Toward an understanding of the molecules that sense myocardial ischemia.

Cardiac afferent neurons are activated in the setting of myocardial ischemia and mediate the sensation of angina. However, the precise stimuli and receptive molecules responsible are not completely understood. To further investigate the molecular components involved, cardiac afferents were isolated in dissociated culture and patch-clamp experiments were performed on these cells. It was found that acidic pH evoked large inward currents in almost all cardiac sympathetic afferents. By comparison, the responses to other potential chemical mediators were inconsistent and much smaller. The biophysical properties of the acid-evoked currents in cardiac afferents match the acid-sensing ion channel 3 (ASIC3).

The role of Army physical therapists as nonphysician health care providers who prescribe certain medications: observations and experiences.

For two decades, Army physical therapists have been granted limited privileges to prescribe certain medications when serving as nonphysician health care providers for the primary evaluation and treatment of patients with neuromusculoskeletal dysfunctions. A brief summary of the events that led to this physician-extender role is presented. This article describes the Army regulations, credentialing process, and expanded clinical privileges developed to prepare and support physical therapists working as primary neuromusculoskeletal screeners who are credentialed to order certain pharmacologic medications. A historical synopsis of Army physical therapists ordering pharmacologic medications. A historical synopsis of Army physical therapists ordering pharmacologic medications in their expanded role as nonphysician health care providers is also presented. Results of a 1994 Army-wide survey of physical therapy clinics are provided in terms of medications prescribed and observations by those involved. The educational opportunities designed to ensure safe and appropriate uses of these privileges are described.

A comparative analysis of several crutch-length-estimation techniques.

The purpose of this study was to determine which of several crutch-fitting techniques best predicts ideal crutch length. One hundred seven active-duty military volunteers were measured for crutches using each of the following methods: (1) axillary fold to heel in the supine position, (2) olecranon to opposite third fingertip, (3) olecranon to opposite fifth fingertip, (4) 77% of height, (5) height minus 16 in (40.6 cm), (6) 77% of arm span, and (7) arm span minus 16 in (40.6 cm). The subject's self-reported heights and their actual measured heights were both used in calculations involving height. Ideal crutch length was determined by an experienced orthopedic physical therapist, with placement of the axillary pad 2.5 in (6.4 cm) below the axillary fold. Mean squared error indices were then computed as the average of the squared deviations of the technique measurements from the ideal crutch length. Of the techniques studied, the two involving minor arithmetical adjustments to the subjects' self-reported height were found to be good predictors: 77% of height and height minus 16 in (40.6 cm). The poorest predictor was axilla to heel in the supine position. Finally, two additional length estimates were derived using linear regression analyses. These estimates provided the best overall predictions based on actual height and reported height. A quick-reference table for crutch-length estimates based on patient heights was developed from these regression results.

The United States Army physical therapy experience: evaluation and treatment of patients with neuromusculoskeletal disorders.

Army physical therapists have had unique experiences relevant to orthopaedic physical therapy. The educational process, expanded clinical privileges, and physician supervisor role as developed to prepare and support physical therapists working as primary neuromusculoskeletal screeners are summarized. After-action reports demonstrate that Army physical therapists can evaluate and treat one-third of all sick-call patients generated in field training missions and significantly improve return-to-duty rates without requiring physician intervention. The historic events that led to the physician-extender role in the evaluation and treatment of patients with neuromusculoskeletal conditions are presented. These events support the current battlefield assignment of physical therapists as far forward as the inflatable Combat Support Hospitals. The scope of Army physical therapy practice continues to evolve and expand to meet the new challenge of nation assistance, peace-keeping, and humanitarian missions.

Increased response of muscle sensory neurons to decreases in pH after muscle inflammation.

Acid sensing ion channels (ASIC) are found in sensory neurons, including those that innervate muscle tissue. After peripheral inflammation there is an increase in proton concentration in the inflamed tissue, which likely activates ASICs. Previous studies from our laboratory in an animal model of muscle inflammation show that hyperalgesia does not occur in ASIC3 and ASIC1 knockout mice. Therefore, in the present study we investigated if pH activated currents in sensory neurons innervating muscle are altered after induction of muscle inflammation. Sensory neurons innervating mouse (C57/Bl6) muscle were retrogradely labeled with 1,1-dioctadecyl-3,3,3,3 tetramethylindocarbocyanine perchlorate (DiI). Two weeks after injection of DiI, mice were injected with 3% carrageenan to induce inflammation (n=8; 74 neurons) or pH 7.2 saline (n=5; 40 neurons, control) into the gastrocnemius muscle. 24 h later sensory neurons from L4-L6 dorsal root ganglia (DRG) were isolated and cultured. The following day the DRG neuron cultures were tested for responses to pH by whole-cell patch-clamp technique. Approximately 40% of neurons responded to pH 5 with an inward rapidly desensitizing current consistent with ASIC channels in both groups. The mean pH-evoked current amplitudes were significantly increased in muscle sensory neurons from inflamed mice (pH 5.0, 3602 ± 470 pA) in comparison to the controls (pH 7.4, 1964 ± 370 pA). In addition, the biophysical properties of ASIC-like currents were altered after inflammation. Changes in ASIC channels result in enhanced responsiveness to decreases in pH, and likely contribute to the increased hyperalgesia observed after muscle inflammation.

Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation.

Sensory neurons that innervate the heart sense ischemia and mediate angina. To use patch-clamp methods to study ion channels on these cells, we fluorescently labeled cardiac sensory neurons (CSNs) in rats so that they could later be identified in dissociated primary culture of either nodose or dorsal root ganglia (DRG). Currents evoked by a variety of different agonists imply the importance of lowered pH (

Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons.

Cardiac afferents are sensory neurons that mediate angina, pain that occurs when the heart receives insufficient blood supply for its metabolic demand (ischemia). These neurons display enormous acid-evoked depolarizing currents, and they fire action potentials in response to extracellular acidification that accompanies myocardial ischemia. Here we show that acid-sensing ion channel 3 (ASIC3), but no other known acid-sensing ion channel, reproduces the functional features of the channel that underlies the large acid-evoked current in cardiac afferents. ASIC3 and the native channel are both especially sensitive to pH, interact similarly with Ca(2+), and gate rapidly between closed, open, and desensitized states. Particularly important is the ability of ASIC3 and the native channel to open at pH 7, a value reached in the first few minutes of a heart attack. The steep activation curve suggests that the channel opens when four protons bind. We propose that ASIC3, a member of the degenerin channel (of Caenorhabditis elegans)/epithelial sodium channel family of ion channels, is the sensor of myocardial acidity that triggers cardiac pain, and that it might be a useful pharmaceutical target for treating angina.

DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature.

Several DEG/ENaC cation channel subunits are expressed in the tongue and in cutaneous sensory neurons, where they are postulated to function as receptors for salt and sour taste and for touch. Because these tissues are exposed to large temperature variations, we examined how temperature affects DEG/ENaC channel function. We found that cold temperature markedly increased the constitutively active Na(+) currents generated by epithelial Na(+) channels (ENaC). Half-maximal stimulation occurred at 25 degrees C. Cold temperature did not induce current from other DEG/ENaC family members (BNC1, ASIC, and DRASIC). However, when these channels were activated by acid, cold temperature potentiated the currents by slowing the rate of desensitization. Potentiation was abolished by a "Deg" mutation that alters channel gating. Temperature changes in the physiologic range had prominent effects on current in cells heterologously expressing acid-gated DEG/ENaC channels, as well as in dorsal root ganglion sensory neurons. The finding that cold temperature modulates DEG/ENaC channel function may provide a molecular explanation for the widely recognized ability of temperature to modify taste sensation and mechanosensation.

The Escherichia coli RuvB branch migration protein forms double hexameric rings around DNA.

The RuvB protein is induced in Escherichia coli as part of the SOS response to DNA damage. It is required for genetic recombination and the postreplication repair of DNA. In vitro, the RuvB protein promotes the branch migration of Holliday junctions and has a DNA helicase activity in reactions that require ATP hydrolysis. We have used electron microscopy, image analysis, and three-dimensional reconstruction to show that the RuvB protein, in the presence of ATP, forms a dodecamer on double-stranded DNA in which two stacked hexameric rings encircle the DNA and are oriented in opposite directions with D6 symmetry. Although helicases are ubiquitous and essential for many aspects of DNA repair, replication, and transcription, three-dimensional reconstruction of a helicase has not yet been reported, to our knowledge. The structural arrangement that is seen may be common to other helicases, such as the simian virus 40 large tumor antigen.

Nonpalpable intratesticular masses detected sonographically.

PURPOSE: There is controversy concerning the implications of impalpable testicular masses. We examine the sonographic findings and pathology of such tumors. MATERIALS AND METHODS: Between 1985 and 1994, 3,019 scrotal ultrasound studies were performed for various indications and 15 impalpable masses were discovered. RESULTS: Pathological study revealed 5 seminomas, 6 nonseminomas, 2 "burned-out" tumors, 1 lipoma and 1 granuloma. CONCLUSIONS: Impalpable intratesticular masses are likely to be malignant. Any young man with retroperitoneal or visceral masses should undergo scrotal ultrasound. A testicular mass is likely to be the primary cancer but it may be regressed. Persistent scrotal pain may be a presentation of malignancy and should be evaluated with ultrasound.

The mammalian sodium channel BNC1 is required for normal touch sensation.

Of the vertebrate senses, touch is the least understood at the molecular level The ion channels that form the core of the mechanosensory complex and confer touch sensitivity remain unknown. However, the similarity of the brain sodium channel 1 (BNC1) to nematode proteins involved in mechanotransduction indicated that it might be a part of such a mechanosensor. Here we show that disrupting the mouse BNC1 gene markedly reduces the sensitivity of a specific component of mechanosensation: low-threshold rapidly adapting mechanoreceptors. In rodent hairy skin these mechanoreceptors are excited by hair movement. Consistent with this function, we found BNC1 in the lanceolate nerve endings that lie adjacent to and surround the hair follicle. Although BNC1 has been proposed to have a role in pH sensing, the acid-evoked current in cultured sensory neurons and the response of acid-stimulated nociceptors were normal in BNC1 null mice. These data identify the BNC1 channel as essential for the normal detection of light touch and indicate that BNC1 may be a central component of a mechanosensory complex.