Detection of stool DNA mutations before and after treatment of colorectal neoplasia

BACKGROUND: Whether stool DNA abnormalities arise solely from colorectal neoplastic lesions or are due to more pervasive field effects is not known. In the current study, the authors conducted a prospective multicenter study to evaluate the performance of stool-based DNA testing in a large cohort and to examine whether the findings before treatment persist after surgical resection and/or adjuvant therapy. METHODS: Patients with newly diagnosed colorectal carcinoma or advanced adenomas (AA) provided stool samples before therapy, 1-3 months after surgical resection, and 6-9 months postresection. Stool samples were analyzed using the multi-target DNA assay panel (MTAP) consisting of 23 markers: 21 mutations in the p53, K-ras, and APC genes, a microsatellite instability marker (BAT-26), and the DNA integrity assay (DIA), a marker of loss of apoptosis. RESULTS: Overall, 49 of 91 individuals (54%) tested positive with the MTAP test. The sensitivity of the MTAP test was 63% for invasive tumors compared with 26% for AA. Individuals whose lesions had a more advanced TNM stage or were located distal to the splenic flexure were significantly more likely to have a positive MTAP test. Of the 79 samples collected at 1-3 months after surgical resection of the neoplasm, 14 (18%) had a positive MTAP result, 12 of which were positive for DIA only. Of those collected at 6-9 months of follow-up, 5 of 72 (7%) tested positive on the MTAP panel. CONCLUSIONS: Although many samples collected 1-3 months after surgical resection of the colorectal neoplasm tested positive on the MTAP, most were negative by 6-9 months, indicating that stool DNA abnormalities disappear after treatment of the neoplastic lesions. Surgery and chemoradiation appear to induce transient DIA abnormalities that may be independent of the presence of neoplasia.     

Ipsilateral fracture dislocations of the hip and knee joints with contralateral open fracture of the leg: a rare case and its management principles

This paper discussed the injury mechanism and management of a patient who had concomitant ipsilateral hip and knee dislocations and contralateral open leg fracture.A 32-year-old man presented with ipsilateral fracture-dislocations of the left hip (Pipkin's type IV) and knee (Moore II) joints and contralateral open fracture of the leg bones after a car accident. After emergency resuscitative measures, the hip joint was reduced and Pipkin's fracture was fixed using Ganz approach with lag screws; knee joint was reduced closely and tibial plateau fracture was stabilized with lateral buttress plate and a transarticular spanning fixator. The open fracture on the other leg was de-brided and fixed with an external fixator. There was no instability in both joints after fixation when he was examined under anesthesia. The fractures united after 3 months and the patient had no residual instability of hip and knee. There was no clinical or radiological evidence of osteonecrosis in the hip joint after 6 months. At one-year follow-up, he had satisfactory functional outcome with almost normal range of motion at both joints.Ipsilateral hip and knee dislocations are rare injuries and more caution is needed for early diagnosis. A timely appropriate intervention can provide good functional outcome to the patient in this situation.     

A Child Presenting with Recurrent Corneal Ulcers: Hereditary Sensory and Autonomic Neuropathy IV (HSAN IV)

Hereditary Sensory and Autonomic Neuropathy IV (HSAN IV) or Congenital Insensitivity to pain and Anhidrosis is an autosomal recessive condition. It is characterized by absence of reaction to painful stimuli, anhidrosis, self-mutilating behaviour and episodic fever. We report a child with HSAN IV who presented primarily with recurrent corneal ulcers and the classical history helped us clinch the diagnosis. Molecular testing revealed a homozygous pathogenic frameshift mutation in NTRK1 c.717delG, p.(Met239fs). Molecular testing is confirmatory and this will help the family in future prenatal diagnosis.     

Rescuing CD4+CD25+ regulatory T-cell functions in rheumatoid arthritis by cytokine-targeted monoclonal antibody therapy

CD4+CD25+ regulatory T cells (Tregs) play a crucial role in controlling the development of autoimmune diseases such as rheumatoid arthritis (RA). However, despite an increased number of Tregs, the persistence of inflammation in the rheumatoid joints suggests that Tregs are unable to suppress ongoing disease, perhaps due to an inhibition of their functions by pro-inflammatory cytokines. Treatment of RA patients with anti-TNF-alpha monoclonal antibodies such as infliximab and adalimumab has been found to induce and restore the functions of Tregs. Thus, manipulation of the pro-inflammatory environment in the inflamed synovia via neutralization of inflammatory cytokines by monoclonal antibodies could represent a novel therapeutic strategy for restoring the suppressive functions of Tregs and induction and/or expansion of Tregs in order to reinforce tolerance mechanisms.     

