Search

IntroductionIntractable lymphatic anomalies (LAs) include cystic lymphatic malformation (LM; macrocystic, microcystic, or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs can present with severe symptoms and poor prognosis. Thus, prospective studies for treatments are warranted. We conducted a prospective clinical trial of sirolimus for intractable LAs.MethodsThis was an open-label, single-arm, multicenter, prospective trial involving five institutions in Japan. All patients with LAs received oral sirolimus once daily, and the dose was adjusted to ensure that the trough concentration remained within 5–15 ng/mL. We prospectively assessed the drug response (response rate for radiological volumetric change in target lesion), performance state, change in respiratory function, visceral impairment (pleural effusion, ascites, bleeding, pain), laboratory examination data, quality of life (QOL), and safety at 12, 24, and 52 weeks of administration.ResultsEleven patients with LAs (9 generalized lymphatic anomaly, 1 cystic LM, 1 Gorham–Stout disease) were treated with sirolimus, of whom 6 (54.5%; 95% confidence interval: 23.4–83.3%) demonstrated a partial response on radiological examination at 52 weeks of administration. No patients achieved a complete response. At 12 and 24 weeks of administration, 8 patients (72.7%) already showed a partial response. However, patients with stable disease showed minor or no reduction after 12 weeks. Adverse events, such as stomatitis, acneiform dermatitis, diarrhea, and fever, were common with sirolimus. Sirolimus was safe and tolerable.ConclusionSirolimus can reduce the lymphatic tissue volume in LAs and may lead to improvements in clinical symptoms and QOL.

Central lymphatic diseases such as intractable chylothorax can be fatal. Lymphatic venous anastomosis at the venous angle level is expected to give a direct therapeutic effect because it opens the obstructed outlet of the main lymphatic vessels. However, the original methods resulted in some important issues, such as the potential for venous reflux. In the present case, we modified the original anastomosis method by interposing a vein graft with venous valves to increase the distance and prevent venous reflux. Collecting the lymphatic flow resulted in termination of the chylothorax with preserved postoperative patency for years, without any complications, including at the graft-harvested extremity.

Abstract Background We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor (EGFR) gene in isocitrate dehydrogenase (IDH)‐wildtype glioblastomas (GBMs). Methods We sequenced EGFR, evaluated the EGFR splicing profile using a next‐generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH‐wildtype GBM cases. Results EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis (p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores (p = 0.014) and lower Ki‐67 scores (p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR‐amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6–7 (Δe 6–7) and exons 2–14 (Δe 2–14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2–14 mutation during recurrence. Conclusions We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH‐wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII.

Lymphatic malformation (LM) of the body surface causes symptoms such as bleeding, pain, lymphatic leakage, or infection of the lesion, usually treated with surgical resection and sclerotherapy, with limited efficacy. The vesicles of the body surface tend to recur after surgical resection and may cause lymphatic leakage, which could be long term a burden for patients, eventually decreasing their quality of life. In recent years, the efficacy of orally administered mammalian target of rapamycin inhibitor (rapamycin) has been reported for LM and other vascular anomalies but few are reported in the East Asian population. We report the case of a Japanese female with intractable gluteal LM that was successfully treated with topical rapamycin for postoperative recurrence and hypertrophic scarring.

Introduction: Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham–Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials. Methods: This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5–15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data. Results: This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature. Conclusions: We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs. Keywords: Lymphatic abnormalities, Lymphatic malformation, Generalized lymphatic anomaly, Gorham–Stout disease, Mammalian target of rapamycin

The efficacy and safety of therapeutic lipiodol lymphangiography have been reported by several studies. However, to our knowledge, no study has reported the use of this procedure in very-low-birth-weight infants. We present a case of an extremely-low-birth-weight infant girl who developed chylothorax on day 34 that was refractory to medical treatment. We performed therapeutic lipiodol lymphangiography on day 59 when her body weight was 800 g. Six days after the procedure, her pleural effusion suddenly decreased, and the chest tube was removed on day 67. No complications occurred.

