Sentinel Lymph Node Detection in Breast Cancer Patients by Real‐Time Virtual Sonography Constructed With Three‐Dimensional Computed Tomography‐Lymphography

Abstract: Ultrasonography (US) is one tool for preoperative diagnosis of lymph node metastases in breast cancer. However, US cannot detect true sentinel lymph nodes (SLNs). We identified SLNs in 60 clinically node‐negative breast cancer patients using a real‐time virtual sonography (RVS) system to display in real time a virtual multi‐planar reconstruction obtained from computed tomography (CT) volume data corresponding to the same cross‐sectional image from US. CT volume data were obtained from our original three‐dimensional CT lymphography (3DCT‐LG), which accurately detects SLNs in breast cancer. SLN metastases were assessed by shape and visibility of the hilum. All patients underwent SLN biopsy and SLN metastases were examined pathologically. In all 60 patients, we were able to detect the same SLNs visualized by 3DCT‐LG. Suspicious SLN metastases were identified in seven of the 60 patients, and four of seven patients were pathologically positive. Positive predictive value was 57%. The remaining 53 patients displayed non‐suspect SLNs in which absence of metastasis from the SLN was confirmed histologically. Overall accuracy was 95%. This is a first attempt at preoperatively identifying SLNs using US guided by the RVS system in breast cancer patients. Although evaluation of SLN metastases was unsatisfactory, this method may be useful for preoperative fine‐needle aspiration cytology for diagnosis of SLN metastases.     

Maternal GABAergic and GnRH/corazonin pathway modulates egg diapause phenotype of the silkworm Bombyx mori

Diapause represents a major developmental switch in insects and is a seasonal adaptation that evolved as a specific subtype of dormancy in most insect species to ensure survival under unfavorable environmental conditions and synchronize populations. However, the hierarchical relationship of the molecular mechanisms involved in the perception of environmental signals to integration in morphological, physiological, behavioral, and reproductive responses remains unclear. In the bivoltine strain of the silkworm Bombyx mori, embryonic diapause is induced transgenerationally as a maternal effect. Progeny diapause is determined by the environmental temperature during embryonic development of the mother. Here, we show that the hierarchical pathway consists of a γ-aminobutyric acid (GABA)ergic and corazonin signaling system modulating progeny diapause induction via diapause hormone release, which may be finely tuned by the temperature-dependent expression of plasma membrane GABA transporter. Furthermore, this signaling pathway possesses similar features to the gonadotropin-releasing hormone (GnRH) signaling system for seasonal reproductive plasticity in vertebrates.

