Effects of AAV-mediated knockdown of nNOS and GPx-1 gene expression in rat hippocampus after traumatic brain injury.

Virally mediated RNA interference (RNAi) to knock down injury-induced genes could improve functional outcome after traumatic brain injury (TBI); however, little is known about the consequences of gene knockdown on downstream cell signaling pathways and how RNAi influences neurodegeneration and behavior. Here, we assessed the effects of adeno-associated virus (AAV) siRNA vectors that target two genes with opposing roles in TBI pathogenesis: the allegedly detrimental neuronal nitric oxide synthase (nNOS) and the potentially protective glutathione peroxidase 1 (GPx-1). In rat hippocampal progenitor cells, three siRNAs that target different regions of each gene (nNOS, GPx-1) effectively knocked down gene expression. However, in vivo, in our rat model of fluid percussion brain injury, the consequences of AAV-siRNA were variable. One nNOS siRNA vector significantly reduced the number of degenerating hippocampal neurons and showed a tendency to improve working memory. GPx-1 siRNA treatment did not alter TBI-induced neurodegeneration or working memory deficits. Nevertheless, microarray analysis of laser captured, virus-infected neurons showed that knockdown of nNOS or GPx-1 was specific and had broad effects on downstream genes. Since nNOS knockdown only modestly ameliorated TBI-induced working memory deficits, despite widespread genomic changes, manipulating expression levels of single genes may not be sufficient to alter functional outcome after TBI.

Surgical treatment of empyema after pulmonary resection using pedicle skeletal muscle plombage, thoracoplasty, and continuous cavity ablution procedures: a report on three cases.

We present three cases of postoperative empyema after pulmonary resection: case 1, acute empyema without fistula after lobectomy and chest wall resection; case 2, continuing empyema with fistula and total left residual lung abscess after upper divisionectomy; and case 3, chronic empyema with middle lobe bronchopleural fistula after lower lobectomy. Pedicle skeletal muscle plombage into the cavity, thoracoplasty, and continuous cavity ablution with 24-h instillation of minocycline and saline solution through drains were used for treatment. In case 2, a completion extrapleural left pneumonectomy was concurrently performed. In all three cases, the surgery was successful; however, case 2 developed a massive gastrointestinal hemorrhage, which led to blood aspiration pneumonitis, renal failure, and death. Muscle plombage effectively achieves the closure of empyema cavity and thoracoplasty complements this. When a residual space remains, cavity ablution is considered to be effective. However, concurrent completion lung parenchyma resection might be excessively aggressive.

The advantages of selecting cartridges with a 1.8 mm height for pulmonary stapling.

PURPOSES: The purpose of this study was to retrospectively analyze the complications arising from stapling of the pulmonary parenchyma and to determine the most appropriate cartridges to use for pulmonary stapling. METHODS: A retrospective multi-institutional review was conducted by the Central Japan Lung Cancer Surgery Study Group. We analyzed both Echelon™ (EC) and EndoGIA™ (EGIA) staplers in this study. The stapling cartridges were classified into 3 colors according to the height of the ß loops: green (2.0 mm), gold (1.8 mm), and blue (1.5 mm). RESULTS: Stapling of the pulmonary parenchyma was performed 9016 times. The total number of complications related to stapling was 61 (0.68 %). These complications were mainly caused by stapler-tissue thickness mismatch (n = 30, 49.2 %) and tissue fragility (n = 27, 44.3 %). The number and rate of complications of the different cartridges were 19 and 0.63 % for EGIA blue, 25 and 0.94 % for EGIA green, 1 and 0.067 % for EC gold, 12 and 0.98 % for EC blue, and 4 and 0.64 % for EC green, respectively. Complications associated with stapling using EC gold cartridges occurred less frequently than with the other cartridges (p = 0.0022). CONCLUSION: The gold cartridge appears to cause the least complications and may therefore be the most appropriate cartridge for stapling the pulmonary parenchyma among the tested staplers.

Stochastic fluctuations in gene expression in aging hippocampal neurons could be exacerbated by traumatic brain injury.

