Diagnosis and treatment of thoracic outlet syndrome

Patients who develop symptoms of thoracic outlet syndrome (TOS) have a predisposing anatomic abnormality. In most patients with TOS, the symptoms are caused by entrapment of the brachial plexus and they do not arise from compression of the subclavian artery, as was previously thought. The tests advocated for diagnosing this common syndrome (i.e., evaluating the positional compression of the artery when the arms are raised, the neck is turned, or the shoulders are braced) cannot accurately diagnose this syndrome. There are two reasons for this. The symptoms of TOS are not related to the compression of the artery in the outlet in 98% of patients, and 75% of normal individuals without symptoms show diminished radial pulse on various provocation tests. We employed four timed provocation tests (minute tests) to diagnose TOS: the timed Morley test, timed Wright test, timed Eden test, and elevated arm stress exercise, all of which are very sensitive. In normal individuals without symptoms, 20% experience transitional symptoms such as slight pain and tiredness, on these tests indicating a subclinical state. TOS is treated by keeping the thoracic outlet wide, this being done either conservatively or surgically. In 1993 and 1994, we conservatively treated 418 of 422 patients with TOS by means of active exercise, a brace, and by block therapy. These measures did not reduce the symptoms in 23 of these patients, so surgical treatment was indicated. In the remaining 4 of the 422 patients, conservative treatment was not indicated and surgery was performed directly. All the patients showed significant clinical improvement of varying degree. Presented at the 69th Annual Meeting of the Japanese Orthopaedic Association, Tokyo, April 12, 1996     

Hypertrophy of medial globus pallidus and substantia nigra reticulata in 6‐hydroxydopamine‐lesioned rats treated with L‐DOPA: Implication for L‐DOPA‐induced dyskinesia in Parkinson's disease

The medial globus pallidus plays a crucial role in generation of L‐DOPA‐induced dyskinesia in patients with Parkinson's disease. The 6‐hydroxydopamine‐lesioned rat exhibiting behavioral sensitization to L‐DOPA is one useful animal model for examining L‐DOPA‐induced dyskinesia. To determine neuropathological abnormality responsible for behavioral sensitization, the medial globus pallidus and the substantia nigra reticulata in 6‐hydroxydopamine‐lesioned rats treated with L‐DOPA were examined. Intermittent L‐DOPA treatment induced hypertrophy of the lesioned‐side of medial globus pallidus and substantia nigra reticulata of 6‐hydroxydopamine‐lesioned rats with behavioral sensitization to L‐DOPA. Additionally, coadministration of a 5‐HT_1A receptor agonist, 8‐hydroxy‐2(di‐n‐propylamino)tetralin with L‐DOPA, alleviated the hypertrophy with improvement of the behavioral sensitization. These results suggest that hypertrophy of the medial globus pallidus and substantia nigra reticulata is associated with induction of behavioral sensitization to L‐DOPA in 6‐hydroxydopamine‐lesioned rats. Therefore, neuropathological changes corresponding to hypertrophy might underlie L‐DOPA‐induced dyskinesia in patients with Parkinson's disease.     

A PKC epsilon-ENH-channel complex specifically modulates N-type Ca2+ channels

Multiple protein kinase C (PKC) isozymes are present in neurons, where they regulate a variety of cellular functions. Due to the lack of specific PKC isozyme inhibitors, it remains unknown how PKC acts on its selective target(s) and achieves its specific actions. Here we show that a PKC binding protein, enigma homolog (ENH), interacts specifically with both PKCepsilon and N-type Ca2+ channels, forming a PKCepsilon-ENH-Ca2+ channel macromolecular complex. Coexpression of ENH facilitated modulation of N-type Ca2+ channel activity by PKC. Disruption of the complex reduced the potentiation of the channel activity by PKC in neurons. Thus, ENH, by interacting specifically with both PKCepsilon and the N-type Ca2+ channel, targets a specific PKC to its substrate to form a functional signaling complex, which is the molecular mechanism for the specificity and efficiency of PKC signaling.     

cAMP-independent decrease of ATP-sensitive K+ channel activity by GLP-1 in rat pancreatic β-cells

Using the patch-clamp method, we studied the mechanism of depolarization of rat pancreatic beta-cells induced by glucagon-like peptide 1 (7-36) amide (GLP-1). GLP-1 caused depolarization in a concentration-dependent manner (0.2-100 nM). Exendin (9-39) amide, a GLP-1 receptor antagonist, prevented the GLP-1-induced depolarization. GLP-1 reduced tolbutamide-sensitive membrane currents evoked by voltage ramps from -90 to -50 mV, recorded in the perforated whole-cell configuration, suggesting that GLP-1 decreased the activity of the ATP-sensitive K+ channel (KATP). This GLP-1 effect was prevented by exendin (9-39) amide. In cells treated with Rp-cAMPS, an inhibitor of the cAMP-dependent protein kinase (PKA), GLP-1 still caused depolarization and reduced the whole-cell membrane current through KATP. Examined in the cell-attached configuration, 20 nM GLP-1, applied out of the patch, had little effect on KATP activity. In the inside-out configuration, the open time probability and the single-channel conductance of KATP in the absence of ATP inside the membrane were unaffected by the presence of 20 nM GLP-1 in the pipette. In both conditions, application of ATP to the inside of the membrane reduced KATP activity. The half-maximal concentrations (ki) of ATP were 11.6 microM without and 5.6 microM with 20 nM GLP-1 in the pipette (P<0.05). The values of the Hill coefficient (h) were 1.03 without and 1.01 with GLP-1. We conclude that GLP-1 reduces KATP activity by elevating the sensitivity of KATP to ATP, resulting in depolarization of pancreatic beta-cells. This GLP-1 action is independent of the cAMP signalling pathway.     

