impaired; (2) thrombin generation and platelet-derived growth factor release are elevated; (3) insulin-induced nitric oxide production by platelets is markedly impaired; and (4) a circulating antibody (immunoglobulin G (IgG)) blocks the antithrombotic effect of both insulin and PGI(2) receptors. Thus, this IgG molecule is thought to be one of the pathological mediators of the increased incidence of CHD in individuals with SCI.

Bell and banana pepper exhibit mature-plant resistance to tomato spotted wilt Tospovirus transmitted by Frankliniella fusca (Thysanoptera: Thripidae).

Tomato spotted wilt virus (family Bunyaviridae, genus Tospovirus, TSWV) causes annual economic losses in pepper, Capsicum annuum L., across the southern United States and is transmitted by several species of thrips, including the tobacco thrips, Frankliniella fusca (Hinds). Reduced virus transmission and symptom severity as plant age increases is known as mature-plant resistance. TSWV transmission to pepper plants was examined in three and four age classes in field and greenhouse trials, respectively. In the field trial, 'Camelot' bell pepper plants were exposed to potentially viruliferous F. fusca 37, 51, or 65 d postsowing. Two greenhouse trials of Camelot bell and one trial each of 'Bounty' and 'Pageant' banana pepper plants were exposed to potentially viruliferous F. fusca, 43, 57, 71, or 85; 48, 62, 75, or 90; 42, 56, 70, or 84; and 43, 57, 71, or 85 d postsowing, respectively. Linear and hyperbolic regressions of percentage of infected plants per block on days postsowing indicated mature-plant resistance in all trials. All models were significant, but hyperbolic curves better fit the data than linear models. Hyperbolic models were used to calculate the number of days posttransplant at which a 50% decrease from the predicted percentage of infected plants at transplant age (42 d postsowing) was expected. This was referred to as days posttransplant-50 (DPT50). DPRT50 occurred within 9 days posttransplant age for all trials, indicating that early TSWV management in pepper is critical.

Quantitative analysis of tau isoform transcripts in sporadic tauopathies.

A number of neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by intraneuronal accumulation of the tau protein. Some forms of FTDP-17 are caused by mutations in the tau gene affecting exon 10 splicing. Therefore, dysregulation of tau pre-mRNA splicing may be a contributing factor to sporadic tauopathies. To address this question, we devised a real-time RT-PCR strategy based on the use of a single fluorogenic probe to evaluate the ratio between tau isoforms containing or lacking exon 10 (4R/3R ratio) in post-mortem brain samples. We found a two- to six-fold increase in the 4R/3R ratio in cases of FTDP-17 linked to a splice site mutation, hence confirming the validity of the strategy. The difference in the 4R/3R ratio in the superior temporal and superior frontal gyri between AD and control brains was not statistically significant. Similarly, there was no significant difference in the 4R/3R ratio between Pick's disease cases and controls, indicating that the predominance of tau3R protein in PiD reflects post-translational modifications of specific isoforms. This study indicates that post-translational events are likely to be the main factors controlling tau isoform composition in sporadic tauopathies and highlights the benefit of quantitative RT-PCR in the assessment of splicing abnormalities in tauopathies.

[Carcinoid tumor from the small bowel]. / Tumeur carcinoïde de l'intestin grêle.

Carcinoid tumors are non-pancreatic digestive neuroendocrine tumors well differentiated. Most of time they are developed from enterochromaffin cells of the digestive tract. Most of them are localized in ileum, rectum, stomach and appendix. Only bronchi are a frequent extra-digestive localization (20 to 25%). Most of these tumors are asymptomatic and discovered incidentally during a laparotomy or secondary to the exploration of a carcinoid syndrome. From a case report and a recent review of literature, diagnosis, histology and treatment of small bowel carcinoid tumors are summarized.

What people want from their family physician.

The public wants and is satisfied by care provided within a patient-physician relationship based on understanding, honesty, and trust. If the U.S. health care system is ever to become patient-centered, it must be designed to support these values and sustain, rather than fracture, the relationships people have with their primary physician.

Few people in the United States can identify primary care physicians.

Almost one decade after the Institute of Medicine (IOM) defined primary care, only one third of the American public is able to identify any of the medical specialties that provide it, and only 17 percent were able to accurately distinguish primary care physicians from medical or surgical specialists and non-physicians. This lack of discrimination compromises the goal of achieving primary care for all and merits immediate attention.

