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DNA-binding protein domains (DBDs) sample diverse conformations in equilibrium facilitating the search and recognition of specific sites on DNA over millions of energetically degenerate competing sites. We hypothesize that DBDs have co-evolved to sense and exploit the strong electric potential from the array of negatively charged phosphate groups on DNA. We test our hypothesis by employing the intrinsically disordered DBD of cytidine repressor (CytR) as a model system. CytR displays a graded increase in structure, stability and folding rate on increasing the osmolarity of the solution that mimics the non-specific screening by DNA phosphates. Electrostatic calculations and an Ising-like statistical mechanical model predict that CytR exhibits features of an electric potential sensor modulating its dimensions and landscape in a unique distance-dependent manner, while DNA plays the role of a non-specific macromolecular chaperone. Accordingly, CytR binds its natural half-site faster than the diffusion-controlled limit and even random DNA conforming to an electrostatic-steering binding mechanism. Our work unravels for the first time the synergistic features of a natural electrostatic potential sensor, a novel binding mechanism driven by electrostatic frustration and disorder, and the role of DNA in promoting distance-dependent protein structural transitions critical for switching between specific and non-specific DNA-binding modes.

The amplitude of thermodynamic fluctuations in biological macromolecules determines their conformational behavior, dimensions, nature of phase transitions and effectively their specificity and affinity, thus contributing to fine-tuned molecular recognition. Unique among large-scale conformational changes in proteins are temperature-induced collapse transitions in intrinsically disordered proteins (IDPs). Here, we show that CytR DNA-binding domain, an IDP that folds on binding DNA, undergoes a coil-to-globule transition with temperature in the absence of DNA while exhibiting energetically decoupled local and global structural rearrangements, and maximal thermodynamic fluctuations at the optimal bacterial growth temperature. The collapse is shown to be a continuous transition through a combination of statistical-mechanical modeling and all-atom implicit solvent simulations. Surprisingly, CytR binds single-site cognate DNA with negative cooperativity, described by Hill coefficients less than one, resulting in a graded binding response. We show that heterogeneity arising from varying binding-competent CytR conformations or orientations at the single-molecular level contributes to negative binding cooperativity at the level of bulk measurements due to the conflicting requirements of collapse transition, large fluctuations and folding-upon-binding. Our work reports strong evidence for functionally driven thermodynamic fluctuations in determining the extent of collapse and disorder with implications in protein search efficiency of target DNA sites and regulation.

Purpose: The effect of a weight-based prescribing method within the electronic health record (EHR) on the rate of prescribing errors was studied., Methods: A report was generated listing all patients who received a prescription by a clinic provider for either infants' or children's acetaminophen or ibuprofen from January 1 to July 28, 2005 (preintervention group) and from July 29 to December 30, 2005 (postintervention group). Patients were included if they were 12 years old or younger, had a prescription ordered for infants' or children's acetaminophen or ibuprofen within the EHR, and had a weight documented in the chart on the visit day. The dosing range for acetaminophen was 10-15 mg/kg every four to six hours as needed, and the regimen for ibuprofen was 5-10 mg/kg every six to eight hours as needed. Dosing errors were defined as overdosage of strength, overdosage of regimen, underdosage of strength, under-dosage of regimen, and incomprehensible dosing directions., Results: Totals of 316 and 224 patient visits were analyzed from the preintervention and postintervention groups, respectively. Significantly more medication errors were found in the preintervention group than in the postintervention group (103 versus 46, p = 0.002). Significantly fewer strength overdosing errors occurred in the postintervention group (8.9% versus 4.0%, p = 0.028)., Conclusion: An automated weight-based dosing calculator integrated into an EHR system in the outpatient setting significantly reduced medication prescribing errors for antipyretics prescribed to pediatric patients. This effect appeared to be strongest for reducing overdose errors.

Cervicocerebral arterial dissections (CAD) are an important cause of strokes in younger patients accounting for nearly 20% of strokes in patients under the age of 45 years. Extracranial internal carotid artery dissections comprise 70%-80% and extracranial vertebral dissections account for about 15% of all CAD. Aetiopathogenesis of CAD is incompletely understood, though trauma, respiratory infections, and underlying arteriopathy are considered important. A typical picture of local pain, headache, and ipsilateral Horner's syndrome followed after several hours by cerebral or retinal ischaemia is rare. Doppler ultrasound, MRI/MRA, and CT angiography are useful non-invasive diagnostic tests. The treatment of extracranial CAD is mainly medical using anticoagulants or antiplatelet agents although controlled studies to show their effectiveness are lacking. The prognosis of extracranial CAD is generally much better than that of the intracranial CAD. Recurrences are rare in CAD.