Background Cleft lip and palate repair requires a deep and small surgical field and is usually performed by surgeons wearing surgical loupes. Surgeons with loupes can obtain a wider surgical view, although headlights are required for the deepest procedures. Surgical microscopes offer comfort and a clear and magnification-adjustable surgical site that can be shared with the whole team, including observers, and easily recorded to further the education of junior surgeons. Magnification adjustments are convenient for precise procedures such as muscle dissection of the soft palate. Methods We performed a comparative investigation of 18 cleft operations that utilized either surgical loupes or microscopy. Paper-based questionnaires were completed by staff nurses to evaluate what went well and what could be improved in each procedure. The operating time, complication rate, and scores of the questionnaire responses were statistically analyzed. Results The operating time when microscopy was used was not significantly longer than when surgical loupes were utilized. The surgical field was clearly shared with surgical assistants, nurses, anesthesiologists, and students via microscope-linked monitors. Passing surgical equipment was easier when sharing the surgical view, and preoperative microscope preparation did not interfere with the duties of the staff nurses. Conclusions Surgical microscopy was demonstrated to be useful during cleft operations.

Postoperative chylothorax in infants prolongs hospital stay and possibly causes developmental delay because of its conservative treatment including inanition. Several medical and surgical treatments may be applied, but none constitute the absolute solution. Treatment with lipiodol during lymphangiography for postoperative chylothorax has been reported to be highly effective and less invasive in adults. On the other hand, few cases have been reported in infants. We demonstrate successful blockage of chyle leakage with lipiodol injection through the inguinal lymph node in a 2-year-old infant. The patient had undergone on-pump coarctectomy and chylothorax developed soon after surgery. Several medical treatments were partially effective, but the chest tube could not be removed because sequential aspiration was required to maintain a normal respiratory status. With the patient under general anesthesia, lipiodol injection combined with indocyanine green (ICG) lymphography was performed. Lymphography combined with ICG significantly contributed not only to intraoperative detection of the inguinal lymph nodes but also to postoperative early detection of lymphedema caused by this procedure. This procedure required a simple maneuver and is probably applicable to other cases of traumatic chylothorax, such as after surgeries on the esophagus, trachea, or other components of the posterior mediastinum.

Lymphatic malformation (LM), also known as lymphangioma, is a rare condition that can occur anywhere in the body in adults and children. LM, especially micro-cystic type, consists of multiple clustering skin/subcutaneous cysts that may involve deeper functional tissue. Although LM is generally benign, it may cause serious location-dependent problems. Periorbital LM, for example, often causes facial disfigurement and visual impairment. Especially, micro-cystic type of lymphatic malformation (mLM), is a challenging condition to treat. Currently available therapies for mLM have limited effectiveness and carry a high risk of complications. Thus, it is necessary to develop a novel treatment for mLM that is less invasive and highly effective. There has been a question of the exact location and direction of lymphatic flow into, within, and out of LM. There were some reports investigating the intra-cystic flow of LM; however, only a few focused on the afferent and efferent lymphatic flow of LM. With our detailed study using lymphography, we were able to determine the lymphatic flow pattern in periorbital LM, which was large enough to perform lymphatic venous anastomosis (LVA). LVA is a surgically-placed bypass between afferent collecting lymphatic vessels and veins, which in our study resulted in decreasing both the influx and the total volume of lymph in the LM. To our knowledge, this is the first study of Indocyanine green (ICG) lymphography on mLM, and LVA for its treatment. Here we present our case of periorbital mLM with LVA and discuss its less invasive surgical strategy.

Local flaps are widely used in soft tissue reconstruction because they result in good colour and texture match. They can be quickly placed without donor site morbidity. However, it is not always easy to preoperatively design a feasible procedure, predict the final scar line or image the tension that may occur on and around the flap, especially for inexperienced surgeons. Because the elasticity of the skin varies with anatomical location and among individuals, unpredictable intraoperative design changes are sometimes required. Therefore, a preoperative back-up plan would be helpful. We evaluated the possibilities and advantages of an intraoperative switch from a hatchet flap (HF) to a reading man flap (RMF) procedure. Using a previously reported computer simulation with the finite element method (FEM) analysis, we developed an intraoperative local flap transformation (iLoFT) model.

