Citations

Abstract Barrett's esophagus is the precursor lesion of esophageal adenocarcinoma, whose progression follows sequential stages. However, the low progression rate and the inadequacy and subjective interpretation of histologic grading in predicting Barrett's esophagus progression call for more objective biomarkers that can improve risk prediction. We conducted a genome-wide profiling of 754 human microRNAs (miRNA) in 35 normal epithelium, 34 Barrett's esophagus, and 36 esophageal adenocarcinoma tissues using TaqMan real-time PCR-based profiling. Unsupervised hierarchical clustering using 294 modestly to highly expressed miRNAs showed clear clustering of two groups: normal epithelium versus Barrett's esophagus/esophageal adenocarcinoma tissues. Moreover, there was an excellent clustering of Barrett's metaplasia (without dysplasia) tissues from normal epithelium tissues. However, Barrett's esophagus tissues of different stages and esophageal adenocarcinoma tissues were interspersed. There were differentially expressed miRNAs at different stages. The majority of miRNA aberrations involved upregulation of expression in Barrett's esophagus and esophageal adenocarcinoma tissues, with the most dramatic alterations occurring at the Barrett's metaplasia stage. Known oncomiRs, such as miR-21, miR-25, and miR-223, and tumor suppressor miRNAs, including miR-205, miR-203, let-7c, and miR-133a, showed progressively altered expression from Barrett's esophagus to esophageal adenocarcinoma. We also identified a number of novel miRNAs that showed progressively altered expression, including miR-301b, miR-618, and miR-23b. The significant miRNA alterations that were exclusive to esophageal adenocarcinoma but not Barrett's esophagus included miR-375 downregulation and upregulation of five members of the miR-17-92 and its homologue clusters, which may become promising biomarkers for esophageal adenocarcinoma development. Cancer Prev Res; 6(3); 196–205. ©2013 AACR.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Intramedullary tibiotalocalcaneal arthrodesis (IMTCA) is an increasingly used procedure for salvage of complex hindfoot and ankle disorders. 1 , 2 To avoid injury to vital plantar neurovascular structures, it is important to begin with an appropriate insertion site during retrograde IMTCA. We use a simple, reproducible method to determine this site based on anatomic landmarks.

An intramedullary fixation device was devised by the senior author (K.A.J.) to use in conjunction with a previously described method for tibiotalocalcaneal arthrodesis. Satisfactory results were obtained in approximately 87% of the initial 30 patients; union was radiographically or clinically evident in all but two patients. Many of these patients had been offered or were considering below the knee amputation; only two ultimately chose this reconstructive option at a follow-up that ranged from 4 to 27 months.

Nineteen patients underwent surgical synovectomy and debridement for the clinical diagnosis of stage I posterior tibial tendon (PTT) dysfunction. Stage I PTT dysfunction is characterized by pain and swelling along the medial aspect of the ankle. Fourteen patients (74%) reported complete relief of pain, 3 patients (16%) reported minor pain, and 1 patient (5%) had moderate pain, and 1 (5%) had continued severe pain. Sixteen (84%) of the patients subjectively reported being “much better” and had a return of function of the PTT, as evidenced by their ability to perform a single limb-heel-rise test. Two patients (10%) underwent subtalar arthrodesis for progressive foot deformity and continued pain. Based on these results, surgical release, tenosynovectomy, and debridement are recommended for the treatment of stage I PTT dysfunction.

The chevron osteotomy for hallux valgus was modified by addition of screw fixation and change of the osteotomy angle. Thirty-six patients underwent this modified osteotomy. All had mild to moderate symptomatic hallux valgus deformities. No other forefoot procedures were performed. Standing radiographs were taken before surgery, at 1 month after surgery, and, for the 15 patients who returned for long-term follow-up, at 1 year or more after surgery. Overall, 35/42 procedures were rated as satisfactory without reservations and 7 were rated as satisfactory with mild reservations. All patients stated that they had some improvement in their preoperative symptoms, which included pain, cosmetic concerns, and shoe wear difficulties. Radiographically, none of the capital fragments displaced and there were no malunions, nonunions, nor evidence of avascular necrosis. The average metatarsophalangeal-1 angle improved 8° and the average intermetatarsal 1–2 angle improved 4°. This modification is relatively simple, increases stability, and allows early weightbearing. In our experience, the modified chevron osteotomy has been a very reliable procedure for mild to moderate symptomatic hallux valgus deformity.

The Rochester bone trephine is a useful instrument for performing small joint arthrodesis in the foot. The technique involves harvesting a dowel graft from the iliac crest and then inserting the graft into a recipient bed across the small joints in the foot. Minimal surgical trauma and patient discomfort result from this technique. Three cases are presented to illustrate the usefulness and diversity of this system.

Thirteen patients (14 feet) were treated for mild rheumatoid forefoot deformities with lesser toe partial proximal phalangectomies and partial syndactylizations. Eleven patients (85%) were reviewed at an average of 8 years postoperatively. The results were completely satisfactory in four patients, satisfactory with minor reservations in three patients, satisfactory with major reservations in one patient, and unsatisfactory in three patients. The major cause of reservations and lack of satisfaction was metatarsalgia. Seven patients (64%) reported that their activities were limited by intermittent metatarsalgia. Four patients (36%) considered the cosmetic appearance of the forefoot to be unsatisfactory. All but one patient required some form of shoewear modification. Based on this study, we believe the indications for this procedure are limited. These include rheumatoid patients with mild forefoot deformities without significant metatarsalgia or ongoing disease who have failed nonoperative treatment. Relative contraindications to this operation appear to include the recent onset of rheumatoid arthritis, active disease, significant metatarsalgia, and strong cosmetic concerns regarding outcome. In borderline clinical decisions that involve whether or not to leave or excise the lesser metatarsal heads, they probably should be excised to decrease late metatarsalgia.

The effects of shoe wear, custom-made inserts, patellar tendon-bearing (PTB) braces, and extra-padded PTB braces on load transmission to neuroarthropathic (Charcot) feet of six diabetic patients were assessed. A PTB brace with a free ankle and an extradepth shoe without external modifications was used. Four distinct anatomical regions were evaluated by an in-shoe technique measuring vertical force. The mean peak force transmitted to the entire foot was higher in the affected than in the unaffected extremity barefoot and shod. The mean peak forces under the midfoot were higher for the affected than for the unaffected extremity for all tested circumstances. In the affected foot, use of the standard PTB brace reduced mean peak force to the entire foot by 15%. Adding extra padding to the brace decreased the mean peak force 32%. The effect of padding on vertical load transmission was greatest for patients who had worn the brace the longest. For the patients who had worn it longer than average, the addition of padding decreased the mean peak force to the entire foot by 19%, to the hindfoot by 37%, and to the midfoot by 20%. Clinical Relevance: In this preliminary study, we found that a properly fitted PTB brace can reduce load transmission to the Charcot foot. Specifically, load transmission was reduced to the hindfoot, but not to the midfoot or forefoot. Based on these results, we cannot recommend its use to reduce vertical force transmission to the Charcot midfoot or forefoot. Long-term PTB brace use, especially in the limited weightbearing patient, should be regularly adjusted to ensure adequate brace fit.