Role of IFN-α in Rheumatoid Arthritis.

PURPOSE OF REVIEW: Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology. RECENT FINDINGS: We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies.

Precision medicine: the precision gap in rheumatic disease.

For many oncological conditions, the application of timely and patient-tailored targeted therapies, or precision medicine, is a major therapeutic development that has provided considerable clinical benefit. However, despite the application of increasingly sophisticated technologies, alongside advanced bioinformatic and machine-learning algorithms, this success is yet to be replicated for the rheumatic diseases. In rheumatoid arthritis, for example, despite an array of targeted biologic and conventional therapeutics, treatment choice remains largely based on trial and error. The concept of the 'precision gap' for rheumatic disease can help us to identify factors that underpin the slow progress towards the discovery and adoption of precision-medicine approaches for rheumatic disease. In a rheumatic disease such as rheumatoid arthritis, it is possible to identify four themes that have slowed progress, solutions to which should help to close the precision gap. These themes relate to our fundamental understanding of disease pathogenesis, how we determine treatment response, confounders of treatment outcomes and trial design.

Depression Is Not Independently Associated with a Clinically Worse Functional Improvement but Associated with a Lower Reported Satisfaction Rate after Total Knee Arthroplasty.

The aim of this study was to assess whether depression had a clinically significant influence on the functional improvement of total knee arthroplasty (TKA) according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and whether it influences patient satisfaction at 1 year. A retrospective cohort of 3,510 primary TKA was identified from an arthroplasty database. Patient demographics, comorbidities, WOMAC, and Short Form-12 (SF-12) scores were collected preoperatively and 1 year postoperatively. Patient satisfaction (overall, pain relief, return to work, and recreational activity) was assessed at 1 year. There were 444 (12.6%) patients who self-reported depression. Patients with depression were younger (p < 0.001), had a higher body mass index (BMI; p < 0.001), were more likely to be female (p < 0.001), had lung (p < 0.001), neurological (p = 0.018), kidney (p = 0.001), liver (p < 0.001), and gastric (p < 0.001) disease, report associated diabetes (p = 0.001), and back pain (p < 0.001) relative to the subgroup without depression. All preoperative WOMAC functional measures were significantly (p < 0.001) worse in patients with reported depression. When adjusting for these confounding differences, patients with depression had a clinically equal improvement in their WOMAC scores at 1 year compared to those patients without. Depression was not associated with a clinically significant difference in improvement of knee-specific outcome (WOMAC) but was independently associated with a lower rate of patient satisfaction 1 year after TKA. Patients with depression were approximately twice as likely to be dissatisfied at 1 year when compared with those without depression. This is a prognostic retrospective cohort study and reflects level of evidence III.

Static compressive loading reduces the mRNA expression of type II and X collagen in rat growth-plate chondrocytes during postnatal growth.

The mechanisms by which chondrocytes modulate longitudinal bone growth are not well understood. This in vitro study investigated the effects of loading on the mRNA expression pattern of key molecular components of the growth-plate related to the extracellular matrix (type II and type X collagen) and the PTH-PTHrP feedback loop. Short-term static compressive loading was applied to rat proximal tibial growth-plate explants. Four age groups at specific developmental stages were investigated. The spatial variation in the mRNA expression was compared among loaded explants, their contralateral sham controls, and uncultured growth plates from normal animals. Basic cell metabolism (18S rRNA) was unaffected by load. Results indicated a narrower spatial distribution of mRNA expression of type II collagen throughout the growth plate; similarly, a narrowed distribution of expression of type X collagen was noted in the lower hypertrophic zone of the growth-plate. This suggests that mechanical compression influences chondrocytes of the hypertrophic zone to alter their expression of specific genes encoding proteins of the extracellular matrix, while PTH-PTHrP receptor mRNA, a regulatory protein, remained unaffected by loading. The effects of compression were similar at the different stages of growth, suggesting that additional factors may be involved in the clinical progression of skeletal deformities observed during growth spurts. Although this study was done in vitro and limited to static loading, it furthers our understanding of growth-plate mechanobiology as a first step toward providing a scientific rationale for treating progressive musculoskeletal deformities.