A biosynthetic pathway generating 12-hydroxy-5,8,14-eicosatrienoic acid from arachidonic acid is active in mouse skin microsomes

The epidermis expresses cyclooxygenases, lipoxygenases, and cytochromes P450, which utilize arachidonic acid to generate a diverse array of lipid mediators affecting epidermal cellular differentiation and functions. Recent studies show that mouse epidermis expresses CYP2B19, a keratinocyte-specific epoxygenase that generates 11,12- and 14,15-epoxyeicosatrienoic (EET) acids from arachidonate. We studied CYP2B19-dependent metabolism in mouse epidermal microsomes, reconstituted in the presence of [1-(14)C]arachidonic acid. The majority of the (14)C products formed independently of NADPH, indicative of robust epidermal cyclooxygenase and lipoxygenase activities. We studied two NADPH-dependent products generated in a highly reproducible manner from arachidonate. One of these (product I) coeluted with the CYP2B19 product 14,15-EET on a reversed-phase high-performance liquid chromatography (HPLC) system; there was no evidence for other regioisomeric EET products. Further analyses proved that product I was not an epoxy fatty acid, based on different retention times on a normal-phase HPLC system and failure of product I to undergo hydrolysis in acidic solution. We analyzed purified epidermal (14)C products by liquid chromatography negative electrospray ionization mass spectrometry. Structures of the NADPH-dependent products were confirmed to be 12-oxo-5,8,14-eicosatrienoic acid (I) and 12-hydroxy-5,8,14-eicosatrienoic acid (II). This was the first evidence for a 12-hydroxy-5,8,14-eicosatrienoic acid biosynthetic pathway in mouse epidermis. Epidermal microsomes also generated 12-hydroperoxy, 12-hydroxy, and 12-oxo eicosatetraenoic acids from arachidonate, possible intermediates in the 12-hydroxy-5,8,14-eicosatrienoic acid biosynthetic pathway. These results predict that hydroxyeicosatrienoic acids are synthesized from arachidonate in human epidermis. This would have important implications for human skin diseases given the known pro- and anti-inflammatory activities of stereo- and regioisomeric hydroxyeicosatrienoic acids.     

Endovascular stent implantation in the coeliac and superior mesenteric arteries in the treatment of chronic mesenteric ischemia

Mesenteric ischemia is a rare but serious cause of abdominal pain.We present the case of a man who had symptomatic mesenteric ischemia, secondary to a superior mesenteric artery stenosis in conjunction with a coeliac artery stenosis. He was treated with balloon angioplasty and stent insertion, and showed good symptomatic improvement.     

Cardiovascular and renal pathologic implications of prorenin, renin, and the (pro)renin receptor: promising young players from the old renin-angiotensin-aldosterone system

The overactivation of the renin–angiotensin–aldosterone system accounts for many cardiovascular and renal abnormalities. At several levels of its cascade, the renin–angiotensin–aldosterone system can be efficiently inhibited, of which interruption of the generation of angiotensin I by renin inhibition is considered most efficacious. All of these interruptions (renin inhibition, angiotensin-converting enzyme inhibition, and AT1 receptor blockade) increase plasma renin levels by inhibiting the negative feedback loop exerted by angiotensin II on renin production. Recent studies show that both prorenin and renin activate angiotensin II-independent signaling cascade through (pro)renin receptor, a new-fangled player of the old renin-angiotensin-aldosterone system. The probable mechanisms by which prorenin, renin, and (pro)renin receptors are functionally interrelated in pathophysiological conditions have been debated over the past decade without satisfactory conclusion. We revisited these areas and critically examined the relationship between elevated levels of circulating prorenin and renin-induced activation of the (pro)renin receptor and incidences of hypertension and end-organ damage. The complexity of the (pro)renin receptor has grown up with recent reports that this multifunctional receptor is a component of the Wnt receptor complex. This complexity and the receptor's function as an adaptor between the Wnt receptor and the vacuolar H+-ATPase complex has also been addressed in this review.