Role of endoscopy in patients with diverticular disease

Acute diverticulitis occurs in 10-25% of patients with diverticulosis. Colonoscopy is advised 6 weeks after an attack of acute diverticulitis in order to completely evaluate the colonic lumen and exclude a potential malignancy. We conducted several studies aimed to evaluate the feasibility and safety of early colonoscopy in patients with acute diverticulitis. Consecutive patients hospitalized for acute diverticulitis were included. In the first phase of the study, patients with adjacent peri-diverticular air/fluid on CT were excluded. In the second phase of the study, we included patients with peri-diverticular air/fluid on CT as well. During the first phase of the study, 39 patients underwent uneventful colonoscopy. During the second phase of the study, 40 patients underwent colonoscopy and 1 of 6 patients with peri-diverticular air had perforation of her sigmoid colon. Two patients had a more protracted course and were clearly those who benefited most from the early colonoscopy. Based on our study, we concluded that early colonoscopy in acute diverticulitis is feasible. It should be reserved either for all patients with no air adjacent to diverticuli on CT or just for those with a more protracted course. In the third phase, a prospective randomized study was conducted on patients with acute diverticulitis with no peri-diverticular air. Such patients were randomized into those who underwent early colonoscopy and those who underwent colonoscopy 6 weeks later. Eighty-three patients were included in both groups and in none has a significant lesion been identified (except polyps). It seems therefore that the current abdominal CT with its excellent resolution is enough to exclude colonic cancer. Colonoscopy should be reserved only for patients with a protracted unresolved course of acute diverticulitis.     

Clopidogrel tapering as a strategy to attenuate platelet rebound phenomenon in patients with bare-metal stents

Early clustering of adverse cardiovascular events after abrupt cessation of clopidogrel has been reported in patients with acute coronary syndromes. A platelet rebound phenomenon may contribute to this increased thrombotic risk and a gradual drug tapering may attenuate this proposed platelet effect. Accordingly, we aimed to assess the effect of clopidogrel tapering on platelet reactivity. Twenty patients who underwent elective percutaneous coronary interventions with bare metal stents receiving 3 months of clopidogrel therapy (75 mg daily) were randomized to either of two discontinuation strategies: (1) Off group–abrupt drug cessation or (2) Tapering group–receiving clopidogrel 75 mg every other day for 4 weeks duration. Light transmission aggregometry, induced by ADP (5 and 10 μM) and collagen, was measured at four time-points (at baseline and 2, 4 and 6 weeks after randomization). In the off group, there was an early rise in platelet reactivity at 2 weeks after abrupt drug cessation compared to baseline, as measured by ADP 5 μmol/l (39.6 ± 2.8 vs. 67.9 ± 6.0, P < 0.001). The tapering regimen suppressed this rebound platelet aggregation by ADP 5 μmol/l at 2 weeks (P = 0.001) and 4 weeks (P = 0.001). Similar results were found with ADP 10 μmol/l and collagen agonists. Abrupt cessation of clopidogrel results in an early rise in platelet aggregability in patients with BMS that is attenuated by a tapering regimen. Clopidogrel administration every other day may achieve similar levels of platelet inhibition as full dose therapy. Further investigations evaluating clopidogrel tapering strategies and their potential clinical impact are warranted.     

Glucose metabolism: key endogenous regulator of β-cell replication and survival

Recent studies in mice have shown that pancreatic β-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that β-cell regeneration is based on the replication of fully differentiated, insulin-positive β-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control β-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for β-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within β-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual β-cell workload, defined as the amount of insulin that an individual β-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on β-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on β-cells may allow for the development of effective regenerative therapies for diabetes.     

