Introduction
Rheumatoid arthritis (RA) is a common systemic autoimmune disease of unknown cause, characterized by a chronic, symmetric, and progressive inflammatory polyarthritis. One of the most ...deleterious effects induced by the chronic inflammation of RA is bone loss. During the last 15 years, the better knowledge of the cytokine network involved in RA allowed the development of potent inhibitors of the inflammatory process classified as biological DMARDs. These new drugs are very effective in the inhibition of inflammation, but there are only few studies regarding their role in bone protection. The principal aim of this review was to show the evidence of the principal biologic therapies and bone loss in RA, focusing on their effects on bone mineral density, bone turnover markers, and fragility fractures.
Methods
Using the PICOST methodology, two coauthors (PC, LM-S) conducted the search using the following MESH terms: rheumatoid arthritis, osteoporosis, clinical trials, TNF- antagonists, infliximab, adalimumab, etanercept, certolizumab, golimumab, IL-6 antagonists, IL-1 antagonists, abatacept, tocilizumab, rituximab, bone mineral density, bone markers, and fractures. The search was conducted electronically and manually from the following databases: Medline and Science Direct. The search period included articles from 2003 to 2015. The selection included only original adult human research written in English. Titles were retrieved and the same two authors independently selected the relevant studies for a full text. The retrieved selected studies were also reviewed completing the search for relevant articles. The first search included 904 titles from which 253 titles were selected. The agreement on the selection among researchers resulted in a Kappa statistic of 0.95 (p < 0.000). Only 248 abstracts evaluated were included in the acronym PICOST. The final selection included only 28 studies, derived from the systematic search. Additionally, a manual search in the bibliography of the selected articles was made and included into the text and into the section of “small molecules of new agents.”
Conclusion
Treatment with biologic drugs is associated with the decrease in bone loss. Studies with anti-TNF blocking agents show preservation or increase in spine and hip BMD and also a better profile of bone markers. Most of these studies were performed with infliximab. Only three epidemiological studies analyzed the effect on fractures after anti-TNF blocking agent’s treatment. IL-6 blocking agents also showed improvement in localized bone loss not seen with anti-TNF agents. There are a few studies with rituximab and abatacept. Although several studies reported favorable actions of biologic therapies on bone protection, there are still unmet needs for studies regarding their actions on the risk of bone fractures.
The structure and infectivity of the oocysts of a new species of Cryptosporidium from the feces of humans are described. Oocysts are structurally indistinguishable from those of Cryptosporidium ...parvum. Oocysts of the new species are passed fully sporulated, lack sporocysts, and measure 4.4–5.4 μm (mean = 4.86) × 4.4–5.9 μm (mean = 5.2 μm) with a length to width ratio 1.0–1.09 (mean 1.07) (n = 100). Oocysts were not infectious for ARC Swiss mice, nude mice, Wistar rat pups, puppies, kittens or calves, but were infectious to neonatal gnotobiotic pigs. Pathogenicity studies in the gnotobiotic pig model revealed significant differences in parasite-associated lesion distribution (P = 0.005 to P = 0.02) and intensity of infection (P = 0.04) between C. parvum and this newly described species from humans. In vitro cultivation studies have also revealed growth differences between the two species. Multi-locus analysis of numerous unlinked loci, including a preliminary sequence scan of the entire genome demonstrated this species to be distinct from C. parvum and also demonstrated a lack of recombination, providing further support for its species status. Based on biological and molecular data, this Cryptosporidium infecting the intestine of humans is proposed to be a new species Cryptosporidium hominis n. sp.
