Miracle-dz/UniFAR-FTUs huggingface dataset:
Non-infectious pulmonary complications of newer biological agents for rheumatic diseases--a systematic literature review.

OBJECTIVE Lung disease is commonly encountered in rheumatological practice either as a manifestation of the underlying condition or as a consequence of using disease-modifying therapies. This has been particularly apparent with the TNF-α antagonists and exacerbations of interstitial lung disease (ILD). In view of this, we undertook a review of the current literature to identify non-infectious pulmonary complications associated with the newer biologic agents used for the treatment of rheumatic conditions. METHODS A systematic literature review (SLR) was conducted using PubMed, the Cochrane Library and EMBASE for reviews, meta-analyses, clinical studies and randomized controlled trials, case studies and series, published up to June 2010 using the terms rituximab (RTX), certolizumab, golimumab (GOL), tocilizumab (TCZ) and abatacept in the advanced search option without limitations. In addition, abstracts from International Rheumatology conferences and unpublished data from the Food and Drug Administration, the European Medicines Agency and drug manufacturers were used to complement our search. References were reviewed manually and only those articles that suggested a potential relationship between the biological agent and lung toxicity, following exclusion of other causes, were included. RESULTS Reported non-infectious pulmonary adverse events with TCZ included a fatal exacerbation of RA-associated ILD, new-onset ILD, idiopathic pulmonary fibrosis and allergic pneumonitis, as well as three cases of microbiological culture-negative pneumonia. Although RTX had a higher incidence of pulmonary toxicity, only 7 of the 121 cases reported involved rheumatological diseases. GOL treatment was associated with four cases of non-infectious pulmonary toxicity and two cases of pneumonia with negative microbiological studies. There were no episodes of pulmonary toxicity identified for either certolizumab or abatacept. CONCLUSION Our results highlight an association between the use of newer biologic agents (TCZ, RTX and GOL) and the development of non-infectious parenchymal lung disease in patients with RA. Post-marketing surveillance and biologic registries will be critical for detecting further cases of ILD and improving our understanding of the pathophysiology of this process. As the use of these drugs increases, clinicians must remain vigilant for potential pulmonary complications and exercise caution in prescribing biologic therapies, particularly to rheumatological patients with pre-existing ILD.
Phenotypic and functional profiling of malaria‐induced CD8 and CD4 T cells during blood‐stage infection with Plasmodium yoelii

It is widely accepted that antibodies and CD4 T cells play critical roles in the immune response during the blood stage of malaria, whereas the role of CD8 T cells remains controversial. Here, we show that both CD8 and CD4 T cells robustly responded to an acute self‐limiting blood‐stage infection with Plasmodium yoelii. Similar to antigen‐specific T cells, both CD8 and CD4 T cells showed dynamic expression of the surface proteins interleukin (IL)‐7R and programmed death‐1 (PD‐1). Additionally, activated CD8 T cells showed differences in the expression of Killer cell lectin‐like receptor G1, L‐selectin and B cell lymphoma‐2 and produced granzyme B, indicating cytotoxic activity, and the initially high expression of T‐box transcription factor TBX21 in malaria‐activated CD4 T cells indicated an early T helper type 1 (Th1)‐skewed immune response. Our data demonstrate that blood‐stage malaria infection results in a striking T‐cell response and that activated CD8 and CD4 T cells have phenotypic and functional characteristics that are consistent with conventional antigen‐specific effector and memory T cells. Therefore, a better understanding of the CD8 and CD4 T‐cell response induced by blood‐stage infection may prove to be essential in the development of a vaccine that targets the erythrocytic stage of the malarial parasite.
Laparoscopy Training Courses in Urology