Complexity analysis of placental blood flow in normal and high-risk pregnancies.

Various strategems of complexity analysis of microvascular blood flow were carried out in several fields of medicine in the past, as such as angiology, ophthalmology and neurology. The introduction of colour-angio-mode, a special form of colour coded Doppler sonography, now makes possible to perform complexity analysis of the placental blood displacement even in the absence of information about hydrodynamic details such as directionality, velocity profile and number of displaced blood cells. Algorithms were developed which allows to extract information concerning the time averaged power of phonon-erythrocytes collision events (from the square of the frequencies of back scattered ultrasound recorded during 166 ms) in 20,000 to 40,000 regions of interest. The obtained values are being displayed as false coloured pixels on a video-screen, we succeeded to obtain quantitative data about displacement rates.In cross-sectional and longitudinal studies we generated typical diagrams displaying the "occurrence rate" of various powers of displacement over time. By this mode of display contour plots can be generated, showing a large amount of low intensity pixels and a small amount of high intensity pixels representing the parenchymatous blood flow inside the placenta. As was to be expected, interdependencies between the placental blood flow and the maternal and fetal heart rates as well as the maternal breathing can be found. While there was only limited influence of maternal and fetal heart rate on the placental blood flow, maternal breathing showed striking influence. Surprisingly, during expiration the power of placental blood movement was decreased, and there was a marked increase during inspiration. In cases of severe intrauterine growth retardation, colour pixel intensities were seen to transiently vanish during end-expiration. The power of placental blood displacement was marked increased subsequent to reducing maternal hematocrit during hemodilution therapy by infusion of artificial colloids. These interdependencies could be confirmed by ex vivo examinations perfusing and percolating the placenta after birth in a hemodynamic model. Additionally, we found interdependencies between fetal and maternal blood displacement inside the placenta. By modelling the decrease of fetal inotropic power in the ex vivo examinations, increase in the power of maternal blood displacement in the intervillous space. The two types of placental blood flow are known to be determined by many factors. While it is currently impossible to measure all these parameters determining an parenchymatous blood flow, it is possible to obtain useful informations about the physiologic and pathophysiologic changes of placental blood flow using colour-angio-mode as a tool of complexity analysis based on the distribution of local blood displacement. This new knowledge can help to understand clinically relevant changes in the individual patient as well their underlying causes.

Entry of US medical school graduates into family practice residencies: 2000-2001 and 3-year summary.

This is the 20th report prepared by the American Academy of Family Physicians (AAFP) on the percentage of each US medical school's graduates entering family practice residency programs. Approximately 12.8% of the 15,825 graduates of US medical schools between July 1999 and June 2000 were first-year family practice residents in 2000, compared with 13.4% in 1999 and 15.4% in 1998. Medical school graduates from publicly funded medical schools were almost twice as likely to be first-year family practice residents in October 2000 than were residents from privately funded schools, 15.6% compared with 8.7%. The West North Central region reported the highest percentage of medical school graduates who were first-year residents in family practice programs in October 2000 at 18.2%; the Middle Atlantic and New England regions reported the lowest percentages at 8.3% and 6.8%, respectively. Nearly half of the medical school graduates (47.0%) entering a family practice residency program as first-year residents in October 2000 entered a program in the same state where they graduated from medical school. The percentages for each medical school have varied substantially from year to year since the AAFP began reporting this information. This article reports the average percentage for each medical school for the last 3 years. Also reported are the number and percentage of graduates from colleges of osteopathic medicine who entered Accreditation Council for Graduate Medical Education-accredited family practice residency programs, based on estimates provided by the American Association of Colleges of Osteopathic Medicine.

Results of the 2001 National Resident Matching Program: family practice.

The results of the 2001 National Resident Matching Program (NRMP) reflect a persistent decline of student interest in family practice residency training in the United States. Compared with the 2000 Match, 240 fewer positions (317 fewer US seniors) were filled in family practice residency programs through the NRMP in 2001, as well as 76 fewer (47 fewer US seniors) in primary care internal medicine, 5 fewer in pediatrics-primary care (7 fewer US seniors), and 7 fewer (1 fewer US senior) in internal medicine-pediatric programs. In contrast, 40 more positions (64 more US seniors) were filled in anesthesiology and 11 more (10 more US seniors) in diagnostic radiology, two "marker" disciplines that have shown increases over the past 3 years. Ninety-one fewer positions (2 fewer US seniors) were also filled in categorical internal medicine, while 49 more positions (67 more US seniors) were filled in categorical pediatrics programs, where trainees perceive options for either practicing as generalists or entering subspecialty fellowships, depending on the market. While the needs of the nation, especially rural and underserved populations, continue to offer a market for family physicians, family practice experienced a fourth year of decline though the 2001 NRMP. Current forces, including student perspectives of specialty prestige, the turbulence of the health care environment, media hype, market factors, lifestyle choices, and student debt, all appear to be influencing many students to choose subspecialty rather than primary care careers.