Objective: To determine the emigration plans after graduation of clinical medical students of Ebonyi State University Abakaliki, Nigeria. Methods: A descriptive cross-sectional study design was used. ...All clinical medical students of the University willing to participate were included. Information was obtained using a pre-tested self-administered questionnaire. Outcome measure included proportion of students willing to emigrate and those willing to practice in rural areas after graduation. Results: A total of 285 students participated in the study, (response rate, 92.5%). Majority, 93.3% intend to pursue specialist training after graduation. Minor proportion, 13.9% intend to specialize in Nigeria, whereas 74.4% prefer to specialize outside Nigeria. Major reasons for preferring specialist training abroad included good equipment/facilities, 33.8%, better remuneration/quality of life, 27.8%; and improved skills, 18.7%. Countries of interest for training outside Nigeria included Canada, 28.3%; United Kingdom, 23.2%; and the United States of America, 18.2%. Minor proportion, 17.2% intend to practice in rural area after graduation. Predictors of willingness to emigrate included being in 400 level class, (adjusted odds ratio (AOR) =2.0, 95% CI = 1.1-4.1), being single, AOR = 4.0, 95% CI = 1.2-13.3) and having decided on specialty of choice, (AOR = 2.6, 95% CI = 1.5-4.5). Predictors of willingness to serve in rural area included family residence in urban area, (AOR = 0.2, 95% CI = 0.2-0.8) and intention to specialize in Nigeria, (AOR = 3.7, 95% CI = 1.6-8.5). Conclusions: Majority of students intend to pursue specialist training and prefer training abroad. Minor proportions were willing to specialize in Nigeria and serve in rural areas. The students may have perceived medical practice in Nigeria as serving in rural areas hence students willing to work in rural areas were more likely to specialize in Nigeria. This may adversely affect health service delivery in Nigeria if left unchecked. Nigerian authorities should ensure that medical graduates willing to practice in Nigeria are not deterred. Also, plans to encourage doctors to practice in Nigeria should receive desired attention.
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•An additional Giardia duodenalis assemblage B genome sequence for Giardia analyses.•De novo assembly comparison of Newbler and de Bruijn methods.•De novo assembly comparison of ...sample and existing draft GS references.•Annotation comparison of sample and existing draft GS references.•Seventy potential intra-assemblage B genotyping genes identified.
Giardia duodenalis assemblage B is potentially a zoonotic parasite. The characterisation and investigation of isolates has been hampered by greater genetic diversity of assemblage B, limiting the application and utility of current genotyping loci. Since whole genome sequencing is the optimal high-throughput method for gene identification, the present study sequenced assemblage B isolate BAH15c1 and compared the sequence to the draft GS references to identify polymorphic genes for potential use in genotyping assays. The majority of the genome sequence was conserved between the two isolates, producing 508 contigs of 10.4Mb with 4968 genes. Seventy polymorphic genes for potential use in genotyping assays were identified ranging in variation from elongation factor 1 α, which was the most conserved, through to triose phosphate isomerase, which was the most variable.
To assess the genetic diversity in Cryptosporidium parvum, we have sequenced the small subunit (SSU) rRNA gene of seven Cryptosporidium spp., various isolates of C. parvum from eight hosts, and a ...Cryptosporidium isolate from a desert monitor. Phylogenetic analysis of the SSU rRNA sequences confirmed the multispecies nature of the genus Cryptosporidium, with at least four distinct species (C. parvum, C. baileyi, C. muris, and C. serpentis). Other species previously defined by biologic characteristics, including C. wrairi, C. meleagridis, and C. felis, and the desert monitor isolate, clustered together or within C. parvum. Extensive genetic diversities were present among C. parvum isolates from humans, calves, pigs, dogs, mice, ferrets, marsupials, and a monkey. In general, specific genotypes were associated with specific host species. A PCR-restriction fragment length polymorphism technique previously developed by us could differentiate most Cryptosporidium spp. and C. parvum genotypes, but sequence analysis of the PCR product was needed to differentiate C. wrairi and C. meleagridis from some of the C. parvum genotypes. These results indicate a need for revision in the taxonomy and assessment of the zoonotic potential of some animal C. parvum isolates.
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► The substitution rate of a gene determines its ability to resolve different relationships formed at different times. ► Mixed-substitution-rate multi-locus-genotyping ensures ...accurate phylogenetic inference in divergent populations. ► Allelic sequence heterozygosity substitution patterns follow the same trend as regular substitution patterns (those at all alleles).
Recent research concerning Giardia duodenalis has focused on resolving possible sub-assemblages within Assemblages A and B to better understand host-specific and zoonotic relationships. In the present study nine cloned, cultured, Assemblage B isolates were used to investigate the intra-Assemblage B substitution patterns of conserved (ssrDNA, ef, h2b, h4) and variable (tpi, gdh, bg) genes to assess their suitability for further application to sub-assemblage analyses. The resolution of each gene was found to be proportional to its substitution rate and for the genetically narrow sample set examined, the variable genes best represented the consensus phylogeny while the conserved genes only established fractions. However it was demonstrated that the spectra of conserved and variable genes were required to ensure accuracy of inferred phylogeny and it was therefore concluded that further research into sub-Assemblage B groups would require a mixture of conserved and variable genes for the multi-locus analyses of this genetically broad assemblage.