Unilateral stress fracture of the femoral neck following total knee arthroplasty (TKA) is a rare complication; only 21 cases are described in English literature so far. Bilateral stress fractures of the femoral neck occurring simultaneously following a bilateral TKA have been seen in only 2 cases till now. We report a patient suffering from rheumatoid arthritis of both knees, who was treated with bilateral TKA. She developed spontaneous fractures of the femoral neck on both sides 12 months following the TKA. She was treated with bilateral total hip arthroplasty (THA). Stress fracture of the femoral neck should be suspected in patients complaining of hip pain who have undergone TKA.

Background:. Less-invasive surgeries, such as lymphaticovenular anastomosis (LVA), are the widely accepted intervention for lymphedema. This study aimed to assess the outcomes of flow-oriented LVA modification on lymphatic malformation (LM). Methods:. We included 19 patients diagnosed with LM mixed type or microcystic type, who came to our clinic from June 2015 to December 2017. Under general anesthesia, all patients were administered an indocyanine green lymphography injection subcutaneously. In the case of a strong inflow, the patient underwent afferent lymph vessel of LM to venous anastomosis (LMVA). Otherwise, the side wall of LMVA was performed to the cysts. Outcomes were classified into the following groups based on the size changes: treatment effect (TE) 4 = >80% reduction rate; TE 3 = 50%–80% reduction rate; TE 2 = 20%–50% reduction rate; and TE 1 = 0%–20% reduction rate. Results:. All cases underwent surgery, with no case having an increased size. The results were as follows: TE 4 = 4 (21%) patients; TE 3 = 6 (32%) patients; TE 2 = 5 (26%) patients; and TE 1 = 4 (21%) patients. No case required study termination due to disease progression. Minor complication occurred in 3 cases. One vesicle increased at the labial mucosa and one wound dehiscence that epithelized within 1 month. Conclusion:. LMVA could be a novel, minimally invasive lymph flow-oriented surgical method for intractable LM.

Background:. Superficial circumflex iliac artery (SCIA) perforator flap is one of the demanding flaps. However, little is known about SCIA anatomy, which is crucial for successful SCIA perforator flap elevation, in children. We assessed the efficacy of our incision design to detect the superficial branch of the SCIA in vivo. Methods:. Eleven consecutive pediatric patients who required harvesting (eg, skin grafts or vascularized lymph node transfer) were assessed. All possible congenital vascular malformation cases were excluded. To reduce potential bias, all groin procedures were performed on the contralateral side of malformations. After inguinal area mapping, 1.5-cm skin incision was made. From the window opened by the skin incision, tiny perforation to the skin surface was detected for further dissection. Following the tiny branch, the main trunk of the superficial circumflex vascular bundle was dissected. The whole vascular bundle, artery, and major vein from the bundle were dissected and their sizes were measured. Results:. Of the 11 patients, 4 were boys; the age range was 5 months to 14 years (mean age: 3.2 years). Vessel bundle size was 0.7–1.5 (mean: 1.1 mm). In all cases, the bundle was detected within 5 min (1–5, mean: 2.5 min). No vascular damage was observed, and all arteries pulsated well, without requiring additional skin incision. The superficial branch of the SCIA was mainly detected right below the initial skin incision. Conclusions:. Our skin incision design can effectively detect the SCIA in pediatric patients and may be used in adult patients.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular anomaly in children, which requires treatment but challenging. The characteristics of KTS include disproportionality of the affected limbs, usually with enlargement due to lymphatic malformation (LM) [1]. Sometimes the condition is accompanied by pain that is difficult to treat. Compression therapy is one option for reducing the swelling; however, this has limitations [2]. We previously reported that lymphatic venous anastomosis (LVA) may be a safe and effective procedure for reducing the size of micro cystic type LM by decreasing the intra cystic lymph [3]. We treated a case of KTS in a 9-year-old boy who had improvement of lower abdominal swelling and penile pain after a single LVA. The method involved is to make a bypass, from the afferent lymph-collecting vessel to subcutaneous veins. However, to apply LVA to LM, it is sometimes problematic to detect the afferent flow in combined vascular malformations, such as KTS. Therefore, we performed VA making a bypass directly from LM, instead. We classify two types of LVA methods for LM: afferent lymph vessel LMVA (A-LMVA), and sidewall LMVA (S-LMVA). S-LMVA has more merits than the previously reported A-LMVA.