The Interdisciplinary Generalist Curriculum (IGC) project: an overview of its experience and outcomes.

The Interdisciplinary Generalist Curriculum (IGC) Project was a competitive, seven-year demonstration project funded by the Health Resources and Services Administration (HRSA). It was established to determine whether specific interdisciplinary innovations in preclinical medical school curricula could affect students' selection of careers in family medicine, general internal medicine, or general pediatrics. Through collaboration among the three generalist disciplines, the IGC innovation exposed all preclinical students in ten demonstration schools to a new or significantly enhanced preclinical curriculum that included a direct supervised clinical experience with a generalist physician preceptor. The project was managed by an interdisciplinary executive committee that was codirected by one representative each from family medicine, general internal medicine, and general pediatrics. A national advisory committee with representation from the academic and professional organizations of family medicine, internal medicine, pediatrics, and osteopathy provided input to the executive committee in guiding the project. The project was externally evaluated. Major outcomes of the IGC Project include sustained curricular changes in ten institutions, prompted by relatively few dollars and demonstration of models for collaboration at institutional and national levels. This supplement describes the IGC Project's experience and outcomes so that others may draw pertinent information to apply to their own efforts in medical education.

Implementation of the Interdisciplinary Generalist Curriculum Project: considerations of structure, funding, and design.

Implementation of the Interdisciplinary Generalist Curriculum (IGC) Project involved complex processes that reflect structural, funding, and intervention design considerations. Among structural considerations, the IGC Project benefited from a national structure above the level of the demonstration schools. Governance by committee was highly effective because it harnessed and balanced power. At the national level, governance by committee was enhanced by strong central coordination, and it had a role-modeling effect for governance at the school level. The IGC experience over the seven-year course of the project suggests that it is important to revisit the role of a national advisory committee over time and to revise that role as warranted. Funding considerations, including the importance of funding evaluation for a period of time long enough to measure intended impacts and the length and amount of funding to demonstration schools, are discussed. Prescription of the IGC intervention and the focus on years one and two of medical education are critical design considerations. The authors conclude that the IGC Project used relatively few federal dollars to demonstrate a highly prescribed intervention in a limited number of medical schools toward a clear and limited goal. IGC lessons apply to programs specifically targeting primary care education, but also to other medical school curricular innovations, and perhaps, to a larger framework of multi-site educational interventions.

Curricular change: recommendations from a national perspective.

Recommendations on future directions, funding, and organizational and curricular issues have emerged from the complexity of the Interdisciplinary Generalist Curriculum (IGC) Project. For example, future demonstration projects aimed at innovations in medical education that are funded through the contracting mechanism are recommended, and funding intended to serve as institutional leverage for demonstrating desired curricular innovations in medical education is encouraged. Funding provided to entities that can maximize influence within the institutions is recommended. Also, the period of time over which funds are provided needs to take into consideration the breadth of the impact of the funded program on the larger curriculum and the length of time needed to measure desired outcomes. Organizational findings are that multi-site projects with administrative oversight bodies should be governed by representatives of concerned disciplines who have stakes in the demonstration of the innovations in medical education, and roles of the executive and advisory committees involved in the effort need to be made explicit at the onset and revisited over time. Similarly, the role of the funder needs to be explicit. Curricular recommendations are that medical schools are encouraged to develop longitudinal generalist preceptorship experiences early in medical education for all students, regardless of their eventual career choices. Schools should anticipate that curricular innovations in the preclinical years may require modifications of the educational process in the clinical years.

Impaired platelet prostacyclin receptor activity: a monozygotic twin study discordant for spinal cord injury.

