Cells use molecular working memory to navigate in changing chemoattractant fields.

In order to migrate over large distances, cells within tissues and organisms rely on sensing local gradient cues which are irregular, conflicting, and changing over time and space. The mechanism how they generate persistent directional migration when signals are disrupted, while still remaining adaptive to signal's localization changes remain unknown. Here, we find that single cells utilize a molecular mechanism akin to a working memory to satisfy these two opposing demands. We derive theoretically that this is characteristic for receptor networks maintained away from steady states. Time-resolved live-cell imaging of Epidermal growth factor receptor (EGFR) phosphorylation dynamics shows that cells transiently memorize position of encountered signals via slow-escaping remnant of the polarized signaling state, a dynamical 'ghost', driving memory-guided persistent directional migration. The metastability of this state further enables migrational adaptation when encountering new signals. We thus identify basic mechanism of real-time computations underlying cellular navigation in changing chemoattractant fields.

If we are injured, or fighting an infection, cells in our body migrate over large distances to the site of the wound or infection to act against any invading microbes or repair the damage. Cells navigate to the damaged site by sensing local chemical cues, which are irregular, conflicting and change over time and space. This implies that cells can choose which direction to travel, and stick to it even if the signals around them are disrupted, while still retaining the ability to alter their direction if the location of the signal changes. However, how cells are able to effectively navigate their way through this field of complex chemical cues is poorly understood. To help resolve this mystery, Nandan, Das et al. studied the epidermal growth factor receptor (EGFR) signaling network which controls how some cells in the body change shape and migrate. The network is activated by specific chemical cues, or ligands, binding to EGFR proteins on the cell surface. The receptors then join together to form pairs, and several tags known as phosphate groups are added to each molecule. This process (known as phosphorylation) switches the receptor pair to an active state, allowing EGFR to relay signals to other proteins in the cell and promote the activity of receptors not bound to a ligand. The phosphorylation state of EGFRs is then modulated over time and across the cell by a network of enzymes called phosphatases which can remove the phosphate groups and switch off the receptor. To study EGFR phosphorylation dynamics in human cells, Nandan, Das et al. imaged individual cells over time using a microscope. This data was then combined with a mathematical model describing the EGFR signaling network and how cells change their shape over time. The experiment revealed that the phosphate groups attached to EGFR are not removed immediately when the chemical cue is gone. Instead, the active state is transiently maintained before complete inactivation. This had the effect of encoding a short-lived memory in the signaling network that allowed the cells to continue to migrate in a certain direction even when chemical cues were disrupted. This memory state is dynamic, enabling cells to adapt direction when the cue changes location. The findings of Nandan, Das et al. reveal the underlying mechanism for how cells decipher complex chemical cues to migrate to where they are needed most. The next steps to follow on from this work will be to understand if other receptors involved in migration work in a similar way.

Immunohistochemical Validation of Rare Tissues and Antigens With Low Frequency of Occurrence: Recommendations From The Anatomic Pathology Patient Interest Association (APPIA).

Laboratories worldwide find it challenging to identify enough tissues and cases for verification and validation studies of low-incidence, rare antigens. These antigens have a low frequency of occurrence in the population, or have little or no expression in normal tissues. Validation studies are essential to assure testing standardization before introducing a new instrument, product, or test into the clinical laboratory. The College of American Pathologists has published comprehensive guidelines for the verification and validation of new immunohistochemical tests introduced into the laboratory menu. Within the guidelines, varied numbers of cases are required for nonpredictive versus predictive markers. However, regarding low-incidence antigens, the laboratory medical director determines the extent of validation required. Recommended practical solutions available to clinical laboratories for low-incidence validation include developing internal resources using the laboratory information system with retrospective and prospective search(s) of archival material and purchase of tissue microarray blocks, slides, or cell lines from external resources. Utilization of homemade multitissue blocks has proved to be extremely valuable in biomarker research and demonstrated great utility in clinical immunohistochemistry laboratories. Participation in External Quality Assessment program(s) may provide insufficient numbers or the ability to calculate concordance rates. However, supplementation with in-house tissues can allow a laboratory to reach the optimal number of cases needed for verification and/or validation schemes. An alternative approach is conducting a thorough literature search and correlating staining patterns of the new test to the expected results. These solutions may be used uniquely or together to assure consistent standardized testing.

Impact of system-level changes and training on alcohol screening and brief intervention in a family medicine residency clinic: a pilot study.