To ensure survival under unfavorable environmental conditions and synchronize populations, most insect species enter diapause, which is a seasonal adaptation that evolved as a specific subtype of dormancy (1, 2). Diapause is not a passive response to changing conditions but rather an actively induced state that precedes adverse natural situations. Therefore, this diapause phenotype is accompanied by changes in energy metabolism or storage to improve cold/stress tolerance in later life stages, or progeny via reproductive switch (3). Although it has been generally suggested that brain/neuroendocrine systems are associated with this seasonal reproductive plasticity in both vertebrates and invertebrates (3, 4), the hierarchical relationship of the molecular mechanisms involved in the perception of environmental signals to integration into morphological, physiological, behavioral, and reproductive responses, known as the diapause syndrome, remains unclear (3).The silkworm Bombyx mori is a typical insect that arrests normal development during early embryogenesis, which is accompanied by metabolic changes in diapause (5, 6). The development of diapause-destined embryos is arrested during the G2 cell cycle stage immediately after the formation of the cephalic lobe and telson and sequential segmentation of the mesoderm (7). The bivoltine strain of B. mori has two generations per year, and progeny diapause is transgenerationally induced as a maternal effect and is determined by the environmental temperature, photoperiod, and nutrient conditions during embryonic and larval development of the mother (5, 6). The temperature signal during the mother’s embryonic development predominantly affects diapause determination, even if silkworms of the bivoltine Kosetsu strain are exposed to all cases of photoperiods during embryonic and larval development. In the Kosetsu strain, when eggs are incubated at 25 °C under continuous darkness, the resultant female moths (25DD) lay diapause eggs in almost all cases. In contrast, incubation of eggs at 15 °C in dark condition results in moths (15DD) that lay nondiapause eggs in almost all cases (6).Embryonic diapause is induced by the diapause hormone (DH) signaling pathway, which consists of highly sensitive and specific interactions between a neuropeptide, DH, and DH receptor (DHR) (6, 8). DH is exclusively synthesized in seven pairs of neurosecretory cells (DH-PBAN–producing neurosecretory cells [DHPCs]) located within the subesophageal ganglion (SG) in the mother’s generation (6). DH is released into the hemolymph during pupal–adult development and acts on the DHR, which belongs to the G protein-coupled receptors (GPCRs) (9). DH levels in the hemolymph are higher in the 25DD than 15DD pupae in the middle of pupal–adult development when the developing ovaries are sensitive to DH (6). Furthermore, the embryonic Bombyx TRPA1 ortholog (BmTRPA1) acts as a thermosensitive channel that is activated at temperatures above ∼21 °C and affects diapause induction through DH release (10). However, there remain questions about the thermal information that is received by BmTRPA1 and linked to DH signaling to induce diapause.From the 1950s, it has been suggested that the DH release was controlled by signals derived from certain region(s) in the brain based on surgical experiments, such as midsagittal bisection or transection (11–13). Especially, the operation in nondiapause producers changed them to diapause producers while transection of the protocerebrum had no effect on the diapause producers. These surgical results suggested the involvement of the protocerebrum in the inhibitory control of DH secretion (12, 14). Furthermore, the accumulation of the ovarian 3-hydroxykynurenine (3-OHK) pigment that accompanies the diapause syndrome was affected by injection with γ-aminobutyric acid (GABA) and the plant alkaloid picrotoxin (PTX), which is a widely used ionotropic GABA and glycine receptor antagonist (15, 16), and the selective ionotropic GABA receptor (GABAR) antagonist bicuculline. This suggests that a GABAergic neurotransmission via ionotropic GABAR is involved in DH secretion, which may be active in nondiapause producers but inactive in diapause producers throughout the pupal–adult development (14, 17). In general, ionotropic GABAR is composed of homo- or hetero-pentameric subunits. All known GABAR subunits display a similar structural scheme, with a large N-terminal extracellular domain involved in the formation of a ligand-binding pocket and a pore domain made of four transmembrane alpha-helices (TM1–TM4) (16, 18). Four homologous sequences of the ionotropic GABAR subunit genes were identified as RDL, LCCH3, GRD, and a GRD-like sequence named 8916 in various insects (19). However, the in vivo physiological roles of both signals derived from the brain and the GABAergic pathway in diapause induction have not been previously investigated.Corazonin (Crz) is an undecapeptide neurohormone sharing a highly conserved amino acid (a.a.) sequence across insect lineages and is involved in different physiological functions, such as heart contraction (20), stress response (21, 22), various metabolic activities (23–25), female fecundity (26), melanization of locust cuticles (27), regulation of ecdysis (28, 29), and control of caste identity (30). Moreover, Crz belongs to the gonadotropin-releasing hormone (GnRH) superfamily alongside adipokinetic hormone (AKH) and AKH/Crz-related peptide (ACP). Duplicates of an ancestral GnRH/Crz signaling system occurred in a common ancestor of protostomes and deuterostomes through coevolution of the ligand receptor (31, 32).Herein, we demonstrated that the hierarchical pathway consists of a GABAergic and Crz signaling system modulating progeny diapause induction by acting on DH release. We propose that the PTX-sensitive GABAergic signal may act to chronically suppress Crz release in dorsolateral Crz neurons (under nondiapause conditions) and that diapause conditions (or PTX injection) inhibits GABAergic signaling, resulting in accelerated Crz release, which in turn induces DH release. GABA signaling may be finely tuned by the temperature-dependent expression of the plasma membrane GABA transporter (GAT), which differs between the 25DD and 15DD conditions. Furthermore, this signaling pathway possesses similar features to the GnRH signaling system with respect to seasonal reproductive plasticity in vertebrates.     

Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies

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Diagnostic usefulness of KL-6 measurements in patients with pulmonary complications after administration of amiodarone

Amiodarone-induced pulmonary toxicity is one of the major complications in patients receiving administration of amiodarone. KL-6 is a useful indicator to evaluate the activity of interstitial pneumonitis. We studied the clinical utility of KL-6 as a marker for amiodarone-induced pulmonary toxicity. We investigated 6 patients in whom chest radiography revealed abnormal consolidations after administration of amiodarone from 1997 to 1999. All patients were male aged 56 to 76 years (mean 66 +/- 7 years). The indications for amiodarone included sustained ventricular tachycardia in 5 patients and atrial fibrillation in one patient with refractory heart failure. The mean left ventricular ejection fraction was 31 +/- 12% (22-52%). KL-6 levels were measured by a sandwich type enzyme immunoassay using a murine monoclonal antibody (KL-6 antibody), and the cutoff level was determined at 520 U/ml. Complications occurred from 17 days to 45 months after treatment with amiodarone. The KL-6 levels were abnormally high (2,100 and 3,000 U/ml) in 2 patients with amiodarone-induced pneumonitis but under the cutoff level in the non-pneumonitis patients. In one patient with amiodarone-induced pneumonitis, the KL-6 level increased from 695 to 2,100 U/ml concurrently with worsening interstitial changes shown by high resolution computed tomography. We conclude that KL-6 has practical uses as a marker for the detection and evaluation of amiodarone-induced pulmonary toxicity.     

An atypical case of "Takotsubo cardiomyopathy" during alcohol withdrawal: abnormality in the transient left ventricular wall motion and a remarkable elevation in the ST segment

A 64-year-old man was admitted due to hypokalemia-related myopathy. He was heavy drinker. He felt the stress of alcohol withdrawal during his hospitalization. The patient suffered a cardiopulmonary arrest lasting approximately 5 minutes on the fifth hospital day. One day later, ST-segment elevation was observed in leads I, aV(L), and V(2-6). Emergent cardiac catheterization was performed for suspicion of acute myocardial infarction. Normal coronary arteries with anterior akinesis of the left ventricle were revealed during the procedure. The present case may be an atypical form of "Takotsubo cardiomyopathy" in which the left ventricular contraction is due to focal anterior wall motion abnormalities.     

Study on congenital complete heart block in children by 24-hour ambulatory electrocardiographic monitoring

Ambulatory electrocardiographic monitoring was performed in 18 children with a congenital complete heart block (CCHB). They had no cardiac structural anomalies. These patients could be divided into 3 groups according to the pattern of fluctuations in beat-to-beat ventricular rates. Type 1 patients showed rapid and transient fluctuations and demonstrated a high correlation between atrial and ventricular rates. Type 3 patients showed a constant ventricular rate and little variation through the 24 hour period and there was no appreciable correlation between atrial and ventricular rates. Twelve of 18 patients had additional arrhythmias. A few sporadic ventricular premature contractions (VPCs) were found in 9 patients, and bigeminy of VPCs or ventricular tachycardias were seen in 2 patients during exercise. Frequent and sudden prolongation of RR intervals was found during sleep in 3 patients. The longest intervals of ventricular asystoles were 7.2, 3.2 and 3.2 sec, respectively. The mechanism of this phenomenon appeared to be not only an exit block, but also arrest or a lack of automaticity of a subsidiary pacemaker. One of these patients developed frequent Stokes-Adams attacks. Type 3 patients with sudden prolongation of RR intervals and/or frequent ventricular arrhythmias should be under careful observation. Ambulatory electrocardiographic monitoring is recommended for children with CCHB for evaluation of potential risk factors for Stokes-Adams attacks.