Traumatic brain injury (TBI) is a risk factor for age-related dementia and development of neurodegenerative disorders such as Alzheimer's disease that are associated with cognitive decline. The exact mechanism for this risk is unknown but we hypothesized that TBI is exacerbating age-related changes in gene expression. Here, we present evidence in an animal model that experimental TBI increases age-related stochastic gene expression. We compared the variability in expression of several genes associated with cell survival or death, among three groups of laser capture microdissected hippocampal neurons from aging rat brains. TBI increased stochastic fluctuations in gene expression in both dying and surviving neurons compared to the naïve neurons. Increases in random, stochastic fluctuations in prosurvival or prodeath gene expression could potentially alter cell survival or cell death pathways in aging neurons after TBI which may lead to age-related cognitive decline.

[Tiny Size Lung Cancer which was not Pathologically Diagnosed before Hilar and Mediastinal Dissection].

A 63-year-old man was found to have abnormally high carcinoembryonic antigen levels in a health examination. Computed tomography scan revealed lymphadenopathy at the right hilum of lung and right upper mediastinum. Malignancy was suggested by endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)for lymph node. Lymph node metastases of lung cancer was suspected, but primary site was unidentified. In order to perform complete hilar dissection, right upper lobectomy was done with systematic mediastinal dissection. Pathological diagnosis was adenocarcinoma of 3 × 3 mm in size in the fibrous scar of the right upper lobe. Immunostaining revealed thyroid transcription factor-1(TTF-1) [+]and paired box-8(PAX-8) [-] indicating the tumor to be a primary lung cancer.

[Recurrence of Anaplastic Lymphoma Kinase Positive Lung Cancer Nineteen-year after the Primary Surgery].

A 77-years-old man who underwent middle lobectomy for lung adenocarcinoma in our hospital 19 years ago. p-Stage IA was pointed out multiple nodules in bilateral lung fields on a medical examination. Computed tomography scan revealed a tumor measuring 34×34 mm in size in the right lower lung and other 40 small pulmonary nodules. Characteristic pattern of metastatic adenocarcinoma from the previous lung cancer was pathologically demonstrated. Immunostaining revealed anaplastic lymphoma kinase (ALK) positivity of the both specimens, which determined the diagnosis of recurrence. Long-team postoperative follow-up for ALK positive lung cancer patients is considered to be necessary especially for younger patients.

Pulmonary carcinosarcoma successfully resected using the rib-cross thoracotomy approach: report of a case.

Pulmonary carcinosarcoma is extremely rare and disease prognosis is very poor. A solid large tumor occupying the left thorax was detected in a 66-year-old female. Rib-cross thoracotomy was performed to excise the tumor; the 5th and 6th ribs and intercostal muscles and vessels were cut along the mid-axillary line, and the thorax was entered posteriorly at the 4th intercostal space and anteriorly at the 6th intercostal space, providing wide exposure of the entire thorax. Left pneumonectomy combined with chest wall resection was successfully performed, followed by chest reconstruction to achieve complete resection. Histopathologically, adenocarcinoma and spindle cell sarcoma containing rhabdomyosarcoma components were identified; the patient was diagnosed with pT3N1M0 stage IIIA true pulmonary carcinosarcoma. Postoperative adjuvant chemotherapy containing cisplatin and vinorelbine was administered. There was no recurrence of the disease 20 months after surgery. Aggressive excision may result in favorable outcomes for pulmonary carcinosarcoma.

En bloc resection of a large tuberculous abscess using the stain plombage procedure.

En bloc resection is highly recommended for treating tuberculous abscess of the chest wall because of possible recurrence due to microscopic residual lesions; however, complete resection is often difficult. We present a case with a large dumbbell-shaped tuberculous abscess that developed inside and outside the thorax. En bloc resection was successfully achieved using intraoperative closed drainage, ablution, and stain solution plombage procedures, which enabled easy identification of the abscess configuration. When the abscess wall was torn, only minimal solution leakage occurred; therefore, contamination of the surgical field was avoided. We report the procedures we devised and discuss treatments for this obstinate disease.

Traumatic brain injury-induced dysregulation of the circadian clock.

