DNA unzipped under a constant force exhibits multiple metastable intermediates

Single molecule studies, at constant force, of the separation of double-stranded DNA into two separated single strands may provide information relevant to the dynamics of DNA replication. At constant applied force, theory predicts that the unzipped length as a function of time is characterized by jumps during which the strands separate rapidly, followed by long pauses where the number of separated base pairs remains constant. Here, we report previously uncharacterized observations of this striking behavior carried out on a number of identical single molecules simultaneously. When several single lambda phage molecules are subject to the same applied force, the pause positions are reproducible in each. This reproducibility shows that the positions and durations of the pauses in unzipping provide a sequence-dependent molecular fingerprint. For small forces, the DNA remains in a partially unzipped state for at least several hours. For larger forces, the separation is still characterized by jumps and pauses, but the double-stranded DNA will completely unzip in less than 30 min.     

Inhibition of C3 with pegcetacoplan results in normalization of hemolysis markers in paroxysmal nocturnal hemoglobinuria

Annals of Hematology - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab)...     

Pneumoretroperitoneum and Pneumomediastinum Revealing a Left Colon Perforation

Left colon perforation usually occurs in complicated diverticulitis or cancer. The most frequent signs are intraperitoneal abscess or peritonitis. In cases of retroperitoneal colonic perforation, diagnosis may be difficult. A 59-year-old woman presented with left thigh pain and with abdominal discomfort associated with mild dyspnea. Computed tomography scan showed air bubbles and purulent collection in the retroperitoneum, with subcutaneous emphysema extending from the left thigh to the neck. Computed tomography scan also revealed portal vein gas and thrombosis with multiple liver abscesses. An emergency laparotomy revealed a perforation of the proximal left colon. No masses were found. A left colectomy was performed. The retroperitoneum was drained and washed extensively. A negative pressure wound therapy was applied. A second-look laparotomy was performed 48 hours later. The retroperitoneum was drained and an end colostomy was performed. Intensive Care Unit postoperative stay was 9 days, and the patient was discharged on the 32nd postoperative day. Pneumoretroperitoneum and pneumomediastinum are rare signs of colonic retroperitoneal perforation. The diagnosis may be delayed, especially in the absence of peritoneal irritation. Clinical, laboratory, and especially radiologic parameters might be useful. Surgical treatment must be prompt to improve prognosis.Key words: Pneumomediastinum, Retroperitoneum, Colonic, PerforationColonic perforation can be caused by either benign or malignant diseases. Left colon perforation is generally due to diverticular disease or cancer.^1–3 Uncommon causes are iatrogenic ischemia, colonic ischemia, trauma, or toxic megacolon.^1,3,4 Symptoms are usually due to abscesses or peritonitis. However, retroperitoneal ruptures can be difficult to diagnose because their presentation can vary widely.^1,2,4–6Through this case of retroperitoneal colonic perforation we aim to describe the presentation and therapeutic management of this entity.     

Cost analysis of the History,ECG, Age,Risk factors,and initial Troponin (HEART) Pathway randomized control trial

Introduction

The HEART Pathway is a diagnostic protocol designed to identify low-risk patients presenting to the emergency department with chest pain that are safe for early discharge. This protocol has been shown to significantly decrease health care resource utilization compared with usual care. However, the impact of the HEART Pathway on the cost of care has yet to be reported.

Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans

The melanocortin-4 receptor (MC4R), a centrally expressed G protein–coupled receptor (GPCR), is essential for the maintenance of long-term energy balance in humans. Mutations in MC4R are the most common genetic cause of obesity. Since activation of this receptor leads to a decrease in food intake, MC4R is also a major therapeutic target for the treatment of obesity. Control of MC4R activity in vivo is modulated by the opposing effects of the anorexigenic agonist α–melanocyte-stimulating hormone (α-MSH) and the orexigenic antagonist agouti-related protein (AGRP). In addition, experiments in vitro have demonstrated that the human MC4R has an intrinsic constitutive activity on which AGRP also acts as an inverse agonist. The physiological role of this constitutive activity in the control of energy balance as well as the domain of the protein implicated in its maintenance are unknown. By systematically studying functional defects in naturally occurring MC4R mutations from obese patients, we defined a cluster of N-terminal mutations that selectively impair the constitutive activity of the receptor. Further characterization of this domain demonstrated that it functions as a tethered intramolecular ligand that maintains the constitutive activity of MC4R and may provide novel avenues for the design of drugs targeting this receptor. Our results also suggest that the tonic satiety signal provided by the constitutive activity of MC4R may be required for maintaining long-term energy homeostasis in humans.     