Background:. Super-microsurgery has widely spread due to the improvement of high magnification microscopes. The cost of multiple microscopes is high. Furthermore, the microscope heads are too large to fit in multiple surgical fields for pediatric patients. We adapted a 2-dimensional magnification system for performing lymphatic venous anastomosis on pediatric lymphedema cases. Methods:. We attached a close-up lens filter to the suspended camera (CHZ-1,360-PTR camera, Carina system, Tokyo, Japan) in the operative field. This was done to achieve 26× magnification using a small camera head, making it possible to perform super-micro anastomoses. Anastomoses time, scar length, and lymph vessel diameters were measured, and the outcomes were statistically analyzed and compared with the contralateral side. Results:. Four pediatric lymphedema patients underwent the aforementioned technique, using the multisite microscopic approach. All anastomoses were completed within 20 minutes. The results were not significantly different from the conventional microscopic lymphatic venous anastomosis. Conclusion:. This system is advantageous because (1) it has less costly initial investments; (2) it requires a small camera head, which provides available space for the multisite microscopic approach even for pediatric patients; and (3) it allows for a wider surgical working space.

Heavy metal-associated (HMA) domains bind metal ions at its Cys-x-x-Cys (CxxC) motif and constitute an intracellular network for trafficking of metal ions for utilization and detoxification. We thus expect that novel metalloproteins can be identified by screening proteins interacting with a HMA domain. In this study, we performed yeast two-hybrid screening of the human proteome and found an uncharacterized protein encoded as open reading frame 123 in chromosome 1 (C1orf123) that can interact specifically with the HMA domain of a copper chaperone for superoxide dismutase (CCSdI). Our X-ray structural analysis of C1orf123 further revealed that it binds a Zn2+ ion in a tetrahedral coordination with four thiolate groups from two conserved CxxC motifs. For the interaction between C1orf123 and CCSdI, the CxxC motifs in both C1orf123 and CCSdI were required, implying metal-mediated interaction through the CxxC motifs. Notably, C1orf123 did not interact with several other HMA domains containing CxxC motifs, supporting high specificity in the interaction between C1orf123 and CCSdI. Based upon these results, we further discuss functional and structural significance of the interaction between C1orf123 and CCS.

Background:. A lymphangioma, also called a lymphatic malformation, is a congenital condition that frequently occurs in young children. It is classified into 3 groups depending on the size of the cysts (macrocystic, microcystic, and mixed). Spontaneous regression occurs in some cases; however, the characteristics of patients who show regression have not been studied previously. Furthermore, the types and the timing of the initial treatment are still controversial. Therefore, we statistically analyzed the occurrence of short-term spontaneous regression, patient age at original occurrence, cyst types, cyst sizes, and cyst locations in patients diagnosed with peripheral localized lymphangiomas in a single children center over 34 years. Methods:. We retrospectively collected the data of 153 patients and reviewed the medical charts. Results:. Spontaneous regression occurred only in macrocystic or mixed type; regression was most frequent in patients who, at the time of onset, were more than 2 years old. Conclusions:. We concluded that elderly patients with macrocystic or mixed type lymphangioma may have to wait for treatment for over 3 months from the initial onset. Conversely, microcystic type could not be expected to show regression in a short period, and prompt initiation of the treatments may be required. The difference of the regression or not may depend on the characteristics of the lymph flow.

In the title compound, C19H15FO3, the dihedral angle between the naphthalene ring system and the benzene ring is 80.46 (4)°. In the crystal, molecules are linked by intermolecular C—H...O hydrogen bonds into chains parallel to the b axis.

The asymmetric unit of the title compound, C18H11Br2ClO3, contains two crystallographically independent molecules in which the dihedral angles between the naphthalene ring systems and the benzene rings are 55.64 (11) and 60.50 (11)°. In each molecule, an intramolecular O—H...O=C hydrogen bond generates a six-membered ring. In the crystal structure, intermolecular C—H...O and C—H...Cl hydrogen bonds and two different Br...O halogen bonds [2.9850 (19) and 3.2169 (19) Å] are observed.

In the title compound, C19H14BrClO3, the naphthalene ring system and the benzene ring make a dihedral angle of 77.36 (10)°. The conformation around the central C=O group is such that the C=O bond vector forms a larger angle to the plane of the naphthalene ring system than to the plane of the benzene ring, viz. 75.73 (15)° versus 2.33 (17)°. In the crystal structure, a π–π interaction is formed between naphthalene ring systems, with a centroid–centroid distance of 3.8363 (14) Å and a lateral offset of 1.606 Å. Intermolecular C—H...Br and C—H...O hydrogen bonds and a C—H...π contact are present in the crystal structure.