Circadian rhythm disturbances are frequently reported in patients recovering from traumatic brain injury (TBI). Since circadian clock output is mediated by some of the same molecular signaling cascades that regulate memory formation (cAMP/MAPK/CREB), cognitive problems reported by TBI survivors may be related to injury-induced dysregulation of the circadian clock. In laboratory animals, aberrant circadian rhythms in the hippocampus have been linked to cognitive and memory dysfunction. Here, we addressed the hypothesis that circadian rhythm disruption after TBI is mediated by changes in expression of clock genes in the suprachiasmatic nuclei (SCN) and hippocampus. After fluid-percussion TBI or sham surgery, male Sprague-Dawley rats were euthanized at 4 h intervals, over a 48 h period for tissue collection. Expression of circadian clock genes was measured using quantitative real-time PCR in the SCN and hippocampus obtained by laser capture and manual microdissection respectively. Immunofluorescence and Western blot analysis were used to correlate TBI-induced changes in circadian gene expression with changes in protein expression. In separate groups of rats, locomotor activity was monitored for 48 h. TBI altered circadian gene expression patterns in both the SCN and the hippocampus. Dysregulated expression of key circadian clock genes, such as Bmal1 and Cry1, was detected, suggesting perturbation of transcriptional-translational feedback loops that are central to circadian timing. In fact, disruption of circadian locomotor activity rhythms in injured animals occurred concurrently. These results provide an explanation for how TBI causes disruption of circadian rhythms as well as a rationale for the consideration of drugs with chronobiotic properties as part of a treatment strategy for TBI.

Accessory lobe of the right liver mocking a pulmonary tumor in an adult woman.

We report a rare case of an accessory lobe of the liver in the right thoracic cavity with the past history of breast cancer. A 66-year-old woman underwent thoracotomy owing to a slowly growing suspected lung tumor identified by computed tomography. The intraoperative findings revealed an accessory lobe of the liver. If this possibility had been considered, the correct diagnosis could have been achieved using computed tomography with multi-directional scanning, so that an unnecessary operation could have been avoided.

Predictive value of margins in diagnostic biopsies of nonmelanoma skin cancers.

BACKGROUND: With geographic regional variation, nonmelanoma skin cancer biopsy reports include assessment of margins. When margins are reported as negative, clinical dilemmas may emerge concerning the necessity of additional treatment. OBJECTIVE: To evaluate the predictive value of biopsy margins with regard to residual tumor present in subsequent excisions of nonmelanoma skin cancers. METHODS: This is a retrospective review of 235 diagnostic nonmelanoma skin cancer biopsies and their corresponding excisions for margin status at biopsy, and the presence of residual tumor in subsequent excisions. RESULTS: Twelve of 148 squamous cell carcinomas (8.1%) had negative biopsy margins and all of the subsequent excisions were free of residual tumor. The squamous cell carcinomas with negative biopsy margins consisted predominantly of nonfacial, superficial tumors of the well-differentiated and keratoacanthoma subtype. Nine of 87 basal cell carcinomas (10.3%) had negative biopsy margins. Seven of those 9 (77.8%) had residual tumor present in subsequent excisions. LIMITATIONS: Statistical analysis performed reached significance, but with small sample size as only 21 of the biopsy specimens had negative margins. Also, residual tumor was determined via standard bread-loafing technique on excisions, which is known to examine only a proportion of the tissue and can lead to false-negative results. CONCLUSIONS: The results of this small pilot study suggest that negative-margin diagnostic biopsies may be therapeutic for well-differentiated or keratoacanthoma subtypes of squamous cell carcinoma because all subsequent excisions were devoid of tumor. Negative biopsy margins from basal cell carcinomas were not predictive of tumor removal.

Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury.