Abstract
Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer’s disease (AD) which is characterized by amyloid-β (Aβ) amyloidosis. Here, we used two
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knock-in mouse ...models,
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NL-F/NL-F
and
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, exhibiting AD-like Aβ pathology to analyze how the brain pathologies translate to CSF proteomes by label-free mass spectrometry (MS). This identified several extracellular matrix (ECM) proteins as significantly altered in
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knock-in mice. Next, we compared mouse CSF proteomes with previously reported human CSF MS results acquired from patients across the AD spectrum. Intriguingly, the ECM protein decorin was similarly and significantly increased in both
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NL-F/NL-F
and
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mice, strikingly already at three months of age in the
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NL-F/NL-F
mice and preclinical AD subjects having abnormal CSF-Aβ42 but normal cognition. Notably, in this group of subjects, CSF-decorin levels positively correlated with CSF-Aβ42 levels indicating that the change in CSF-decorin is associated with early Aβ amyloidosis. Importantly, receiver operating characteristic analysis revealed that CSF-decorin can predict a specific AD subtype having innate immune activation and potential choroid plexus dysfunction in the brain. Consistently, in
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NL-F/NL-F
mice, increased CSF-decorin correlated with both Aβ plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human Aβ42 induces decorin secretion from mouse primary neurons. Interestingly, we finally identify decorin to activate neuronal autophagy through enhancing lysosomal function. Altogether, the increased CSF-decorin levels occurring at an early stage of Aβ amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects.
IMPORTANCE: Persistent pain is highly prevalent, costly, and frequently disabling in later life. OBJECTIVE: To describe barriers to the management of persistent pain among older adults, summarize ...current management approaches, including pharmacologic and nonpharmacologic modalities; present rehabilitative approaches; and highlight aspects of the patient-physician relationship that can help to improve treatment outcomes. This review is relevant for physicians who seek an age-appropriate approach to delivering pain care for the older adult. EVIDENCE ACQUISITION: Search of MEDLINE and the Cochrane database from January 1990 through May 2014, using the search terms older adults, senior, ages 65 and above, elderly, and aged along with non-cancer pain, chronic pain, persistent pain, pain management, intractable pain, and refractory pain to identify English-language peer-reviewed systematic reviews, meta-analyses, Cochrane reviews, consensus statements, and guidelines relevant to the management of persistent pain in older adults. FINDINGS: Of the 92 identified studies, 35 evaluated pharmacologic interventions, whereas 57 examined nonpharmacologic modalities; the majority (n = 50) focused on older adults with osteoarthritis. This evidence base supports a stepwise approach with acetaminophen as first-line therapy. If treatment goals are not met, a trial of a topical nonsteroidal anti-inflammatory drug, tramadol, or both is recommended. Oral nonsteroidal anti-inflammatory drugs are not recommended for long-term use. Careful surveillance to monitor for toxicity and efficacy is critical, given that advancing age increases risk for adverse effects. A multimodal approach is strongly recommended—emphasizing a combination of both pharmacologic and nonpharmacologic treatments to include physical and occupational rehabilitation, as well as cognitive-behavioral and movement-based interventions. An integrated pain management approach is ideally achieved by cultivating a strong therapeutic alliance between the older patient and the physician. CONCLUSIONS AND RELEVANCE: Treatment planning for persistent pain in later life requires a clear understanding of the patient’s treatment goals and expectations, comorbidities, and cognitive and functional status, as well as coordinating community resources and family support when available. A combination of pharmacologic, nonpharmacologic, and rehabilitative approaches in addition to a strong therapeutic alliance between the patient and physician is essential in setting, adjusting, and achieving realistic goals of therapy.
Sequence analysis of a polymerase chain reaction (PCR)-amplified 298-bp region of the Cryptosporidium parvum 18S rRNA gene was carried out on 10 human and 9 animal isolates. Eight of the 9 animal ...isolates and 3 human isolates displayed the recognition sequence TATATTT, whereas 7/10 human isolates exhibited the recognition sequence TTTTTTTTTTT. Sequence analysis of the ninth animal isolate, which was recovered from a Koala, revealed this isolate to be different from both human and animal isolates. The AT richness of the rDNA recognition sequences rendered them unsuitable for primer design and therefore a diagnostic randomly amplified polymorphic DNA fragment previously developed in our laboratory was also sequenced. Analysis of 2 human and 2 animal isolates again revealed distinct differences between animal and human isolates. On the basis of this sequence information, diagnostic primers were designed that could directly differentiate between animal and human isolates on the basis of the size of the PCR product. The ability to differentiate directly between human and animal isolates has important implications for studies of the transmission and zoonotic potential of this organism. These results also raise further doubts about the uniformity of the species C. parvum.
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