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.

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.

[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.

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.

[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.

[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.

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.

[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.

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.

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.

Individualized norms of optimal fetal growth: fetal growth potential.

OBJECTIVE: To demonstrate that individualized optimal fetal growth norms, accounting for physiologic and pathologic determinants of fetal growth, better identify normal and abnormal outcomes of pregnancy than existing methods. METHODS: In a prospective cohort of 38,033 singleton pregnancies, we identified 9,818 women with a completely normal outcome of pregnancy and characterized the physiologic factors affecting birth weight using multivariable regression. We used those physiologic factors to individually predict optimal growth trajectory and its variation, growth potential, for each fetus in the entire cohort. By comparing actual birth weight with growth potential, population, ultrasound, and customized norms, we calculated for each fetus achieved percentiles, by each norm. We then compared proportions of pregnancies classified as normally grown, between 10th and 90th percentile, or aberrantly grown, outside this interval, by growth potential and traditional norms, in 14,229 complicated pregnancies, 1,518 pregnancies with diabetes or hypertensive disorders, and 1,347 pregnancies with neonatal complications. RESULTS: Nineteen physiologic factors, associated with maternal characteristics and early placental function, were identified. Growth potential norms correctly classified significantly more pregnancies than population, ultrasound, or customized norms in complicated pregnancies (26.4% compared with 18.3%, 18.7%, 22.8%, respectively, all P<.05), pregnancies with diabetes or hypertensive disorders (37.3% compared with 23.0%, 28.0%, 34.0%, respectively, all P<.05) and neonatal complications (33.3% compared with 19.7%, 24.9%, 29.8%, respectively, all P<.05). CONCLUSION: Growth potential norms based on the physiologic determinants of birth weight are a better discriminator of aberrations of fetal growth than traditional norms. LEVEL OF EVIDENCE: II.

Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury.

Increases of synaptically released zinc and intracellular accumulation of zinc in hippocampal neurons after traumatic or ischemic brain injury is neurotoxic and chelation of zinc has been shown to reduce neurodegeneration. Although our previous studies showed that zinc chelation in traumatically brain-injured rats correlated with an increase in whole-brain expression of several neuroprotective genes and reduced numbers of apoptotic neurons, the effect on functional outcome has not been determined, and the question of whether this treatment may actually be clinically relevant has not been answered. In the present study, we show that treatment of TBI rats with the zinc chelator calcium EDTA reduces the numbers of injured, Fluoro-Jade-positive neurons in the rat hippocampus 24 h after injury but does not improve neurobehavioral outcome (spatial memory deficits) 2 weeks post-injury. Our data suggest that zinc chelation, despite providing short-term histological neuroprotection, fails to improve long-term functional outcome, perhaps because long-term disruptions in homeostatic levels of zinc adversely influence hippocampus-dependent spatial memory.

Cyclic adenosine 5'-monophosphate-stimulated neurotensin secretion is mediated through Rap1 downstream of both Epac and protein kinase A signaling pathways.

Neurotensin (NT), a gut peptide, plays important roles in gastrointestinal secretion, inflammation, and growth of normal and neoplastic tissues. cAMP regulates the secretion of hormones via its effector proteins protein kinase A (PKA) or Epac (exchange protein directly activated by cAMP). The small GTPase Rap1 can be activated by both PKA and Epac; however, the role of Rap1 in hormone secretion is unknown. Here, using the BON human endocrine cell line, we found that forskolin (FSK)-stimulated NT secretion was reduced by inhibition of Rap1 expression and activity. FSK-stimulated NT secretion was enhanced by overexpression of either wild-type or constitutively active Rap1. Epac activators and wild-type Epac enhanced NT release and Rap1 activity. In contrast, overexpression of a cAMP binding mutant, EpacR279E, decreased NT release and Rap1 activity. PKA activation increased NT release and Rap1 activity. FSK-stimulated NT release was reduced by PKA inhibition and the dominant negative Rap1N17. NT secretion, stimulated by Epac activation, was reduced by PKA inhibition; NT release, stimulated by PKA activation, was enhanced by wild-type Epac but reduced by the mutant EpacR279E. Finally, prostaglandin E2 (PGE2), a physiological agent that increases cAMP, stimulated NT secretion via cAMP/PKA/Rap1. Importantly, we demonstrate that PKA and Epac mediate the cAMP-induced NT secretion synergistically by converging at the common downstream target protein Rap1. Moreover, PGE2, a potent mediator of inflammation and associated with colorectal carcinogenesis, stimulates NT release suggesting a possible link between PGE2 and NT on intestinal inflammatory disorders and colorectal cancers.