In the title compound, C19H15FO3, the dihedral angle between the naphthalene ring system and the benzene ring is 62.93 (5)°. The bridging carbonyl C—C(=O)—C plane makes dihedral angles of 45.55 (6) and 28.62 (7)°, respectively, with the naphthalene ring system and the benzene ring. Weak intermolecular C—H...O hydrogen bonds and C—H...π interactions stabilize the crystal packing.

In the title compound, C20H16O5, the dihedral angle between the naphthalene ring system and the benzene ring is 67.43 (5)°. The bridging carbonyl C—C(=O)—C plane makes dihedral angles of 82.64 (6) and 41.79 (7)°, respectively, with the naphthalene ring system and the benzene ring. The dihedral angle between the carboxy O—C(=O)—C plane and the benzene ring is 36.38 (7)° and that between the bridging carbonyl C—C(=O)—C plane and the carboxy O—C(=O)—C plane is 51.88 (8)°. The crystal structure is stabilized by intermolecular O—H...O and C—H...O hydrogen-bonding interactions. An intramolecular C—H...O hydrogen bond occurs between a naphthalene H atom and the carbonyl O atom of the carboxy group.

In the title compound, C19H15NO5, the dihedral angle between the naphthalene ring system and the benzene ring is 61.97 (5)°. The dihedral between the naphthalene ring system and the bridging carbonyl C—C(=O)—C plane is 54.68 (6)°, far larger than that [12.54 (7)°] between the phenyl group and the bridging carbonyl group. The nitro group and the phenyl ring are almost coplanar [O—N—C—C torsion angle = 2.94 (19)°]. In the crystal, molecules are linked by C—H...π interactions and the phenyl rings are involved in a centrosymmetric π–π interaction with a perpendicular distance of 3.523 Å and a lateral offset of 1.497 Å. In addition, weak intermolecular C—H...O hydrogen bonds are formed between an H atom of one methoxy group and a nearby carbonyl O atom.

In the title compound, C21H18O5, the dihedral angle between the naphthalene ring system and the benzene ring is 86.65 (6)°. The bridging carbonyl C—C(=O)—C plane makes dihedral angles of 83.57 (7) and 20.21 (8)°, respectively, with the naphthalene ring system and the benzene ring. The ester O—C=O plane and the benzene ring are almost coplanar, making a dihedral angle of 3.81 (18)°. The two methoxy groups lie essentially in the naphthalene ring plane [C—O—C—C torsion angles = 2.1 (2) and −1.44 (19)°]. In the crystal structure, a centrosymmetric dimer is formed through C—H...O bonds connecting the 7-methoxy group and the carbonyl O atom of the ester group. The dimers are further linked by C—H...O hydrogen bonds between the methoxycarbonyl group and the bridging carbonyl O atom.

In the title compound, C26H18Br2O4, the two 4-bromobenzoyl groups at the 1- and 8-positions of the naphthalene ring system are anti to each other. The dihedral angle between the two benzene rings is 50.92 (14)°. The dihedral angles between the two benzene rings and the naphthalene ring system are 70.18 (11) and 74.98 (12)°. A weak intermolecular C—H...O hydrogen bond exists between the methyl group and the carbonyl O atom.

The title compound, C26H18F2O4, is a naphthalene derivative in which the two aroyl groups at the 1- and 8-positions (peri positions) are anti to each other. There is an appreciable difference in the dihedral angles between the naphthalene ring system and the two benzene rings [66.88 (7)° and 88.09 (6)°]. In the crystal, weak C—H...O interactions involving one of the carbonyl groups and an aromatic C—H group ortho to the F atom seem to stabilize the packing of the molecules.

The molecule of the title compound, C26H20O4, is located on a twofold rotation axis. The two benzoyl groups are situated in an anti orientation. The dihedral angle between the mean planes of the phenyl ring and the naphthalene ring system is 80.25 (6)°. The phenyl and carbonyl groups in each benzoyl group are almost coplanar. The molecular packing is stabilized by weak C—H...O hydrogen bonds and a π–π stacking interaction between the phenyl rings [centroid–centroid and interplanar distances of 3.6383 (10) and 3.294 Å, respectively].

