Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Juvenile Paget's disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss‐of‐function mutations within the TNFRSF11B gene that encodes OPG. We report a 3‐year‐old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year‐of‐life followed by bone deformities, delayed development, failure‐to‐thrive, and pneumonias. At 1 year‐of‐age, biochemical studies of serum revealed marked hyperphosphatasemia together with low‐normal calcium and low inorganic phosphate and 25‐hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine‐rich domain of OPG that binds receptor activator of NF‐κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient's serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective therapy for the skeletal disease caused by the OPG deficiency form of JPD.     

Midterm outcomes of laparoscopic surgery for rectal cancer

In this study, the authors examine midterm survival and recurrence after laparoscopic and open surgery for rectal cancer. This is a retrospective review of a prospective database for rectal cancer surgeries performed at the authors' institution, with follow-up data obtained through chart review. In all, 74 patients in this study had open surgery, and 93 had laparoscopic surgery. The 5-year overall survival was 73.6% ± 12.0% in the open group and 80.0% ± 12.8% in the laparoscopic group (P = .159). Disease-free survival at 5 years was better in the laparoscopic group (71.0% ± 13.4%) than in the open group (50.3% ± 12.7%), with a P value of .01. Laparoscopic surgery remained an independent predictor of disease-free survival in the multivariate analysis. Results of prospective randomized trials are awaited, and the authors expect that the laparoscopic approach will be shown to be a safe and effective option for the management of rectal cancer.     

Fertility and infertility implications in rheumatoid arthritis; state of the art

Background

A bulk of investigations imply that women with rheumatoid arthritis (RA) deliver fewer children in comparison to healthy women.

Purpose

This review article attempts to clarify the involvement of infertility-related issues in both RA men and women. Moreover, the effect of RA disease on the fertility quality and quantity will be discussed.

Results

Declined fertility rate in RA women seems to stem from modified inflammatory settings, advanced maternal age, limited sexual activity, and adverse effects of drugs on ovarian function. Women with RA may have smaller families and seem to be slower to conceive relative to their peer women. The chance of gestation in RA women may drop due to suppressed sexual function through pain and fatigue. In addition, treatment of RA women with non-steroidal anti-inflammatory drugs (NSAIDs) may prevent ovulation and therefore hinder the conception.

Conclusions

A complex interaction between RA disease and fertility related issues is present. Despite an increase rate of infertility in RA females or males, the mechanisms involved in this outcome is still unknown. Plausible causes of the decreased fertility rate in RA patients might be due to inflammatory cytokines, suppressed sexual activity, drug treatments, mother age, personal choice, or a combination of these elements.

     

HER2 drives lung fibrosis by activating a metastatic cancer signature in invasive lung fibroblasts

Progressive tissue fibrosis, including idiopathic pulmonary fibrosis (IPF), is characterized by excessive recruitment of fibroblasts to sites of tissue injury and unremitting extracellular matrix deposition associated with severe morbidity and mortality. However, the molecular mechanisms that control progressive IPF have yet to be fully determined. Previous studies suggested that invasive fibroblasts drive disease progression in IPF. Here, we report profiling of invasive and noninvasive fibroblasts from IPF patients and healthy donors. Pathway analysis revealed that the activated signatures of the invasive fibroblasts, the top of which was ERBB2 (HER2), showed great similarities to those of metastatic lung adenocarcinoma cancer cells. Activation of HER2 in normal lung fibroblasts led to a more invasive genetic program and worsened fibroblast invasion and lung fibrosis, while antagonizing HER2 signaling blunted fibroblast invasion and ameliorated lung fibrosis. These findings suggest that HER2 signaling may be a key driver of fibroblast invasion and serve as an attractive target for therapeutic intervention in IPF.     

Self-reported awareness and use of the International Classification of Diseases coding of inflammatory bowel disease services by Ontario physicians.

RATIONALE: Population and health services research can be performed by linkage analysis of administrative data. However, the robustness of study results is determined by the accuracy of the diagnostic coding. OBJECTIVES: To estimate the awareness, use and accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) coding by physicians providing services for patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: All Ontario gastroenterologists and a 10% random sample of internists, pediatricians, pediatric or general surgeons, and family physicians were surveyed by postal questionnaire to estimate the frequency and 95% CI of using codes 555 or 556 when billing for CD- and UC-related services, respectively. c2 tests were used for between-group comparisons. RESULTS: Of the physicians who were surveyed, 67.7% (416 of 614) responded; 258 of 391 (66%) who were still practising in Ontario saw patients with inflammatory bowel disease (IBD), and 54% had more than 10 IBD patients; 86.5% (95% CI 82.4% to 90.6%) were familiar with ICD-9 codes, and 91.4% (95% CI 88.1% to 95.6%) used the codes 555 (CD) or 556 (UC) for billing. Rates of ICD-9 use did not differ by sex but were used more frequently by those graduating after 1981 (P<0.02). Gastroenterologists used ICD-9 IBD codes 555 or 556 significantly more often than all other physicians (P=0.001). Most (more than 75%) Ontario physicians used ICD-9 IBD codes always or frequently when billing for IBD-related services. Few (10%) used these codes to bill for non-IBD-related problems. CONCLUSIONS: These data suggest that there is acceptable use and accuracy of ICD-9 diagnostic coding for CD and UC services - comparable with results from studies of other diseases. Administrative data may thus be used to undertake epidemiological studies in IBD in Ontario.     

Local overexpression of TIMP-1 prevents aortic aneurysm degeneration and rupture in a rat model.

Although matrix metalloproteinases (MMPs) are expressed in abundance in arterial aneurysms, their contribution to arterial wall degeneration, dilation, and rupture has not been determined. We investigated MMP function in a rat model of aneurysm associated with arterial dilation, elastin loss, medial invasion by mononuclear inflammatory cells, and MMP upregulation. Rupture was correlated with increased gelatinase B (MMP-9) and activated gelatinase A (MMP-2). Syngeneic rat smooth muscle cells retrovirally transfected with tissue inhibitor of matrix metalloproteinases (TIMP)-1 cDNA (LTSN) or with the vector alone as a control (LXSN) were seeded onto the luminal surface of the vessels. The seeding of LTSN cells resulted in TIMP-1 local overexpression. The seeding with LTSN cells, but not LXSN cells, decreased MMP-9, activated MMP-2 and 28-kD caseinase and elastase activity, preserved elastin in the media, and prevented aneurysmal degeneration and rupture. We conclude that MMP overexpression is responsible for aneurysmal degeneration and rupture in this rat model and that local pharmacological blockade might be a reasonable strategy for controlling the formation of aneurysms in humans.     

10-Year Outcomes of the Vertical Transected Gastric Bypass for Obesity: a Systematic Review

With increasing worldwide obesity rates, the surgery of choice has become the vertical transected gastric bypass, showing short-term improvements in weight loss and comorbidities. However, corresponding 10-year data regarding such endpoints is limited. The objective of this review was to assess such evidence. A literature search yielded a total of five studies, of which three had extractable data. Results revealed a reduction in the weighted mean body mass index (BMI), from a pre- to post-operative mean BMI of 47.5 kg/m²?±?2.0 to 33.4 kg/m²?±?4.4 at 10 years. The weighted mean excess weight loss was 61.4 %?±?13.5. Although these results suggest that weight reduction may be sustainable in the long term, this systematic review demonstrates a lack of strong evidence to support favorable long-term outcomes following vertical transected gastric bypass for obesity.