A histological evaluation for guided bone regeneration induced by a collagenous membrane

This study was designed to evaluate the histological changes during ossification and cellular events including osteogenic differentiation responding to collagenous bioresorbable membranes utilized for GBR. Standardized artificial bony defects were prepared at rat maxillae, and covered with a collagenous bioresorbable membrane. These animals were sacrificed at 1, 2, 3 and 4 weeks after the GBR-operation. The paraffin sections were subject to tartrate resistant acid phosphatase (TRAP) enzyme histochemistry and immunohistochemistry for alkaline phosphatase (ALP), osteopontin (OP) and osteocalcin (OC). In the first week of the experimental group, woven bone with ALP-positive osteoblasts occupied the lower half of the cavity. The collagenous membrane included numerous ALP-negative cells and OP-immunoreactive extracellular matrices. At 2 weeks, the ALP-, OP- and OC-immunoreactivity came to be recognizable in the region of collagenous membrane. Since ALP-negative soft tissue separated the collagenous membrane and the new bone originating from the cavity bottom, the collagenous membrane appeared to induce osteogenesis in situ. At 3 weeks, numerous collagen fibers of the membrane were embedded in the adjacent bone matrix. At 4 weeks, the membrane-associated and the cavity-derived bones had completely integrated, showing the same height of the periosteal ridge as the surrounding alveolar bones. The collagen fibers of a GBR-membrane appear to participate in osteogenic differentiation.     

A di-synaptic projection from the lateral cerebellar nucleus to the laterodorsal part of the striatum via the central lateral nucleus of the thalamus in the rat

We have examined a cerebello–thalamo–striatal pathway from the lateral cerebellar nucleus (LCN) to the laterodorsal part of the striatum (LDS) through the central lateral nucleus (CL) using light and electron microscopy through the employment of a combination of anterograde and retrograde tracing techniques. Biotinylated dextran amine (BDA) was injected into the unilateral LCN, and used as an anterograde tracer. Cholera toxin B subunit (CTb), used for light microscopy, and wheat germ agglutinin–horseradish peroxidase (WGA-HRP), used for electron microscopy, were injected into the contralateral LDS as retrograde tracers. Light microscopic analysis showed a good overlap of the distribution of BDA-labeled axon terminals and CTb-labeled neurons in the middle third of the CL in both dorsoventral and rostrocaudal axes on the LDS injection side. Electron microscopy confirmed the presence of direct synaptic contacts between BDA-labeled terminals and WGA-HRP-labeled dendrites in the CL.     

Ecthyma gangrenosum caused by Staphylococcus aureus in hematological malignancies: Case reports and literature review

Rationale:Ecthyma gangrenosum (EG) is a potentially life-threatening, systemic infection generally caused by Pseudomonas aeruginosa. Data on EG caused by Staphylococcus aureus in patients with hematological malignancies are scarce. The present case report aimed to describe the clinical features of EG caused by S. aureus in patients with hematological malignancies and to provide a comprehensive review of previous studies on the topic.Patient concerns:The first patient was a 61-year-old man with acute myeloid leukemia who presented fever and multiple lesions during chemotherapy. The second patient was a 47-year-old man with myelodysplastic syndrome who developed progressive erythematous necrotic plaques on his extremities and face.Diagnosis:Both cases were diagnosed as EG caused by S. aureus. While the first patient had concurrent methicillin-resistant S. aureus (MRSA) bacteremia, the second patient had positive results only for tissue culture of the skin lesion isolated methicillin-sensitive S. aureus.Interventions:Vancomycin was initiated with critical care to the first patient. Cefazolin was administered to the second patient for 3 weeks, followed by cephalexin for 1 week.Outcomes:The first patient died of a brain hemorrhage and multiple organ failure. The second patient was cured without relapse.Lessons:Of 18 patients in the previous and current studies with EG caused by S. aureus, 6 (33%) had an underlying hematological malignancy, and 10 (56%) had EG caused by MRSA. While 28% of the patients had positive blood cultures, all tissue cultures were positive. All 3 fatalities had concurrent bacteremia (MRSA caused two). EG caused by MRSA with concurrent bacteremia can be fatal, especially in patients with hematological malignancies. Although S. aureus-associated EG in patients with hematological malignancies is relatively uncommon, tissue cultures with an initial gram stain smear are essential for selecting appropriate empirical antimicrobials, including the coverage of S. aureus.     

Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan

We retrospectively surveyed the data of 233 patients who underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) for non-Hodgkin lymphoma (NHL). Donors were HLA-matched relatives in 154 patients (66%) or unrelated volunteers in 60 (26%). Ninety patients (39%) were in complete remission. One hundred ninety-three (83%) received a total body irradiation (TBI)-based regimen, and 40 (17%) received a non-TBI-based regimen. Acute graft-versus-host disease (GVHD) occurred in 155 (67%) of the 233 evaluable patients; grade II to IV in 90 (39%), and grade III to IV in 37 (16%). Treatment-related mortality (TRM) was observed in 98 patients (42%), and 68% of them were related to GVHD. In a multivariate analysis, chemoresistance, prior autograft, and chronic GVHD were identified as adverse prognostic factors for TRM. Relapse or progression of lymphoma was observed in 21%. The 2-year overall survival rates of the patients with indolent (n = 38), aggressive (n = 111), and lymphoblastic lymphoma (n = 84) were 57%, 42%, and 41%, respectively. In a multivariate analysis, chemoresistance, prior autograft, and prior radiotherapy were identified as adverse prognostic factors for overall survival. Although myeloablative allo-HSCT represents an effective therapeutic option for patients with NHL, more work is still needed to decrease TRM and relapse.