Sunburn risk factors for beachgoing children.

Sunburn prevention in children and the early establishment of sun protective behavior is predicted to result in a decreased future incidence of skin cancer. A survey of beachgoing families was conducted to evaluate the parental/guardian role in the use of sun protection for their minor children. Ethnicity and Fitzpatrick Skin Type of children and their parents were the best predictors for sunburn. White, non-Hispanic children were 7.8 times more likely to have a history of sunburn than children whose parents identified them as Hispanic when controlled for the same Fitzpatrick Skin Types.

Injured Fluoro-Jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury.

Hippocampal damage contributes to cognitive dysfunction after traumatic brain injury (TBI). We previously showed that Fluoro-Jade, a fluorescent stain that labels injured, degenerating brain neurons, quantifies the extent of hippocampal injury after experimental fluid percussion TBI in rats. Coincidentally, we observed that injured neurons in the rat hippocampus also stained with Newport Green, a fluorescent dye specific for free ionic zinc. Here, we show that, regardless of injury severity or therapeutic intervention, the post-TBI population of injured neurons in rat hippocampal subfields CA1, CA3 and dentate gyrus is indistinguishable, both in numbers and anatomical distribution, from the population of neurons containing high levels of zinc. Treatment with lamotrigine, which inhibits presynaptic release of glutamate and presumably zinc that is co-localized with glutamate, reduced numbers of Fluoro-Jade-positive and Newport Green-positive neurons equally as did treatment with nicardipine, which blocks voltage-gated calcium channels through which zinc enters neurons. To confirm using molecular techniques that Fluoro-Jade and Newport Green-positive neurons are equivalent populations, we isolated total RNA from 25 Fluoro-Jade-positive and 25 Newport Green-positive pyramidal neurons obtained by laser capture microdissection (LCM) from the CA3 subfield, linearly amplified the mRNA and used quantitative ribonuclease protection analysis to demonstrate similar expression of mRNA for selected TBI-induced genes. Our data suggest that therapeutic interventions aimed at reducing neurotoxic zinc levels after TBI may reduce hippocampal neuronal injury.

Increased incidence of well-differentiated thyroid cancer associated with Hashimoto thyroiditis and the role of the PI3k/Akt pathway.

BACKGROUND: The link between inflammation and cancer is well-established, but the link between Hashimoto thyroiditis (HT) and thyroid cancer remains controversial. The purpose of our study was to determine the incidence of patients with thyroid cancer and associated HT at our institution, to correlate our patient population demographics with the Surveillance, Epidemiology and End Results (SEER) database, and to assess the expression of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in patients with HT. STUDY DESIGN: Demographic and histologic data were collected from patients undergoing thyroid resection at the University of Texas Medical Branch from 1987 to 2002 and compared with the SEER database. Immunohistochemistry for phosphorylated Akt (a marker of PI3K activity), Akt isoforms and PTEN (an inhibitor of PI3K) was performed on paraffin-embedded blocks of resected thyroid tissue. RESULTS: Our patient population demographics and thyroid cancer incidence by histologic type were similar to patients in the SEER database. Ninety-eight (37.7%) resected specimens had pathologic changes consistent with HT; 43 (43.8%) had an associated well-differentiated thyroid cancer. Increased phosphorylated Akt, Akt1, and Akt2 expression was noted in regions of HT and thyroid cancer compared with regions of normal surrounding thyroid tissue. CONCLUSIONS: Patients with HT were three times more likely to have thyroid cancer, suggesting a strong link between chronic inflammation and cancer development. PI3K/Akt expression was increased in both HT and well-differentiated thyroid cancer, suggesting a possible molecular mechanism for thyroid carcinogenesis.

[A case of postoperative recurrent lung cancer with long survival due to gefitinib efficacy].

A 70-year-old woman underwent a right middle lobectomy and partial resection of right upper lobe for lung cancer. The pathological findings were well-differentiated adenocarcinoma, pT2N0M0, Stage IB. About 6 years after the operation, the serum CEA level increased and chest CT revealed right pleural dissemination and right pleural effusion. We diagnosed it as a recurrence of the lung cancer. Although we recommended chemotherapy, she hesitated and went without treatment for about 1 year. Then, 1 month after beginning gefitinib, her serum CEA level normalized and the recurrent lesion disappeared on chest CT. She has since a shown complete response with gefitinib for over 4 years and is still alive.