Coronary artery disease (CAD) has been reported to occur prematurely in individuals with spinal cord injury (SCI). Although persons with SCI have metabolic abnormalities that may predispose them to CAD, other potential aetiologies may also be operative. Increased platelet aggregation, among other factors, initiates thrombus formation at the site of the vessel injury, which may acutely obstruct arterial blood flow. Prostacyclin is known to have a beneficial effect to inhibit platelet aggregation and prevent thrombus formation. Platelets were studied from 12 pairs of monozygotic twins, one co-twin with SCI. Each twin pair had similar patterns of platelet aggregation with adenosine diphosphate (ADP), thrombin or collagen, as well as inhibition of platelet aggregation by prostacyclin (PGE1/I2) and synthesis of cyclic adenosine mono phosphate (AMP) by the prostanoid. However, the twin pairs differed in their response to PGE1/I2 inhibition of platelet-stimulated thrombin generation that was completely inhibited in non-SCI platelets but not in SCI platelets. Scatchard analysis of the binding of 3H-prostaglandin E1, a stable prostacyclin receptor probe, showed the presence of one high-affinity (Kd1=8.1 +/- 2.8 nM; nl=168 +/- 35 sites per platelet) and one low-affinity (Kd2=1.1 +/- 0.22 microM; n2=1772 +/- 220 sites per cell) prostacyclin receptor in normal platelets, whereas in SCI platelets there was a significant loss (P<0.00l) of high-affinity receptor sites (Kd1=6.34 +/- 1.80 nM; n1=42 +/- 11 sites per platelet) with no significant change in the low-affinity receptor sites (Kd2=1.2 +/- 0.23 microM; n2=1860 +/- 412 sites per cell). These discordant platelet findings in identical twin pairs raises the possibility of an environmental aetiology for accelerated CAD in those with SCI. The loss of inhibitory effect of PGI2 on thrombin generation in the twin with SCI appears to be because of loss of platelet high-affinity prostanoid receptors, which may contribute to atherogenesis in individuals with SCI.

Purification and properties of insulin-activated nitric oxide synthase from human erythrocyte membranes.

A membrane bound form of nitric oxide synthase of human erythrocytes that could be activated by insulin was purified to homogeneity by detergent solubilization of the purified membrane preparation of these cells. The purified enzyme (M(r) 230 KD) was found to be composed of one heavy chain (M(r) 135 KD) and one light chain (Mr 95 KD) held together by disulphide bond(s). Scatchard plot analysis of insulin binding to the purified enzyme showed the presence of 2 different populations of the binding sites and the activation were directly related to the hormone binding to the protein. Line weaver Burk plot of the purified enzyme showed that the stimulation of the enzymic activity by insulin was related to the decrease of K(m) with simultaneous increase of V(max). Treatment of the purified enzyme with anti insulin receptor antibody inhibited the activation of the enzyme and the binding of the hormone to the protein. Furthermore NO itself, at low concentration (<0.4 microM) activated the enzyme, but at higher concentration (>0.8 microM) had no effect on the activation. Incubation of the purified enzyme with insulin simultaneously stimulated the tyrosine kinase and nitric oxide synthase activities of the preparations, that could be inhibited by genistein (an inhibitor of tyrosine kinase). These results indicated that the insulin activated nitric oxide synthase could be the insulin receptor itself.

Entry of US medical school graduates into family practice residencies: 1999-2000 and 3-year summary.

This is the 19th report prepared by the American Academy of Family Physicians (AAFP) on the percentage of each US medical school's graduates entering family practice residency programs. Approximately 13.4% of the 16,143 graduates of US medical schools between July 1998 and June 1999 were first-year family practice residents in 1999, compared with 15.4% in 1998 and 16.6% in 1997. Medical school graduates from publicly funded medical schools were almost twice as likely to be first-year family practice residents in October 1999 than were residents from privately funded schools, 16.2% compared with 9.3%. The West North Central region reported the highest percentage of medical school graduates who were first-year residents in family practice programs in October 1999 at 20.6%; the Middle Atlantic and New England regions reported the lowest percentages at 7.7% and 8.0%, respectively. Nearly half of the medical school graduates (48.4%) entering a family practice residency program as first-year residents in October 1999 entered a program in the same state where they graduated from medical school. The percentages for each medical school have varied substantially from year to year since the AAFP began reporting this information. This article reports the average percentage for each medical school for the last 3 years. Also reported are the number and percentage of graduates from colleges of osteopathic medicine who entered Accreditation Council for Graduate Medical Education-accredited family practice residency programs, based on estimates provided by the American Association of Colleges of Osteopathic Medicine.