The effects of mechanical loading on the mRNA expression of growth-plate cells.

Bone growth is a complex process involving proliferation, maturation and hypertrophy of chondrocytes in the growth plates. Mechanical forces applied to growing bones alter their longitudinal growth. However, the mechanisms by which chondrocytes modulate longitudinal bone growth are not well understood. This in vitro study investigated the effects of mechanical loading on the mRNA expression pattern of key molecular components of the growth-plate. Short-term static loading was applied to rat proximal tibial growth-plate explants. Various age groups at specific developmental stages were investigated. In situ hybridization was used to assess the mRNA expression of the cells in different zones of the growth-plate. Four key components were investigated: 18s (basic cell metabolism), type II collagen (major extracellular matrix component), type X collagen (matrix component in hypertrophic zone) and PTH-PTHrP receptors (pre-hypertrophic chondrocytes). The spatial variation in the mRNA expression between loaded explants and their contralateral controls was compared to establish: -the sensitivity of the different growth-plate zones to mechanical loading; -the sensitivity of the different developmental stages to loading. Preliminary results indicated that static loading on the growth plate of 80 d.o. rats affects type II and X collagen gene expressions while PTH-PTHrP remains insensitive to static loading. Improved understanding of growth-plate mechanics and the underlying biology is required to provide a scientific basis for the treatment of progressive deformities.

New lessons from the sentinel node.

Sentinel node biopsy to determine the presence of metastatic disease in regional lymph nodes has been described in a variety of solid tumors. Sentinel node biopsy has proven that drainage of cancer cells to the regional lymph nodes is an orderly process with metastasis predominantly to one or two nodes first before involvement of subsequent nodes. The use of this technique has resulted in the increased identification of regional metastasis suggesting that patients previously identified as node negative may have unidentified regional metastasis. The clinical significance of these microscopic tumor deposits in lymph nodes remains controversial.

Axillary dissection in the context of the biology of lymph node metastases.

BACKGROUND: Modern breast surgery, as the primary treatment of invasive breast carcinoma, has been evolving over the last century. Aggressive radical surgery, which included chest wall resection, complete axillary clearance and internal mammary node dissection, has slowly changed to a less aggressive approach. This has been based on an improved understanding of the biology of the disease. Over the years, randomized prospective trials, performed at centers all over the world, have demonstrated that axillary dissection does not impact on the overall survival while it helps with loco-regional control of breast cancer. Its major role, at the present time, is limited to staging and prognostication; functions that are equally well served by the limited approach of a sentinel node biopsy. SOURCES: This review is based on the available medical literature involving the biology and organ specificity of the metastatic process, not only in breast cancer but also in other malignancies. In addition, studies pertaining to clinical breast cancer, and the role of surgery in its treatment, were reviewed. The ongoing trials on the role of sentinel node biopsy in the management of the clinically node negative patients are discussed. CONCLUSIONS: This review covers the history, pathophysiology, and clinical basis of the current role of axillary dissection for invasive breast cancer. From the data presented we hope that the medical community will agree that there is no therapeutic role for extended axillary dissection at the current time.

Detection of beta-amyloid peptide aggregation using DNA electrophoresis.

DNA could readily associate with the aggregated forms of the beta-amyloid peptides beta(1-40) and beta(25-35), giving rise to a shift in the electrophoretic mobility of DNA. As a result, DNA was retained at the top of a 1% agarose gel. In contrast, the electrophoretic mobility of DNA was little influenced by the monomeric forms of beta(1-40) and beta(25-30). DNA from different sources such as lambda phage, Escherichia coli plasmid, and human gene showed similar results. However, the electrophoretic mobility of RNA was shifted by the monomeric beta(1-40) and beta(25-35) as well as by the aggregated beta(1-40) and beta(25-35). The association of DNA with the aggregated beta-amyloid peptides could occur at pH 4-9. The inhibitory action of hemin on beta-amyloid aggregation could be confirmed using the DNA mobility shift assay. These results indicate that the DNA mobility shift assay is useful for kinetic study of beta-amyloid aggregation as well as for testing of agents that might modulate beta-amyloid aggregation.

Biologic and clinical significance of lymphadenectomy.