Background: Iron deficiency anaemia (IDA) is a recognised feature of coeliac disease in adults and can be its only presentation., Objective: To determine the yield of routine distal duodenal biopsies in diagnosing coeliac disease in adult and elderly patients with IDA whose endoscopy revealed no upper gastrointestinal cause of iron deficiency., Study Design: Prospective study in a teaching hospital endoscopy unit., Method: Altogether 504 consecutive patients with IDA, aged 16-80 years, attending for endoscopy were included in this study. At least two distal duodenal biopsies were taken if endoscopy revealed no cause of iron deficiency., Result: In nine (1.8%) patients duodenal biopsies revealed typical histological features of coeliac disease. Of these, five patients were above 65 years old., Conclusion: In adult and elderly patients undergoing endoscopy for IDA, the endoscopist should take distal duodenal biopsies to exclude coeliac disease if no upper gastrointestinal cause of anaemia is found. Coeliac disease is not an uncommon cause of IDA in patients >65 years of age and a history of chronic diarrhoea increases diagnostic yield in this age group.

Background: Unsedated oesophagogastroduodenoscopy (OGD) is considered by most endoscopists to be a quick, safe, and well tolerated procedure. Older patients are said to tolerate it better than younger patients. However, patients' perception of the discomfort for the unsedated OGD has not been well studied., Objective: This study was undertaken to compare (1) patients' perception of discomfort with the endoscopist's perception of patients' discomfort for the unsedated OGD, (2) tolerability between older (> or =75 years) and younger (<75 years) patients., Design and Subjects: A total of 130 consecutive patients attending a day case endoscopy unit were recruited for the study. The patients and endoscopist recorded their assessment using a visual analogue scale (VAS). The results were analysed using non-parametric tests. Thirty patients were excluded from the study based on exclusion criteria. Sixty three (57%) patients were aged > or =75 years and 37 (43%) were <75 years., Results: A significant difference was noted between patients' perception of the discomfort and the endoscopist's assessment of the patient's discomfort as suggested by the overall higher VAS scores for patients (median 4.9, SD 2.6) than those of the endoscopist (median 2.2, SD 1.2), giving a significant difference in median VAS score of 3.4 (p<0.001). Older and younger patients had similar scores, with median (SD) VAS scores of 4.8 (2.5) for > or =75 years and 4.9 (2.8) for <75 years. The endoscopist's median scores for these two groups were 2.2 (1.2) and 2.1 (1.3), respectively., Conclusions: Patients' discomfort during OGD performed without sedation was greatly underestimated by the endoscopist. There was no significant difference in acceptability between old and the young patients.

Parkinson's disease is often recognised as a motor disease characterised by rest tremor, rigidity, bradykinesia, and postural disturbances. However, there are several non-motor aspects of the disease that are of at least equal importance in the management of patients with Parkinson's disease. They include depression, cognitive impairment, anxiety, and psychosis among others. It is important to recognise them, as they are common and they contribute significantly to patients' morbidity, quality of life, and institutionalisation to long term care homes. In addition to the disease duration and severity, other factors including drugs may contribute to their occurrence. Pathogenesis of these aspects is not fully understood, though there has been a significant increase in the knowledge in recent years. Management of these aspects involves a multidisciplinary approach.

Acute confusional states in the older patient often have a remediable cause. Every effort should be made to ascertain the cause so that appropriate treatment can be given and future episodes prevented. A patient is described who presented with recurrent episodes of acute psychosis after ingestion of Atropa belladonna (deadly nightshade).

Background: In a retrospective case-note and computer database analysis we assessed the outcome of very elderly patients (> or = 75 years old) with end-stage renal disease (ESRD) on renal replacement therapy (RRT)., Methods: Fifty-eight individuals aged 75 or over (group 1) commenced RRT between 1 January 1991 and 31 December 1995. Comparisons were made with other patients commencing RRT who were divided into two groups: group 2 (201 individuals 65-74 years old) and group 3 (379 patients <65 years old). All subjects were followed up until the point of assessment (30 June 1998), the time of death, or withdrawal from dialysis. Survival rates in the three groups were compared using Kaplan-Meier method. The number of hospital admissions, length of in-patient stay, and complications rate on RRT were assessed for group 1., Results: One-year survival rates in groups 1, 2 and 3 were 53.5, 72.6, and 90.6% respectively and the 5-year survival rates were 2.4, 18.8, and 61.4% respectively. The very elderly spent 20% of their time in hospital, 46% had two co-morbid factors at the outset, and 26% developed multiple complications while on RRT. Withdrawal from dialysis remained the most common cause of death in this group of individuals (38%), followed by cardiovascular causes (24%) and infections (22%)., Conclusion: Very elderly ESRD patients on RRT have a very poor outcome and, since they are the largest growing group of RRT patients, this has important implications for future health policies.