The history of laparoscopic surgery began with man’s attempts to inspect concealed areas of the body. Early endoscopy from Bozzini’s “lichtleiter” in 1805 to the development of modern cystoscopy by Nitze in the late 1800s helped develop the optical tools required for laparoscopy. The early 1900s saw the birth of laparoscopy with Kelling, a surgeon from Dresden, describing the technique of celioscopy in dogs and Jacobaeus from Sweden reporting two cases of thoraco-laparoscopy in which he used a trocar to create pneumoperitoneum in humans and then inserted a cystoscope. Kurt Semm, an engineer and gynecologist helped develop many of the other tools associated with laparoscopy including an automatic insufflation device that monitored gas flow and intra-abdominal pressure, thermocoagulation for use during the procedure as well as many early laparoscopy instruments. (Gomella & Strup, 1994) The first laparoscopic nephrectomy was performed by Clayman and colleagues in 1990. (Clayman et al., 1991) With improvements and refinement of the technology, the first laparoscopic living donor nephrectomy soon followed. (Ratner et al., 1995) In 1997, Nakada and colleagues, performed the first hand-assisted laparoscopic nephrectomy (HALN) with a sleeve in the United States. (Nakada et al., 1997) By placing a hand in the abdomen, the HALN provided urologists tactile sensation and helped decrease the learning curve for laparoscopy. (Gaston KE et al., 2004) The hand-assisted approach also allowed older urologists that had not been trained in laparoscopy to begin to perform laparoscopic cases and helped bridge the gap from open surgery and a pure laparoscopic approach. (Munver R et al., 2004) With the rapid advances in technology in the field of urology, post-graduate training courses are important to help bridge the technology gap for current practicing urologists. The development of newer high-fidelity simulators and metrics for assessing laparoscopic skill acquisition are essential in order for us to better teach laparoscopic surgery.
Crystal Structure of a Josephin-Ubiquitin Complex

The Josephin domain is a conserved cysteine protease domain found in four human deubiquitinating enzymes: ataxin-3, the ataxin-3-like protein (ATXN3L), Josephin-1, and Josephin-2. Josephin domains from these four proteins were purified and assayed for their ability to cleave ubiquitin substrates. Reaction rates differed markedly both among the different proteins and for different substrates with a given protein. The ATXN3L Josephin domain is a significantly more efficient enzyme than the ataxin-3 domain despite their sharing 85% sequence identity. To understand the structural basis of this difference, the 2.6 Å x-ray crystal structure of the ATXN3L Josephin domain in complex with ubiquitin was determined. Although ataxin-3 and ATXN3L adopt similar folds, they bind ubiquitin in different, overlapping sites. Mutations were made in ataxin-3 at selected positions, introducing the corresponding ATXN3L residue. Only three such mutations are sufficient to increase the catalytic activity of the ataxin-3 domain to levels comparable with that of ATXN3L, suggesting that ataxin-3 has been subject to evolutionary restraints that keep its deubiquitinating activity in check.
Cytotoxic T lymphocyte perforin and Fas ligand working in concert even when Fas ligand lytic action is still not detectable

The reason(s) why individual cytotoxic T lymphocytes (CTL) possess a fast‐acting, perforin/granzyme‐mediated, as well as a much slower, Fas ligand (FasL) ‐driven killing mechanism is not clear, nor is the basis for wide variations in killing activity exhibited by individual CTL, ranging from minutes to hours. We show that perforin expression among individual, conjugated CTL varies widely, which can account for the heterogeneity in killing speeds exhibited by individual CTL. Despite a 2‐hr lag in FasL‐based killing, CTL lytic action is enhanced when the two mechanisms operate in concert. This is explained by finding that the two pathways in fact are jump‐started simultaneously with the lag in FasL lytic action reflecting pre‐lytic caspase‐8 activation and BH3‐interacting domain (BID) cleavage. The complementary action of the two lytic pathways, co‐expressed at varying levels among individual CTL, facilitates the lytic action of late‐stage poor perforin‐expressing CTL, ensuring optimal cytocidal action throughout the CTL response.
Local Sequence Targeting in the AID/APOBEC Family Differentially Impacts Retroviral Restriction and Antibody Diversification*