Evaluation and Management of the Premenopausal Woman with Low BMD

Interpretation of bone mineral density (BMD) results in premenopausal women is particularly challenging, since the relationship between BMD and fracture risk is not the same as for postmenopausal women. In most cases, Z scores rather than T scores should be used to define “low BMD” in premenopausal women. The finding of low BMD in a premenopausal woman should prompt thorough evaluation for secondary causes of bone loss. If a secondary cause is found, management should focus on treatment of this condition. In a few cases where the secondary cause cannot be eliminated, treatment with a bone active agent to prevent bone loss should be considered. In women with no fractures and no known secondary cause, low BMD is associated with microarchitectural defects similar to young women with fractures; however, no longitudinal data are available to allow use of BMD to predict fracture risk. BMD is likely to be stable in these women with isolated low BMD, and pharmacologic therapy is rarely necessary. Assessment of markers of bone turnover and follow-up bone density measurements can help to identify those with an ongoing process of bone loss that may indicate a higher risk for fracture, and possible need for pharmacologic intervention.     

Neurophysiologic Monitoring Can Predict Iatrogenic Injury During Acetabular and Pelvic Fracture Fixation

Background:

Nerve injury during acetabular and pelvic fracture fixation can have devastating consequences for trauma patients already in a compromised situation.

Questions/Purposes:

This study aims to evaluate the efficacy of multimodality intraoperative neurophysiologic monitoring during acetabular and pelvic fracture fixation in identifying emerging iatrogenic nerve injury.

Methods:

Sixty patients were retrospectively identified after surgical fixation following acetabular or pelvic fracture. Neuromonitoring during surgery was performed using three different modalities, transcranial electric motor evoked potential (tceMEP), somatosensory evoked potential (SSEP), and electromyographic (EMG) monitoring. Each modality was evaluated for sensitivity and specificity of detecting an intraoperative nerve injury.

Results:

tceMEP monitoring was found to be 100% sensitive and 86% specific at detecting an impending nerve injury. The sensitivity and specificity of SSEP were 75% and 94%, while EMG sensitivity was unacceptably low at 20% although specificity was 93%.

Conclusions:

Multimodality neuromonitoring of transcranial electric motor and peroneal nerve somatosensory evoked potentials with or without spontaneous EMG monitoring is a safe and effective method for detecting impending nerve injury during acetabular and pelvic surgery.     

Success rates of nuclear short tandem repeat typing from different skeletal elements

Aim

To evaluate trends in DNA typing success rates of different skeletal elements from mass graves originating from conflicts that occurred in the former Yugoslavia (Bosnia and Herzegovina and Kosovo) during the 1990s, and to establish correlation between skeletal sample age and success of high throughput short tandem repeat (STR) typing in the large data set of the International Commission on Missing Persons.

Method

DNA extraction and short tandem repeat (STR) typing have been attempted on over 25 000 skeletal samples. The skeletal samples originated from different geographical locations where the conflicts occurred and from different time periods from 1992 to 1999. DNA preservation in these samples was highly variable, but was often significantly degraded and of limited quantity. For the purpose of this study, processed samples were categorized according to skeletal sample type, sample age since death, and success rates tabulated.

Results

Well-defined general trends in success rates of DNA analyses were observed with respect to the type of bone tested and sample age. The highest success rates were observed with samples from dense cortical bone of weight-bearing leg bones (femur 86.9%), whereas long bones of the arms showed significantly lower success (humerus 46.2%, radius 24.5%, ulna 22.8%). Intact teeth also exhibited high success rates (teeth 82.7%). DNA isolation from other skeletal elements differed considerably in success, making bone sample selection an important factor influencing success.