Experimental evidence suggests that random, spontaneous (stochastic) fluctuations in gene expression have important biological consequences, including determination of cell fate and phenotypic variation within isogenic populations. We propose that fluctuations in gene expression represent a valuable tool to explore therapeutic strategies for patients who have suffered traumatic brain injury (TBI), for which there is no effective drug therapy. We have studied the effects of TBI on the hippocampus because TBI survivors commonly suffer cognitive problems that are associated with hippocampal damage. In our previous studies we separated dying and surviving hippocampal neurons by laser capture microdissection and observed unexplainable variations in post-TBI gene expression, even though dying and surviving neurons were adjacent and morphologically identical. We hypothesized that, in hippocampal neurons that subsequently are subjected to TBI, randomly increased pre-TBI expression of genes that are associated with neuroprotection predisposes neurons to survival; conversely, randomly decreased expression of these genes predisposes neurons to death. Thus, to identify genes that are associated with endogenous neuroprotection, we performed a comparative, high-resolution transcriptome analysis of dying and surviving hippocampal neurons in rats subjected to TBI. We found that surviving hippocampal neurons express a distinct molecular signature--increased expression of networks of genes that are associated with regeneration, cellular reprogramming, development, and synaptic plasticity. In dying neurons we found decreased expression of genes in those networks. Based on these data, we propose a hypothetical model in which hippocampal neuronal survival is determined by a rheostat that adds injury-induced genomic signals to expression of pro-survival genes, which pre-TBI varies randomly and spontaneously from neuron to neuron. We suggest that pharmacotherapeutic strategies that co-activate multiple survival signals and enhance self-repair mechanisms have the potential to shift the cell survival rheostat to favor survival and therefore improve functional outcome after TBI.

[Limitation of apoptosis induced by gefitinib in a long-surviving postoperative recurrent lung cancer case].

Although gefitinib is known to possess an effect inducing apoptosis against lung cancer, it is not clear how clinically effective it is in this regard in patients with lung cancer. Therefore, we tried to reduce its administration from every to every other day in a 73-year-old woman in good condition over 5 years after the recurrence of lung cancer. As a result, her CEA serum level then commenced to increase to the abnormal range within a month. Apoptosis induced by gefitinib was thought not sufficient to kill all lung cancer cells even though well controlled by it for a long period.

[Postpneumonectomy syndrome treated with an air infusion through a central vein (CV) port].

A 65-year-old woman underwent a right pneumonectomy 3 years before, because of lung cancer. Two years and 9 months after the operation, she developed a productive cough and complained of dyspnea At that time, the chest X-ray film showed a remarkable mediastinal shift to the right and herniation of the left lung. The computed tomography (CT) scan showed a marked rightward and posterior deviation of the mediastinum, and severe stenosis of the left main bronchus. A 18 gauge-silicon catheter was inserted into the right pleural cavity in order to inject air and 100 ml of air was infused through it. Immediately after injection, she was relieved from severe symptoms. A central vein (CV) port was implanted in the subcutaneous tissue at the right chest wall for periodic infusion of air with safety and ease.

[Neurinoma arising from brachial plexus with intrathoracic extension resected through the second intercostal space].

A case of neurinoma arising from the right brachial plexus with intrathoracic extension was reported. The patient was a 41-year-old man who had an abnormal shadow in the right apical area on the routine chest X-ray examination. Magnetic resonance imaging (MRI) revealed that the mass had some features of benign neurinoma. The tumor was resected through the 2nd intercostal space under an axillary skin incision approach and diagnosed as neurinoma on histological examination. He had a complaint of hyperesthesia of the right upper arm for 2 months postoperatively.

Speckle reduction mechanism in laser rear projection displays using a small moving diffuser.

Recently, a practical method of speckle reduction in laser rear projection displays that uses an optical system with a small moving diffuser has attracted much attention. In this paper, a model of the speckle generation and reduction mechanism in the system is presented. We investigated the speckle, focusing on the physical aspects of its generation, rather than treating it statistically. We found that the granularity of the speckle patterns generated by the small diffuser corresponded to the size of the coherent regions on the projection screen. This determined the efficiency of the speckle reduction when the small diffuser was rotated.

Television depictions about dermatology and skin diseases in Seinfeld.

The iconic television situation comedy Seinfeld frequently referenced dermatologists and topics involving the integument, using satire for comedic effect. However, selecting satire to portray an already misunderstood and unknown subject matter may perpetuate incorrect public beliefs and stereotypes about those with skin diseases and diminish cultural sensitivity towards people who have dermatologic conditions and their caregivers.