Interest in the lymphatic system and its relationship to metastases has developed owing to renewed interest in sentinel node biopsy. This article summarizes the anatomy, physiology, and biology of the lymphatic system and lymph node metastases, and reviews studies of lymph node metastases and surgical resection of cancers in different anatomic sites. On the basis of these studies, the authors conclude that lymph node metastasis functions as an indicator of prognosis, not the controlling or determining factor of prognosis. Thus, varying degrees of treatment of regional lymph nodes and metastases do not seem to be controlling factors in the outcome of cancer.

The surgeon's role in outcome in contemporary breast cancer.

Details of surgical removal of invasive breast cancer do not govern survival or cure. They do, however, control local recurrence rates and regional recurrence risk. The surgeon's role in breast cancer in the new millennium is to produce a cosmetic and functional result that is as good as possibly can be achieved while minimizing recurrence. Guidelines for incision placement, tissue volume removal, and nodal removal are critical determinants of cosmetic and functional outcome and need to be appreciated by surgeons.

Use of state hospital discharge data to assess the morbidity from rotavirus diarrhea and to monitor the impact of a rotavirus immunization program: A pilot study in Connecticut.

OBJECTIVES: Now that rotavirus vaccines have been licensed and recommended for routine immunization of US infants, there is an urgent need for data to assess the morbidity from rotavirus diarrhea and to monitor the impact of a rotavirus immunization program. In a pilot study, we have assessed the usefulness of state hospital discharge data on diarrhea in children to provide this information by examining data from Connecticut. DESIGN: Retrospective analysis of discharge records from acute care, nongovernmental hospitals in Connecticut. Patients. Children 1 month through 4 years of age with a diarrhea-associated diagnosis listed on the discharge record. Setting. Connecticut, 1987 through 1996. RESULTS: During the 10-year study period, a total of 11 324 diarrhea-associated hospitalizations (49.4 hospitalizations per 10,000 children) were reported. Diarrhea-associated hospitalizations peaked during February through April, especially among children 4 to 35 months of age. The seasonality and age distribution of diarrhea-associated hospitalizations of presumed noninfectious and viral etiologies resembled those of rotavirus-associated hospitalizations. During 1993 to 1996, rotavirus was coded for 10.4% of diarrhea-associated hospitalizations increasing from 8.6% in 1993 to 14.7% in 1996. The unadjusted median cost of a diarrhea-associated hospitalization during 1987 to 1996 and 1993 to 1996 was $1,941 and $2,428, respectively. CONCLUSIONS: Diarrhea causes substantial morbidity in children from Connecticut. The winter seasonal peak of diarrhea-associated hospitalizations in children 4 to 35 months of age coinciding with the peak of rotavirus-specific hospitalizations suggests that rotavirus is an important contributor to the overall morbidity. Although our findings suggest incomplete coding of rotavirus cases, state hospital discharge data should provide sensitive and timely information to monitor the impact of a rotavirus immunization program in Connecticut.

Optimal surgical treatment of invasive lobular carcinoma of the breast.

BACKGROUND: The roles of breast conservation and surgical evaluation of the contralateral breast in the treatment of lobular carcinoma of the breast remain unclear. The aim of this study was to compare local recurrence, 5-year survival, and incidence of contralateral breast cancer in women with lobular carcinoma to that in women with infiltrating ductal carcinoma. METHODS: Women with infiltrating ductal carcinoma (IDC) and invasive lobular breast carcinoma (ILC) diagnosed during the years 1984 to 1994 were identified through a statewide tumor registry. The women were divided into groups based on their histology and treatment (breast conservation or modified radical mastectomy). The incidences of contralateral breast cancer, local recurrence, and 5-year survival were compared within each histologic group and treatment category. RESULTS: During the period 1984 to 1994, 4886 women were diagnosed with invasive lobular or ductal breast carcinoma. Of these, 316 (6.5%) had infiltrating lobular cancer. The 5-year survival rates were 68% and 71% for ILC and IDC, respectively (p = 0.5). The local recurrence rates were 2.8% and 4.3% for ILC treated with lumpectomy and axillary nodal dissection (LAND) and modified radical mastectomy (MRM), respectively, which were not significantly different from that obtained with IDC (LAND = 2.5%, MRM = 2.1%). The incidence of contralateral breast cancer during the period was 6.6% and 6.5% for ILC and IDC, respectively. CONCLUSIONS: Invasive lobular carcinoma can be safely treated with breast conservation with no difference in local recurrence or survival. In the absence of a suspicious finding on clinical or radiologic examination, routine contralateral breast intervention is not recommended.