Nucleic acid cytidine deaminases of the activation-induced deaminase (AID)/APOBEC family are critical players in active and innate immune responses, playing roles as target-directed, purposeful mutators. AID specifically deaminates the host immunoglobulin (Ig) locus to evolve antibody specificity, whereas its close relative, APOBEC3G (A3G), lethally mutates the genomes of retroviral pathogens such as HIV. Understanding the basis for the target-specific action of these enzymes is essential, as mistargeting poses significant risks, potentially promoting oncogenesis (AID) or fostering drug resistance (A3G). AID prefers to deaminate cytosine in WRC (W = A/T, R = A/G) motifs, whereas A3G favors deamination of CCC motifs. This specificity is largely dictated by a single, divergent protein loop in the enzyme family that recognizes the DNA sequence. Through grafting of this substrate-recognition loop, we have created enzyme variants of A3G and AID with altered local targeting to directly evaluate the role of sequence specificity on immune function. We find that grafted loops placed in the A3G scaffold all produced efficient restriction of HIV but that foreign loops in the AID scaffold compromised hypermutation and class switch recombination. Local targeting, therefore, appears alterable for innate defense against retroviruses by A3G but important for adaptive antibody maturation catalyzed by AID. Notably, AID targeting within the Ig locus is proportionally correlated to its in vitro ability to target WRC sequences rather than non-WRC sequences. Although other mechanisms may also contribute, our results suggest that local sequence targeting by AID/APOBEC3 enzymes represents an elegant example of co-evolution of enzyme specificity with its target DNA sequence.
Targeting prevention programs for young and new healthcare workers: what is the association of age and job tenure with occupational injury in healthcare?

BACKGROUND previous evidence suggests young and new workers experience an increased risk of occupational injury. We sought to confirm this observation for healthcare workers. METHODS a retrospective cohort of 42,771 healthcare workers (88.2% women) was constructed from an active injury surveillance database. Over 2 years, incidence rates and crude and adjusted relative risks for occupational injury were compared between age groups and job tenures. RESULTS there were opposite trends in the two main types of injuries which cancelled each other: new workers and young workers had a decreased (not increased) risk of musculoskeletal sprain and strain injuries (adjusted RR [95% CI] for new hires was 0.60 [0.48, 0.73], and 0.85 [0.73, 0.98] for workers <25 years old); but an increased risk of cut and puncture injuries (1.25 [1.07, 1.45] for new hires, 1.28 [0.99, 1.67] for workers <25 years old). CONCLUSIONS contrary to studies of other sectors, younger age and shorter tenure were not universal risk factors for occupational injuries in the female dominated healthcare sector. Young and new workers had increased risk of cuts and punctures, but a decreased risk of musculoskeletal injuries.
Human natural killer cells expressing the memory‐associated marker CD45RO from tuberculous pleurisy respond more strongly and rapidly than CD45RO− natural killer cells following stimulation with interleukin‐12

Natural killer (NK) cells are known as innate immune lymphocytes that respond rapidly when challenged by pathogens but little is known about adaptive immune features including memory related to NK cells from human beings. In the present study, we demonstrate for the first time that human NK cells expressing the memory‐associated marker CD45RO were persistent in pleural fluid cells (PFCs) from tuberculous patients. CD45RO+ NK cells produced significantly more interferon‐γ and were more cytotoxic compared with CD45RO− NK cells from PFCs when stimulated with interleukin‐12 (IL‐12). Consistently, IL‐12 enhanced the expression of granzyme B, CD69, CD25, NKG2D, IL‐12 receptors β1 and β2 on CD45RO+ NK cells from PFCs. Our experiments contribute to a better understanding of the NK cells from PFCs and indicate that human CD45RO+ NK cells from PFCs expressing a ‘memory‐like’ phenotype may have an important role in defending against infection by Mycobacterium tuberculosis.
Long‐term carriers generate Epstein–Barr virus (EBV)‐specific CD4+ and CD8+ polyfunctional T‐cell responses which show immunodominance hierarchies of EBV proteins