The "away" dermatology elective for visiting medical students: Educational opportunities and barriers.

Dermatology electives allow medical students an opportunity to explore the field of dermatology. In order to gain greater exposure to the specialty of dermatology, some medical students have an interest in taking "away" dermatology electives at other U.S. medical schools. A telephone survey was conducted to better understand the opportunities and barriers that exist for visiting medical students to take an elective in dermatology. Areas of focus in the survey included dermatology elective offerings, institutional policies toward visiting students, academic requirements for visiting students, timing of electives, financial costs of electives incurred by the student and institutional and regional preferences of the host medical school. Survey results indicated considerable opportunities for medical students to explore the field of dermatology among U.S. medical schools, but variance among schools regarding the number and types of dermatology electives offered. Medical schools with dermatology residencies were statistically more likely to offer dermatology electives to visiting medical students than those that did not (p<0.0001). Students from schools that do not provide more advanced electives may find it difficult to explore the field beyond a general dermatology elective because of the limited availability of subspecialty elective rotations for visiting students. Other barriers for "away" electives include academic requirements, priority in course registration for a school's own students, differing rotation schedules, and additional financial costs.

Lymphatic invasion detected by D2-40/S-100 dual immunohistochemistry does not predict sentinel lymph node status in melanoma.

BACKGROUND: Sentinel lymph node biopsy provides important prognostic information with controversial therapeutic advantages. D2-40 is a novel immunohistochemical stain specific for lymphatic endothelium often utilized to study tumor lymphangiogenesis and lymphatic invasion. OBJECTIVE: To increase the detection of lymphatic invasion in primary cutaneous melanomas with D2-40/S-100 dual immunohistochemistry, and then apply the technique to melanomas with known sentinel lymph node status. The primary aim was to assess whether the presence or absence of lymphatic invasion could predict sentinel lymph node status. The secondary aims were to assess whether lymphatic invasion and/or sentinel lymph node involvement were associated with clinicopathologic parameters commonly studied in melanomas. METHODS: Twenty-seven biopsy specimens of primary cutaneous melanoma from 27 patients with known sentinel lymph node status were retrospectively reviewed and labeled with D2-40/S-100 dual immunohistochemistry. The following clinicopathologic variables were evaluated: age, gender, histologic type, Breslow thickness, Clark level, ulceration, mitoses, lymphovascular invasion by routine staining and D2-40/S-100 dual immunohistochemistry, and overall survival. Statistical analyses were performed to assess for associations. RESULTS: D2-40/S-100 dual immunohistochemistry showed unequivocal lymphatic invasion in 10 of 27 melanomas compared with 1 of 27 with routine histology. Eight of 10 melanomas with lymphatic invasion were sentinel lymph node negative. There was no statistical association between the presence or absence of lymphatic invasion and sentinel lymph node status. LIMITATIONS: The major limitation was the small sample size. CONCLUSION: D2-40/S-100 dual immunohistochemistry increases the sensitivity of detection of lymphatic invasion in melanoma but does not predict sentinel lymph node involvement.

Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling.

BACKGROUND: Curcumin, a natural polyphenol product of the plant Curcuma longa, has been shown to inhibit the growth and progression of colorectal cancer; however, the anticancer mechanism of curcumin remains to be elucidated. MATERIALS AND METHODS: Colorectal cancer cells were treated with curcumin and changes in proliferation, protein and mRNA levels were analyzed. RESULTS: Curcumin inhibited proliferation of colorectal cancer cells. This effect was mediated by inhibition of mammalian target of rapamycin (mTOR) signaling as evidenced by decreased phosphorylation of downstream effectors of mTOR complex 1 (mTORC1), p70S6K and 4E-BP1. Curcumin decreased total expression of mTOR, Raptor and Rictor protein and mRNA levels. Surprisingly, curcumin induced phosphorylation of Akt(Ser 473); this effect may be attributed to a decrease in levels of the PHLPP1 phosphatase, an inhibitor of Akt. CONCLUSION: Our data suggest that curcumin, a natural compound, may exert its antiproliferative effects by inhibition of mTOR signaling and thus may represent a novel class of mTOR inhibitor.