Tachycardiomyopathy secondary to nonreentrant atrioventricular nodal tachycardia: recovery after slow pathway ablation

Nonreentrant atrioventricular (AV) nodal tachycardia is a rare form of arrhythmia due to simultaneous anterograde conduction in dual AV pathways, one atrial impulse triggering two ventricular complexes. We report the case of a 74-year-old man referred for incessant palpitations resistant to antiarrhythmic medication, and effort dyspnea. A nonreentrant AV nodal tachycardia is diagnosed with electrophysiological study. A dilated cardiomyopathy with left ventricular dysfunction is found with gated blood pool single-photon emission computed tomography. A radiofrequency catheter ablation of the slow pathway is successfully performed. The patient is reassessed 11 months after ablation. He is asymptomatic and left ventricular function has fully recovered.     

The effect of intraoperative hypotension on the outcomes of initial hybrid palliation for single ventricle congenital heart disease: an historical cohort study

Background

The “hybrid procedure” is an alternative surgical palliation strategy for single ventricle congenital heart disease. The purported benefit is improved cognitive ability secondary to avoidance of cardiopulmonary bypass in the neonatal period when neuronal apoptosis is greater. It is unknown whether survival is improved after this procedure. Intraoperative hypotension is common in these patients, and we hypothesized that this hypotension was associated with mortality or morbidity.

Methods

We reviewed the records of 58/58 patients undergoing a first-stage hybrid procedure from 2004 to 2010 in a tertiary pediatric academic centre. Risk factors for poor outcome and the association between intraoperative hypotension and morbidity or mortality were investigated.

Results

Average preoperative arterial blood pressure (ABP) [systolic/diastolic presented as mean (standard deviation)] were 68 (12.7) / 38 (9.4) mmHg. Post-induction ABP was 65 (15.2) / 37 (8.6) mmHg. The average intraoperative nadir of ABP was 45 (7.0) / 26 (4.8) mmHg. On return to the intensive care unit (ICU), the average ABP was 69 (13.7) / 38 (11.6) mmHg. The nadir lasted longer than ten minutes in 32/58 patients. The mortality at 48 hr, 60 days, and 12 months was 3/58 (5%), 10/58 (17%), and 15/58 (26%), respectively. Six patients returned to the ICU on extracorporeal membrane oxygenation (ECMO). There was a weak statistical correlation between the average mean and diastolic BP pre-induction and changes of > 20% in systolic and diastolic BP during the case.

Conclusion

In this patient cohort, we can show an association between short periods of intraoperative hypotension and mortality or return to the ICU on ECMO, but the importance of this is not certain.     

Postoperative management and restrictions for female pelvic surgery: a systematic review

Introduction and hypothesis

We sought to systematically review the literature regarding the effect of postoperative restrictions on clinical outcomes after pelvic surgery.

Methods

English-language articles were identified by a MEDLINE and Cochrane Central Register of Controlled Trials search from inception to July 2010. We used key words describing various gynecologic surgical procedures and postoperative activities, including mobility, lifting, work, coitus, and exercise. Randomized and nonrandomized studies comparing interventions with outcomes of interest were included.

Results

The literature search yielded of 3,491 articles; 115 full-text articles were reviewed, and 38 met eligibility criteria and are reported and analyzed here. Our analysis revealed that expedited discharge protocols and early postoperative feeding and catheter removal result in shorter hospital stay without negative health outcomes. However, there are limited data to guide many other aspects of postoperative care, particularly regarding exercise and resumption of sexual activity after surgery.

Conclusions

There is good evidence to support early postoperative feeding and catheter removal after pelvic surgery. There are limited data to guide many other aspects of postoperative care.