Conclusion

The success of DNA typing is related to the type of skeletal sample. By carefully evaluating skeletal material available for forensic DNA testing with regard to sample age and type of skeletal element available, it is possible to increase the success and efficiency of forensic DNA testing.The aftermath of the 1992-1995 conflict in the area of former Yugoslavia was marked with estimated 40 000 missing individuals. To address the issue of missing persons, the International Commission on Missing Persons (ICMP) was created in 1996 following the G-7 Summit in Lyon, France. ICMP’s mandate was expanded to also cover the DNA typing of missing persons resulting from 1999 conflict in Kosovo region.ICMP employs a “population based, DNA-led” identification system for the identification of missing persons in the region of former Yugoslavia. On a regional scale, DNA profiles from reference samples of living relatives of missing persons are continuously compared in a batch mode to the DNA profiles obtained from mortal remains of victims. To date, more than 84 000 blood samples representing over 28 000 missing individuals have been collected, analyzed, and entered into the database. Since 2001, short tandem repeat (STR) profiles from more than 21 000 skeletal samples, representing more than 15 000 different individuals, have also been entered into the ICMP database (1). DNA matching reports of greater than 99.95% probability of identity have been issued for over 11 600 individuals.ICMP DNA laboratories currently operate at a target rate of 105 bone or tooth extractions per day, using a silica-based extraction method (1-3). Bone and teeth samples tested are between 8 and 15 years post mortem. The quality of DNA preservation in these bones is highly variable and often substantially limited or/and degraded. This reflects the fact that the remains were buried or disposed in many different environmental contexts, with differential exposure to potentially harsh extrinsic factors such as temperature, UV radiation, humidity, and exposure to animals, insects, and microbes. Different disposal conditions are marked by burial in different soil types, complete or partial immersion of remains in water, contact with fire, or use of plastic sheeting. Microbial degradation is variably evidenced in these samples by both bone morphology and co-extraction of sometimes large amounts of microbial DNA (our unpublished observation). As always in this type of work, co-extraction of DNA inhibitors is a serious issue, and is also variable among samples.Bone and teeth samples clearly protect DNA through their physical and/or chemical robustness to environmental degradation and/or biological attack. An elementary manifestation of this is that bone and teeth are often the only surviving material that can be tested. However, the mechanisms by which DNA is preserved in bone are not very well characterized (4). Bone tissue is primarily composed of protein and mineral. The two most abundant proteins in bone tissue are collagen and osteocalcin. Approximately 70% of the mineral portion of the bone is composed of hydroxyapatite, which includes calcium phosphate, calcium carbonate, calcium fluoride, calcium hydroxide, and citrate. Structural arrangement of bone tissue is such that the mineral portion provides structural support to the protein portion in the bone and, by doing so, physically excludes exogenous/extracellular agents/enzymes that are potentially harmful to the protein portion of the bone (4). DNA has a very strong affinity for hydroxyapatite. DNA degradation is linked to the loss of crystallinity in the hydroxyapatite, but it may also be related to the loss of collagen (5).Overall, it seems reasonable to suppose that the characteristics of the bone that are correlated with its general long term survival, ie its resistance to morphological degradation at the macroscopic and microscopic level, would be those that contribute to the protection of DNA from degradation. Bone density, ie the extent of mineralization, is one of the most important intrinsic factors in survival of bone material. There is a significant difference in bone density between men and women, with the latter showing lower density values. The difference in bone density is also specific for different areas of the skeletal element morphology, with the highest density values noted for the mid-shaft region (6). Teeth are the hardest tissue in the human body because of the dental enamel (7).To know which bones best preserve DNA is of fundamental importance to DNA identification casework in mass fatality incidents and mass graves from armed conflict or genocide. The question equally applies to “ancient DNA” analyses in archaeological or human molecular evolutionary investigations. Despite the logical expectation that denser, more intact bones may be preferable, there is very little empirical data published on this issue (8). We also note that a successful recovery of DNA is linked not only to the degree of protection within the bone, but also the total amount of starting DNA. One reason for the lack of precise information on the best samples for DNA testing from degraded bone is the difficulty in performing controlled experiments, with regard to the effect of relevant environmental variables, inter-individual variation (related to for example sex or age), the long periods of time involved, and the need for large sample size.The aim of our study was to analyze DNA typing success rates from very large sample sizes of various skeletal elements from victims of conflict in the former Yugoslavia. Given the large number of variables affecting DNA preservation, a large sample size helps to average out the influences of a wide range of environmental contexts and permit general conclusions. Further, we divided our data into three time periods, with respect to time since death. This allows the analysis of the relative rate of degradation in different skeletal elements over time. These empirical data can serve as a useful guide to sampling strategies from degraded skeletal remains.