Kv2.1 is a major delayed-rectifier voltage-gated potassium channel widely expressed in neurons of the CNS. Kv2.1 localizes in highdensity cell-surface clusters in the soma and proximal dendrites as well as in the axon initial segment (AIS). Given the crucial roles of both of these compartments in integrating signal input and then generating output, this localization of Kv2.1 is ideal for regulating the overall excitability of neurons. Here we used fluorescence recovery after photobleaching imaging, mutagenesis, and pharmacological interventions to investigate the molecular mechanisms that control the localization of Kv2.1 in these two different membrane compartments in cultured rat hippocampal neurons of mixed sex. Our data uncover a unique ability of Kv2.1 channels to use two molecularly distinct trafficking pathways to accomplish this. Somatodendritic Kv2.1 channels are targeted by the conventional secretory pathway, whereas axonal Kv2.1 channels are targeted by a nonconventional trafficking pathway independent of the Golgi apparatus. We further identified a new AIS trafficking motif in the C-terminus of Kv2.1, and show that putative phosphorylation sites in this region are critical for the restricted and clustered localization in the AIS. These results indicate that neurons can regulate the expression and clustering of Kv2.1 in different membrane domains independently by using two distinct localization mechanisms, which would allow neurons to precisely control local membrane excitability. [ABSTRACT FROM AUTHOR]

We suggest a novel method that uses artificial blood cells (hemoglobin vesicles, Hb-Vs) as photosensitizers in dye laser treatment (at 595-nm wavelength) for port-wine stains (i.e., capillary malformations presenting as red birthmarks) based on the results of animal experiments. As compared with human red blood cells, Hb-Vs have the same absorbance of 595 nm wavelength light and produce the same level of heat following dye laser irradiation. Small sized Hb-Vs (250 nm) distribute in the plasma phase in blood and tend to flow in the marginal zone of microvessels. Intravenous injections of Hb-Vs caused the dilatation of microvessels, and dye laser treatment with Hb-Vs destroyed the vessel wall effectively. Following the intravenous injection of Hb-Vs, the microvessels contained more Hb that absorbed laser photons and produced heat. This extra Hb tended to flow near the endothelial cells, which were the target of the laser treatment. These attributes of Hb-Vs will potentially contribute to enhancing the efficacy of dye laser treatment for port-wine stains. Hemoglobin is a type of porphyrin. Thus, our proposed treatment may have aspects of photodynamic therapy using porphyrin that leads to a cytotoxicity effect by active oxygen. [ABSTRACT FROM AUTHOR]

GABA acts as the major inhibitory neurotransmitter in the mammalian brain, shaping neuronal and circuit activity. For sustained synaptic transmission, synaptic vesicles (SVs) are required to be recycled and refilled with neurotransmitters using an H+ electrochemical gradient. However, neither the mechanism underlying vesicular GABA uptake nor the kinetics of GABA loading in living neurons have been fully elucidated. To characterize the process of GABA uptake into SVs in functional synapses, we monitored luminal pH of GABAergic SVs separately from that of excitatory glutamatergic SVs in cultured hippocampal neurons. By using a pH sensor optimal for the SV lumen, we found that GABAergic SVs exhibited an unexpectedly higher resting pH (~6.4) than glutamatergic SVs (pH ~5.8). Moreover, unlike glutamatergic SVs, GABAergic SVs displayed unique pH dynamics after endocytosis that involved initial overacidification and subsequent alkalization that restored their resting pH. GABAergic SVs that lacked the vesicular GABA transporter (VGAT) did not show the pH overshoot and acidified further to ~6.0. Comparison of luminal pH dynamics in the presence or absence of VGAT showed that VGAT operates as a GABA/H+ exchanger, which is continuously required to offset GABA leakage. Furthermore, the kinetics of GABA transport was slower (Τ > 20 s at physiological temperature) than that of glutamate uptake and may exceed the time required for reuse of exocytosed SVs, allowing reuse of incompletely filled vesicles in the presence of high demand for inhibitory transmission. [ABSTRACT FROM AUTHOR]