BACKGROUND: Although screening and brief intervention (SBI) are effective in reducing unhealthy alcohol use, major challenges exist in implementing clinician-delivered SBI in primary care settings. This 2006-2007 pilot study describes the impact of systems changes and booster trainings designed to increase SBI rates in a family medicine residency clinic which annually screened adults with a self-administered AUDIT-C questionnaire and used paper prompts to encourage physician interventions for patients with positive screens. METHODS: Investigators added the Single Alcohol Screening Question (SASQ) to nursing vital signs forms, added a checkbox for documenting brief interventions to the clinicians' outpatient encounter form, and conducted one-hour nurse and clinician booster trainings. Impact was measured using chart reviews conducted before implementing systems changes, then six weeks and six months post-implementation. RESULTS: At all three time points screening rates using AUDIT-C plus SASQ exceeded 90%, however AUDIT-C screening decreased to 85% after 6 months (p=.025). Identification of unhealthy alcohol users increased from 4% to 22.9% at six weeks and 18.8% at six months (p=.002) using both screens. Nursing vital signs screening using the SASQ reached 71.4% six weeks after implementation but decreased to 45.5% at six months. Changes in clinician brief intervention rates did not achieve statistical significance. CONCLUSIONS: This is the second study reporting sustained primary care alcohol screening rates of more than 90%. Screening patients with SASQ and/or AUDIT-C identified a higher percentage of patients with unhealthy alcohol use. Dissemination of effective strategies for identifying unhealthy alcohol users should continue, while future research should focus on identifying more effective strategies for increasing intervention rates.

The College of American Pathologists and National Society for Histotechnology workload study.

Limited data exist in regard to productivity and staffing in the anatomic pathology laboratory. In 2004, the National Society for Histotechnology (NSH) conducted a pilot study to examine productivity and staffing in the histology laboratory. After review of the data, The College of American Pathologists (CAP)/NSH Histotechnology Committee concluded that a larger survey was required to further address and expand on the pilot study findings. In 2007, a total of 2674 surveys were sent out to North American laboratories. From the responses, comparisons of laboratory demographics and productivity were examined by institution type and workload volume. Productivity was measured as the number of paraffin-embedded tissue blocks processed per full-time equivalent per year. This manuscript presents and discusses the data collected from the CAP/NSH Workload Study.

Medication adherence among acne patients: a review.

BACKGROUND: Acne is a chronic disease often requiring the use of medications for extended periods of time. In general, adherence decreases over time in patients with chronic diseases, and adherence to topical medications is poor compared to adherence to oral medications, placing individuals using topical medications at increased risk for nonadherence and treatment failure. Poor adherence may also be a common cause of treatment failure in teens with acne. PURPOSE: We reviewed the current literature on medication adherence in teenagers with acne to assess adherence levels and predictors of adherence. We hope to provide a foundation for further research into medication adherence in acne patients. METHODS: A Medline search was conducted using the key words "acne" and "adherence" or "compliance." Studies reporting adherence were included in the analysis. RESULTS: A positive correlation was found between quality of life of patients with acne and medication adherence. Weaker predictors of adherence include increased age, female gender, and employment. The most commonly reported reason for nonadherence was inadequate time to use the treatment medication. Patients taking medications requiring less frequent dosing had better adherence, and medication adherence correlated with better health status among acne patients. A longer duration between office visits may be associated with decreased compliance. Limitations Few studies investigating the prevalence and causes of nonadherence in acne patients were identified. CONCLUSIONS: Adherence to medications is difficult to measure and rates reported by patients often overestimate actual adherence. Patients cite lack of time as a common reason for nonadherence to topical medications.

The existence of hypoglossal root ganglion cells in adult humans: potential clinical implications.

INTRODUCTION: Ganglion cells of the hypoglossal nerve (HN) have been confirmed in certain animals but have been thought not to be present in man. To investigate for the presence of these structures in adult humans and if present, to verify their functionality, the present study was performed. MATERIALS AND METHODS: We harvested adult cadaveric HN and observed for ganglion cells. Histological and immunohistochemical analyses were performed on all specimens. RESULTS: Ganglion cells were found in 33% of specimens. Using immunohistochemistry, we found that these ganglia were sympathetic in nature. Based on our findings, ganglion cells do exist in the human HN although they are located sporadically and are found inconstantly. CONCLUSIONS: Such information may be valuable in elucidating other functions of the HN and may aid in the histological diagnosis of this nerve. Additionally, pathology involving HN such as paragangliomas, are supported by our findings of the presence of autonomic ganglion cells in some HN specimens.

