Plant Genome Editing and the Relevance of Off-Target Changes.

Site-directed nucleases (SDNs) used for targeted genome editing are powerful new tools to introduce precise genetic changes into plants. Like traditional approaches, such as conventional crossing and induced mutagenesis, genome editing aims to improve crop yield and nutrition. Next-generation sequencing studies demonstrate that across their genomes, populations of crop species typically carry millions of single nucleotide polymorphisms and many copy number and structural variants. Spontaneous mutations occur at rates of ∼10-8 to 10-9 per site per generation, while variation induced by chemical treatment or ionizing radiation results in higher mutation rates. In the context of SDNs, an off-target change or edit is an unintended, nonspecific mutation occurring at a site with sequence similarity to the targeted edit region. SDN-mediated off-target changes can contribute to a small number of additional genetic variants compared to those that occur naturally in breeding populations or are introduced by induced-mutagenesis methods. Recent studies show that using computational algorithms to design genome editing reagents can mitigate off-target edits in plants. Finally, crops are subject to strong selection to eliminate off-type plants through well-established multigenerational breeding, selection, and commercial variety development practices. Within this context, off-target edits in crops present no new safety concerns compared to other breeding practices. The current generation of genome editing technologies is already proving useful to develop new plant varieties with consumer and farmer benefits. Genome editing will likely undergo improved editing specificity along with new developments in SDN delivery and increasing genomic characterization, further improving reagent design and application.

Dissection of a QTL reveals an adaptive, interacting gene complex associated with transgressive variation for flowering time in rice.

A days to heading QTL (dth1.1) located on the short arm of rice chromosome 1 was sub-divided into eight sub-introgression lines (SILs) to analyze the genetic basis of transgressive variation for flowering time. Each SIL contained one or more introgression(s) from O. rufipogon in the genetic background of the elite Oryza sativa cultivar, Jefferson. Each introgression was defined at high resolution using molecular markers and those in the dth1.1 region were associated with the presence of one or more flowering time genes (GI, SOC1, FT-L8, EMF1, and PNZIP). SILs and controls were evaluated for flowering time under both short- and long-day growing conditions. Under short-day lengths, lines with introgressions carrying combinations of linked flowering time genes (GI/SOC1, SOC1/FT-L8, GI/SOC1/FT-L8 and EMF1/PNZIP) from the late parent, O. rufipogon, flowered earlier than the recurrent parent, Jefferson, while recombinant lines carrying smaller introgressions marked by the presence of GI, SOC1, EMF1 or PNZIP alone no longer flowered early. Under long-day length, lines carrying SOC1/FT-L8, SOC1 or PNZIP flowered early, while those carrying GI or EMF1 delayed flowering. Across all experiments and in the field, only SIL_SOC1/FT-L8 was consistently early. A preliminary yield evaluation indicated that the transgressive early flowering observed in several of the SILs was also associated with a measurable and positive effect on yield. These SILs represent a new source of variation that can be used in breeding programs to manipulate flowering time in rice cultivars without the reduction in yield that is often associated with early maturing phenotypes.

Epiploic appendagitis: the great mimicker.

Epiploic appendagitis is a benign, self-limited, clinicopathological, and radiological entity that has become more commonly recognized. The clinical presentation resembles a variety of other medical and surgical intra-abdominal conditions and may easily be confused with many of them. Computed tomography (CT) demonstrates characteristic features that help make the diagnosis in most cases, thus avoiding unneeded treatment or surgery. Here, we discuss a case series of five patients who presented with abdominal pain and were ultimately diagnosed with epiploic appendagitis.

Nissen fundoplication and gastrointestinal-related complications: a guide for the primary care physician.

Gastroesophageal reflux disease is a common condition affecting many individuals in the Western world. Most patients are managed successfully with acid suppression, while others may require more invasive interventions. The majority of patients undergoing antireflux surgery will have favorable outcomes. A small percentage, however, will be considered surgical failures and will either present with new or recurrent symptoms, or develop postoperative complications. These include, but are not limited to, symptoms such as dysphagia, gas-bloat syndrome, and bowel dysfunctions that may significantly impair the patient's health and quality of life. As the number of antireflux procedures for this condition continue to increase, the number of complications is also likely to become more prevalent. The primary care physician will be challenged to recognize them and initiate appropriate management. In this review, we address the more common gastrointestinal complications of laparoscopic Nissen fundoplication and offer general guidelines in their diagnosis and management.

