Germinal center and activated b-cell profiles separate Burkitt lymphoma and diffuse large B-cell lymphoma in AIDS and non-AIDS cases

Morphologic features of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) overlap. No single phenotypic marker or molecular abnormality is pathognomonic. We tested a panel of 8 germinal center (GC) and activated B-cell (ABC) markers for their ability to separate BL and DLBCL. We diagnosed 16 BL and 39 DLBCL cases from 21 patients with AIDS and 34 without AIDS based on traditional morphologic criteria, Ki-67 proliferative index, and c-myc rearrangement (fluorescence in situ hybridization). After immunohistochemically staining tissue microarrays of BL and DLBCL for markers of GC (bcl-6, CD10, cyclin H) and ABC (MUM1, CD138, PAK1, CD44, bcl-2), we scored each case for the percentage of positive cells. Hierarchical clustering yielded 2 major clusters significantly associated with morphologic diagnosis (P < .001). For comparison, we plotted the sum of the GC scores and ABC scores for each case as x and y data points. This revealed a high-GC/low-ABC group and a low-GC/high-ABC group that were associated significantly with morphologic diagnosis (P < .001). Protein expression of multiple GC and ABC markers can separate BL and DLBCL.     

The effect of trimodal prehabilitation on the physical and psychological health of patients undergoing colorectal surgery: a randomised clinical trial

Prehabilitation aims to increase the endurance capacity of patients who are awaiting major surgery. However, there are no studies investigating the implementation of this demanding and expensive intervention in low-income countries. This study aimed to assess the impact of a 4-week trimodal prehabilitation program on the physical and psychological health of patients waiting for colorectal surgery compared with a control group managed according to enhanced recovery after surgery principles supplemented by nutritional care. This study was a single-centre, randomised controlled trial. The primary outcome measures for the physical aspects were 6-minute walking distance (6MWD) and incentive spirometry, whereas the psychological elements were measured using the 36-item short form survey questionnaire and the hospital anxiety and depression score. In total, data from 149 patients were analysed (77 in the prehabilitation group and 72 in the control group). At the time of surgery, patients in the prehabilitation group had improved 6MWD and incentive spirometry compared with the control group (median (IQR [range]) percentage improvement 131% (112–173 [68–376]) vs. 107% (99–120 [63–163]); p < 0.001 and 113% (100–125 [75–200]) vs. 100% (100–112 [86–167]); p < 0.001 respectively). Patients in the prehabilitation group also had reduced anxiety scores compared with the control group (mean (SD) anxiety score (4 (3) vs. 5 (3) respectively; p = 0.032). However, these effects did not translate into improvements in postoperative mortality and morbidity, or a reduction in duration of hospital stay. Trimodal (physical, emotional and nutritional) prehabilitation is able to improve functional status as well as some parameters of emotional and physical well-being of patients waiting for colorectal surgery.     

The inappropriate use of acute hospital beds in an inner London District Health Authority

The requirement for District Health Authorities to assess the health care needs of their population implies that they must consider how well acute hospital care meets these identified needs. This study, which was conducted in an inner London health district, identified that 123 (14.6%) patients were perceived by medical and/or nursing staff to be inappropriately located in an acute bed. This group was dominated by patients aged 65 years or above, those in general and geriatric medicine, those with a length of stay of 30 days or more, and those with high levels of physical and mental dependency. The main reasons for patients being labelled as 'inappropriate' were the need for non-acute health services (eg rehabilitation, terminal care etc), a need for nursing home places or because of social or housing problems. Five months after identification, the notes of 100 of the 123 inappropriate patients were traced. Retrospective classification of these notes using the more 'objective' Oxford Bed Study Instrument showed that 97 patients were still defined as inappropriate. Details of the length of inappropriate stay were available for 74 patients who accrued 7,519 inappropriate bed days at a cost of 836,547 pounds. These patients are an illustration of the potential failings of current health and social care systems and highlight the need for imaginative care solutions which bridge this divide.     

Conventional magnetic resonance imaging in confirmed progressive supranuclear palsy and multiple system atrophy

Conventional magnetic resonance imaging (cMRI) is often used to aid the diagnosis of progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), but its ability to predict the histopathological diagnosis has not been systematically studied. cMRI from 48 neuropathologically confirmed cases, including PSP (n = 22), MSA (n = 13), Parkinson's disease (PD) (n = 7), and corticobasal degeneration (n = 6), and controls (n = 9) were assessed blinded to clinical details and systematically rated for reported abnormalities. Clinical diagnosis and macroscopic postmortem findings were retrospectively assessed. Radiological assessment of MRI was correct in 16 of 22 (72.7%) PSP cases and 10 of 13 (76.9%) MSA cases with substantial interrater agreement (Cohen's kappa 0.708; P < .001); no PSP case was misclassified as MSA or vice versa. MRI was less sensitive but more specific than clinical diagnosis in PSP and both more sensitive and specific than clinical diagnosis in MSA. The “hummingbird” and “morning glory” signs were highly specific for PSP, and “the middle cerebellar peduncle sign” and “hot cross bun” for MSA, but sensitivity was lower (up to 68.4%) and characteristic findings may not be present even at autopsy. cMRI, clinical diagnosis, and macroscopic examination at postmortem have similar sensitivity and specificity in predicting a neuropathological diagnosis. We have validated specific radiological signs in pathologically confirmed PSP and MSA. However, the low sensitivity of these and macroscopic findings at autopsy suggest a need for imaging techniques sensitive to microstructural abnormalities without regional atrophy. © 2012 Movement Disorder Society     

Positive allosteric modulators to peptide GPCRs: a promising class of drugs

The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABA_A receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world''s first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.