T cells simultaneously producing multiple cytokines and possessing cytotoxic capacity termed polyfunctional cells (PFCs) are increasingly recognized as the immune correlate of protection against pathogenic viruses. We investigated co‐expression of four cytokines (interferon‐γ, macrophage inflammatory protein 1‐α, tumour necrosis factor‐α and interleukin‐2) and degranulation capacity (CD107a surface expression) of Epstein–Barr virus (EBV) ‐specific CD4+ and CD8+ T cells upon stimulation by overlapping peptides of EBV lytic (BZLF1) and latent (EBNA1, EBNA3 and LMP2) proteins, in 20 healthy Chinese long‐term carriers. Two patients with post‐transplant lymphoproliferative disorder (PTLD), who had impaired T‐cell immunity, were studied for comparison. Both EBV‐specific CD4+ and CD8+ PFCs were readily generated in long‐term carriers and showed immunodominance hierarchies of latent proteins (EBNA1 > EBNA3/LMP2 and EBNA3 > LMP2 > EBNA1 for CD4+ and CD8+ T cells, respectively), as evidenced by a higher proportion of PFCs generated by immunodominant EBV proteins than by subdominant viral proteins. In contrast, the proportion of EBV‐specific PFCs was markedly decreased in patients with PTLD. The EBV‐specific PFCs produced more cytokine per cell than single‐functional T cells and comprised different subsets. Five‐functional CD4+ and CD8+ T cells were detected and four‐functional CD4+ T cells were mainly CD107a negative and expressed all four cytokines whereas four‐functional CD8+ T cells were mainly CD107a positive and expressed three of the four cytokines (interleukin‐2‐negative). We conclude that EBV‐specific PFCs are generated in much higher proportions in the long‐term carriers than in the patients with PTLD and maintain the immunodominant characteristics of the virus.
Antiobesity activity of aqueous and ethanol extracts of Enicostemma littorale in high fat diet induced obese rats

Obesity is a chronic disorder of global prevalence and associated with morbidity and mortality. Therefore, attention is being focused on the investigation of plant-based drugs used in the traditional medicine for the treatment of obesity. The presents work evaluates the anti-lipase and antiobesity activity of ethanol and aqueous extracts of Enicostemma littorale (ElEe & ElAe) (Genitanaceae) (Synonym – Enicostemma axillare ) in HFD induced obesity in rats. Male Wistar rats weighing 150-200 g were divided into different group’s i.e. Normal control, HFD control, Orlistat (lipase inhibitor), ElEe & ElAe at doses of 200, 400, 250 and 500 mg/kg p.o . Treatment was started after 6 weeks upto 12 weeks alongwith HFD (except normal control). Oxidative stress was measured by measuring MDA, SOD and GSH level. Obesity was assessed by measuring morphological parameters, serum glucose, serum cholesterol, triglycerides and HDL level. ElEe & ElAe at 200, 400, 250 and 500 mg/kg/orally significantly attenuated morphological parameters i.e. weight gain, BMI, WHR, obesity index and adiposity index respectively as compare to HFD control group. Similarly, serum glucose, triglyceride, total cholesterol and oxidative stress were found to be attenuated as compare to HFD control group. The aqueous and ethanol extracts of Enicostemma littorale exhibit significant anti-lipase and antiobesity activity in high fat diet induced obesity in rats.
"Sarcoid like" granulomatous pulmonary disease (SLGPD) in WTC responders.

The WTC Medical Monitoring and Treatment Program (MMTP) centered at Mount Sinai is appreciated for adding its report on an increased incidence of SLGPD [Crowley et al., 2011] to those published by the New York Fire Department [Izbicki et al., 2007] and presented by the WTC Health Registry [Jordan et al., 2008]. The authors make a valuable contribution in refining the estimate of the exposed population. Their case identification methods leave open the question of patients entering the MMTP because they had been diagnosed with sarcoidosis elsewhere and were seeking benefits or advised to contribute their experience to the program. This is another source of bias to that of making a diagnosis or an earlier diagnosis because the patient was enrolled in the program. Another issue raised by these reports is howwell SLGPD resembles the disease sowell known especially to pulmonologists as sarcoidosis, a disease remarkable for its diverse clinical manifestations. The patients reported by Crowley et al. are indeed more consistent with sarcoidosis than those reported by Izbicki who had less frequent extrathoracic involvement. The authors had the singular opportunity to utilize a diagnostic modality for sarcoidosis which is unique for its specificity and for its availability at, and identification with, Mount Sinai, namely the Kveim–Siltzbach test. Louis Siltzbach, who did much to standardize and demonstrate the usefulness of the test, was Chief of Pulmonary Medicine at Mount Sinai. In his classic article, ‘‘The Kveim Test in Sarcoidosis,’’ in 1961, he reported 84% positivity in 165 patients with biopsy proven sarcoidosis compared with<1% (possibly 2 patients) among 303 patients with other diseases including such granulomatous diseases as tuberculosis and Crohn’s disease. He concluded that ‘‘wide use of the test may help to determinewhether sarcoidosis is the same disease’’ in its various settings [Siltzbach, 1961]. The authors made use of the Kveim test as one proof of the diagnosis in an unidentified number of patients. Information on its rate of positivity in various presentations of SLGPDwould domuch to address the issue of whether WTC SLGPD is truly sarcoidosis. It is disappointing that authors from an institution so wealthy in both WTC and sarcoidosis patients have not provided fuller information on their cases of SLGPD. Pulmonary function testing in their 38 cases was limited to spirometry (itself lacking in a third of the patients). Decreased exercise tolerance and its equivalent, shortness of breath, were not graded or described anymore specifically. No mention was made of indications for or response to therapy. These remarks may be interpreted as a plea for a follow-up report.
The burden of occupational injury: a 1-year prospective study in Xuan Tien Commune, Viet Nam.