In vitro antitumor and antimicrobial activities of N-substituents of maleimide by adamantane and diamantane.

New N-1-adamantylcitraconimide (compound 1) and N-1-diamantylcitraconimide (compound 2) were synthesized by reaction of citraconic anhydride with 1-aminoadamantane, and 1-aminodiamantane, respectively, followed by imidization with acetic anhydride and sodium acetate. Compound 1, N-1-adamantylmaleimide (compound 3) and N-1-diamantylmaleimide (compound 4) exhibited strong growth-inhibitory activity against four cancer cell lines (Colo 205, Hep G2, SK-BR-3 and Molt-4). Moreover, compound 1 showed relatively specific cytotoxicity against the test tumor cell lines. Compound 2 exhibited growth inhibitory activity against Colo 205, and SK-BR-3 cells, similar to 5-fluorouracil. It was noted that compound 2 showed relatively low cytotoxicity against Molt-4 cells, approximately 42 times lower than 5-fluorouracil. The N-substituents of imides with adamantly substituents have a more potent antitumor activity than the imides with diamantyl substituents. The imides with methyl substituents (compounds 1 and 2) showed relatively higher selectivity against the tested cancer cell lines than the imides without methyl substituents (compounds 3 and 4). Compounds 3 and 4 show good in vitro activities against Staphylococcus aureus and Trichophyton mentagrophytes. Compound 1 had weak antimicrobial activity against T. mentagrophytes.

Galactosemia in infancy: diagnosis, management, and prognosis.

Galactosemia is an inherited metabolic disorder in which the individual is unable to metabolize lactose. In the newborn, classic galactosemia presents with symptoms of severe feeding intolerance, malnutrition, and rapid organ damage. Without immediate treatment, the infant will almost certainly succumb to rampant disease or sepsis. Through increased clinical awareness, pediatric care providers can be better prepared to detect and manage an infant with this disorder. A multidisciplinary approach is often necessary to maintain optimal health. The nurse can play an important role in coordinating specialty services and in helping the family to manage the disease and its sequelae over time.

Surgical management and treatment of gastric and duodenal fistulas.

Gastroduodenal fistulas compose only a small portion of gastrointestinal fistulas. They usually occur in the postoperative setting in association with an anastomotic leak. As with all fistulas, attention to adequate supportive care is needed. Interventional endoscopy may play a role in the future. The three surgical management approaches include exclusion, resection, and closure of the fistula. The success rate of closure ranges from 25% to 75% with supportive care only to 100% with proper surgical management.

A fork head/HNF-3 homolog expressed in the pharynx and intestine of the Caenorhabditis elegans embryo.

We have cloned a member of the fork head/HNF-3 family of transcription factors from the nematode Caenorhabditis elegans. Within the predicted DNA binding domain, this gene, called Ce-fkh-1, is 75-78% identical to the Drosophila fork head and rat liver HNF-3 alpha, beta, and gamma genes. Ce-fkh-1 mRNA is highly enriched in embryos. The Ce-fkh-1 gene produces three major transcripts: the longest mRNA retains its original 5'-end but two shorter mRNAs are trans-spliced at the beginning of exons 2 and 3, respectively. In situ hybridization and transgenic Ce-fkh-1::lacZ reporter constructs indicate that the Ce-fkh-1 gene is expressed in both pharynx and intestine of the embryo, beginning at the midproliferation stage. A second phase of Ce-fkh-1 expression occurs in cells of the larval somatic gonad. The pharynx-gut expression of Ce-fkh-1 in the C. elegans embryo is compared with expression of fork head throughout the gut of Drosophila embryos and with expression of HNF-3 (alpha beta gamma) in the endoderm of mammalian embryos. Such conserved patterns of gene expression point to universal features of gastrulation and of digestive tract formation.