Immunohistochemical study of the phrenic ganglion.

Peripheral nerve 'pseudoganglia' are described in the literature with little focus on histology. The phrenic ganglia, which are located on the inferior surface of the diaphragm and are associated with the phrenic nerves, have been described by some authors as potentially sympathetic ganglia although this, to the authors' knowledge, has not been proven. The purpose of the present study was to elucidate further the true autonomic nature of this collection of nerve cell bodies. In eight fresh adult cadavers < 6 h after death, the left and right phrenic ganglia were harvested and subjected to immunochemistry. All phrenic ganglia were vasoactive intestinal polypeptide negative but tyrosine hydroxylase positive. These findings indicate that the phrenic ganglia are sympathetic ganglia with most likely a vasomotor function.

Histopathological basis for neurogenic thoracic outlet syndrome. Laboratory investigation.

OBJECT: To the best of the authors' knowledge, no report exists that has demonstrated the histopathological changes of neural elements within the brachial plexus as a result of cervical rib compression. METHODS: Four hundred seventy-five consecutive human cadavers were evaluated for the presence of cervical ribs. From this cohort, 2 male specimens (0.42%) were identified that harbored cervical ribs. One of the cadavers was found to have bilateral cervical ribs and the other a single right cervical rib. Following gross observations of the brachial plexus and, specifically, the lower trunk and its relationship to these anomalous ribs, the lower trunks were submitted for immunohistochemical analysis. Specimens were compared with two age-matched controls that did not have cervical ribs. RESULTS: The compressed plexus trunks were largely unremarkable proximal to the areas of compression by cervical ribs, where they demonstrated epi- and perineurial fibrosis, vascular hyalinization, mucinous degeneration, and frequent intraneural collagenous nodules. These histological findings were not seen in the nerve specimens in control cadavers. The epineurium was thickened with intersecting fibrous bands, and the perineurium appeared fibrotic. Many of the blood vessels were hyalinized. The nerve fascicles contained frequent intraneural collagenous nodules in this area, and focal mucinous degeneration was identified. CONCLUSIONS: Cervical ribs found incidentally may cause histological changes in the lower trunk of the brachial plexus. The clinician may wish to observe or perform further evaluation in such patients.

Does the ganglion of Ribes exist?

Some have included the ganglion of Ribes (Francois Ribes, 1765-1845), lying on the anterior communicating artery, as the most superior ganglion of the sympathetic nervous system. To verify the presence of this structure, the anterior communicating artery was harvested from 40 fresh adult cadavers and histological analysis and immunochemistry performed. Grossly and with magnification, no ganglion-like structures were found in or around the anterior communicating artery in any specimen. However, scattered neuronal cell bodies were found in the adventitia of the anterior communicating artery with histological immunochemical analysis. Based on the lack of vasoactive intestinal peptide staining and the positive reaction to tyrosine hydroxylase, these neurons are most likely sympathetic in nature. Based on our findings, a grossly visible ganglion of Ribes does not exist. However, neuronal cell bodies were found in the adventitia of the anterior communicating artery although the function of such cells remains speculative.

Complete ossification of the human falx cerebri.

During the routine dissection of the head and neck of an adult male cadaver complete ossification of the falx cerebri was noted. Anomalous ossification was not found in any other dural component or other parts of the body. The brain appeared grossly normal. Histological sections showed normal ossification processes involving the falx cerebri. In addition, rare scattered deposits of metastatic poorly differentiated carcinoma within the trabecular spaces were seen. Reports of isolated islands of ossification involving primarily the most anterior part of the falx cerebri in man are found in the literature. Our case report represents to our knowledge, the first report of complete ossification of this dural partition. Whether this is simply an anomalous configuration or due to the few metastatic cells found within this region remains unclear.

The filum terminale externum.

OBJECT: The filum terminale externum (FTE) is the extradural component of the filum terminale internum and little attention has been dedicated to this structure in the literature. The authors theorized that the rare intrasacral ependymomas may originate from ependymal cell collections within the FTE. METHODS: To address this hypothesis, the FTE was dissected and analyzed histologically in 15 adult cadavers. None of the specimens was found to harbor ependymal or other glial cell collections. CONCLUSIONS: The authors found previously undescribed smooth-muscle cells within the FTE. Furthermore, histological analysis identified adipose, nerve, bone, and cartilage cells.