BACKGROUND Developing nations carry a substantial portion of the global burden of injury, but without reliable injury surveillance, there is no way to characterize or prioritize the causes of work-related injury for prevention. METHODS Injury data from 52 treatment sites in the Xuan Tien Commune, Vietnam with over 10,000 inhabitants were collected between January 1 and December 31, 2006. Injured residents were interviewed to determine work-relatedness, relevant causes, disability, and burden. RESULTS Five hundred four work-related injuries were reported from formal treatment sites (incidence rate of 87 per 1,000 FTE) with a mean lost work day of 11 days. Four thousand five hundred seventy-four lost work day equivalents were estimated based on actual days lost to recover plus work days lost earning income to pay for medical costs, accumulating a total direct burden to the community of 8,641 lost work day equivalents. Almost half of that burden was caused by work in manufacturing. First aid boxes placed in 40 manufacturing enterprises yielded the 2nd highest reporting source. CONCLUSION This study demonstrated the feasibility and value at the local level to build an active injury surveillance system which could have a large impact on preventing the burden of injuries in workplaces in Vietnam.
Social marketing to plan a fall prevention program for Latino construction workers.

BACKGROUND Latino construction workers experience disparities in occupational death and injury rates. The Occupational Safety and Health Administration funded a fall prevention training program at the University of Nevada, Las Vegas in response to sharp increases in fall-related accidents from 2005 to 2007. The grant's purpose was to improve fall protection for construction workers, with a focus on Latinos. This study assessed the effectiveness of social marketing for increasing fall prevention behaviors. METHODS A multi-disciplinary team used a social marketing approach to plan the program. We conducted same day class evaluations and follow-up interviews 8 weeks later. RESULTS The classes met trainee needs as evidenced by class evaluations and increased safety behaviors. However, Spanish-speaking Latinos did not attend in the same proportion as their representation in the Las Vegas population. CONCLUSIONS A social marketing approach to planning was helpful to customize the training to Latino worker needs. However, due to the limitations of behavior change strategies, future programs should target employers and their obligation to provide safer workplaces.
The Evolution of Aortic Aneurysm Repair: Past Lessons and Future Directions

The history and evolution of aortic aneurysm repair demonstrates an important paradigm within surgery, namely the importance of surgical pioneers and innovators who have strived to achieve technical excellence and improve patient care. It also highlights the wider evolution of surgery from traditional open operative techniques to the modern minimally invasive procedures. The following chapter discusses the surgical innovators and the techniques they have described that have enabled the repair of both thoracic aortic aneurysms (TAA) and abdominal aortic aneurysms (AAA). Aortic aneurysms represent a significant health risk particularly for the elderly population. AAA is the 14th-leading cause of death for the 60- to 85-year–old age group in the United States (10.8 deaths per 100,000 population). TAA by contrast is less frequent with an incidence of 10.4 per 100,000. Both AAA and TAA are known to increase in prevalence with advancing age and have an increased prevalence in males. The risk of aneurysm rupture increases with increasing aneurysm diameter over 5.5-6.0 cm and is the primary indication for the repair of both TAA and AAA.Therefore surgery to repair both AAA and TAA is either pre-emptive to prevent rupture or emergent to repair a rupture. Repair of TAA and AAA by either open or minimally invasive techniques significantly reduces the risk of rupture and improves patient mortality. The establishment of these techniques has required the development of procedures from embryonic thoughts in the minds of the surgeons of antiquity through to the utilisation of ever increasing modern technologies.