Obesity and complicated diverticular disease: is there an association?

OBJECTIVE: Obesity is becoming a growing health concern in the general population. Multiple studies have linked diverticular disease to obesity. Furthermore, recent research has shown fat to be a critical element in the regulation of immunity and the inflammatory response. In this study, we sought to determine if body mass index (BMI) is associated with a higher incidence of complicated diverticulitis. METHODS: A retrospective review of patients hospitalized with complicated diverticulitis between 1997 and 2006 was conducted. Medical, surgical and CT (Computed Tomography) guided interventions were evaluated in reference to age, gender, BMI and length of hospital stay (LOS). RESULTS: Charts of 104 controls and 614 patients hospitalized with complicated diverticulitis were reviewed based on specified inclusion and exclusion criteria. There was no significant difference between groups by either gender (P = 0.066) or BMI (P = 0.648). There was a significant difference in age and LOS between three of the analyzed groups. No correlation was noted between BMI and LOS in any of the groups. DISCUSSION: There has been increasing interest in obesity and its ramifications in all areas of medicine, including diverticular disease. Numerous studies have shown a strong correlation between acute diverticulitis and obesity, particularly in the young population. This study was undertaken to identify a possible link between complicated diverticulitis and obesity. Anecdotal reports and a few studies have found a parallel association. However, in this retrospective study, no correlation was found between BMI and the incidence of complicated diverticulitis.

Necrotizing panniculitis: a skin condition associated with acinar cell carcinoma of the pancreas.

Pancreatic panniculitis (PP) is a rare cutaneous eruption that is associated with severe pancreatic disease. A patient presented with a fever, joint pains, and an erythematous rash with draining pustules that had spread from his legs to his arms over 4 months. Thorough investigation revealed stage IV acinar cell carcinoma of the pancreas. The rash was a result of necrotizing PP. The variable cutaneous manifestations of internal malignancies may challenge primary care physicians and dermatologists when patients present without findings associated with malignancy. Panniculitis should be kept in mind in the differential diagnosis of inflamed appearing nodules and pustules with an erythematous base, particularly when they are progressive and unrelenting.

Cerebellar vermis involvement in cocaine-related behaviors.

Although the cerebellum is increasingly being viewed as a brain area involved in cognition, it typically is excluded from circuitry considered to mediate stimulant-associated behaviors since it is low in dopamine. Yet, the primate cerebellar vermis (lobules II-III and VIII-IX) has been reported to contain axonal dopamine transporter immunoreactivity (DAT-IR). We hypothesized that DAT-IR-containing vermis areas would be activated in cocaine abusers by cocaine-related cues and, in healthy humans, would accumulate DAT-selective ligands. We used BOLD fMRI to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and positron emission tomography imaging of healthy humans to determine whether the DAT-selective ligand [11C]altropane accumulated in those vermis regions. Cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, we found appreciable [11C]altropane accumulation in lobules VIII-IX, possibly indicating DAT presence in this region. These data suggest that parts of cerebellar vermis mediate cocaine's persisting and acute effects. In light of prior findings illustrating vermis connections to midbrain dopamine cell body regions, established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, we propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related behaviors.

Serum sickness-like reactions in patients receiving intravenous infliximab.

Infliximab, a monoclonal antibody against tumor necrosis factor (TNF) has been used successfully for the treatment of certain forms of Crohn's disease and rheumatoid arthritis. Both acute and delayed hypersensitivity reactions have been associated with the intravenous use of this drug. The delayed forms may present as a serum sickness-like illness and recognition of the clinical manifestations becomes crucial for early diagnosis and treatment. With the dramatic increase in the use of infliximab, there will likely be increased numbers of patients with this type of reaction. These patients may have received this drug days or even weeks before the clinical presentation. These types of reactions also have been reported with the use of other monoclonal antibodies.

Early laminar organization of the human cerebrum demonstrated with diffusion tensor imaging in extremely premature infants.

Diffusion tensor imaging (DTI) was used to delineate early laminar organization of the cerebrum in two extremely premature infants imaged postnatally at estimated ages of 25 and 27 menstrual weeks. The diffusivity and anisotropy of the cortical plate, subplate zone, intermediate zone, subventricular and periventricular zones, and germinal matrix are examined. Automated segmentation of diffusion tensor images to reveal the laminar architecture of the developing human cerebrum is also demonstrated.