The role of multidetector computed tomography in predicting the site of gastroduodenal perforation.

OBJECTIVE: This study aims to evaluate the value of multidetector computed tomography (MDCT) in detecting the location of gastroduodenal perforation. PATIENTS AND METHODS: This cross-sectional descriptive study was conducted with 47 patients who underwent contrast-enhancing MDCT and were diagnosed with gastroduodenal perforation during surgery between July 2021 and June 2022. Radiologic findings included pneumoperitoneum (distribution and quantity) and analyzed the image findings for localizing the site of gastroduodenal perforation. RESULTS: Pneumoperitoneum was the most common finding [95.74% (45 out of 47 patients)]. Regarding air distribution, the sensitivity (Se) and negative predictive value (NPV) of abdominal free air and supramesocolic free air were the highest (100% for both). The accuracy (Acc) of supramesocolic free air was the highest (93.6%), followed by abdominal free air (89.4%). Subphrenic free air also had a high Acc value (89.4%), with Se, specificity (Sp), and positive predictive value (PPV) being 90%, 85,7%, and 97.3%, respectively. The Sp PPV of falciform ligament/ligamentum teres sign, and periportal free air were also high (100% for both). In contrast, retroperitoneal free air was valuable in determining retroperitoneal duodenal perforation with an Sp, Se of 100%, and Acc of 89.4%. The thickness of abdominal free air was ≥5.5 mm, suggesting gastroduodenal perforation with a Se, Sp, PPV, NPV, and Acc of 82.5%, 100%, 100%, 50%, and 85.1%, respectively. CONCLUSIONS: Subphrenic free air, periportal free air, falciform ligament sign, and the air above transverse mesocolon were correlated to gastric and duodenal bulb perforation. Retroperitoneal air indicates the perforation at the retroperitoneal duodenum. The thickness of abdominal free air ≥5.5 mm indicates gastric and duodenal bulb perforation.

Discriminating glioblastoma from solitary brain metastases on 3 Tesla magnetic resonance imaging: the roles of fractional anisotropy and mean diffusivity.

OBJECTIVE: This study determined the diagnostic value of diffusion tensor imaging (DTI) sequences using fractional anisotropy (FA) and mean diffusivity (MD) for discriminating glioblastoma (GBM) from solitary brain metastases (SBM) using 3 Tesla magnetic resonance imaging (MRI). PATIENTS AND METHODS: A retrospective study was conducted, including 40 patients who underwent biopsy or surgery and received a histological diagnosis of GBM or SBM between August 2020 and December 2021. All preoperative examinations were performed on 3 Tesla MRI using conventional and DTI sequences. Three regions of interest (ROIs) were placed to measure a solid tumor component, peritumoral edema, and the opposite normal white matter to evaluate FA and MD values. Parametric and nonparametric statistical tests were used to determine differences between GBM and SBM. The diagnostic value of significantly different parameters between the two tumor entities was analyzed using the receiver operating characteristic (ROC) curve. RESULTS: The FA value for peritumoral edema (eFA) in GBM cases was significantly larger than that in SBM cases (p < 0.05), with no significant difference in MD values. The FA and MD values for the solid tumor component (sFA and sMD, respectively) and the ratio of the sFA value to the FA value of the opposite normal white matter (rFAs/n) in GBM cases were significantly larger than those in SBM cases (p < 0.05). Combining the sFA and sMD values provided the highest area under the ROC curve (AUC) value of 0.96, with a sensitivity, specificity, positive predictive value, and negative predictive value of 85.2%, 100%, 85.2%, and 87.1%, respectively, for distinguishing GBM from SBM. CONCLUSIONS: MRI parameters, including sFA, sMD, eFA, and rFAs/n, are useful for differentiating between GBM and SBM. The combination of sFA and sMD may increase the diagnostic performance of MRI for these two tumor entities.

Diagnostic performance of MRI perfusion and spectroscopy for brainstem glioma grading.

OBJECTIVE: This study investigated the roles of dynamic susceptibility contrast (DSC) perfusion and multivoxel magnetic resonance spectroscopy (MRS) in grading brainstem glioma (BSG). PATIENTS AND METHODS: Our retrospective study comprised 12 patients, including 6 with pathology verified low-grade BSGs and 6 with high-grade BSGs. We examined differences in age, relative cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and the metabolite ratios of choline (Cho)/N-acetyl aspartate (NAA) and Cho/creatine (Cr) between these two groups using the Mann-Whitney U test and Chi-square test. Receiver operating characteristic (ROC) curve analysis was used to establish cutoff values and assess their usefulness in grading BSG. RESULTS: The Cho/NAA metabolite ratio had the strongest preoperative predictive performance for identifying the correct histological grade among BSGs, with an area under the ROC curve (AUC) value of 0.944 (cutoff: 3.88, sensitivity [Se]: 83.3%; specificity [Sp]: 100%), followed by the Cho/Cr ratio (cutoff: 3.08; AUC: 0.917; Se: 83.3%; Sp: 100%), rCBF (cutoff: 3.56, AUC: 0.917; Se: 83.3%; Sp: 100%), rCBV (cutoff: 3.16, AUC: 0.889; Se: 100%; Sp: 66.7%), and age (cutoff: 9.5 years, AUC: 0.889; Se: 100%; Sp: 83.3%). CONCLUSIONS: rCBF and rCBV values comparing solid tumors with the normal brain parenchyma and the metabolite ratios for Cho/NAA and Cho/Cre may serve as useful indices for establishing BSG grading and provide important information when determining treatment planning and prognosis in patients with BSG.

Diagnostic performance of quantitative signal intensity measurements on magnetic resonance imaging for distinguishing cerebellopontine angle meningioma from acoustic schwannoma.

OBJECTIVE: Our study investigated magnetic resonance imaging measurements for differentiating cerebellopontine angle (CPA) meningioma from vestibular schwannoma (VS). PATIENTS AND METHODS: This retrospective study compared 36 meningioma and 36 VS patients. The tumor volume (Vtumor) and peritumor edema index (EI) relationship was analyzed. T2-weighted three-dimensional gradient-echo image signal intensity (T23D) and apparent diffusion coefficient (ADC) differentiation cutoff values were defined. Mann-Whitney U test, independent-samples t-test, receiver operating characteristic curve, and Spearman's correlation analyses were applied. RESULTS: Meningioma had higher Vtumor (p=0.009) and EI (p=0.031) values than VS. Meningioma had significantly (p<0.001) lower values than VS for mean ADC (ADCmean: 0.841±0.083×10-3 vs.1.173±0.190×10-3 mm2/s), minimum ADC (ADCmin: 0.716±0.078×10-3 vs.1.045±0.178×10-3 mm2/s), tumor:white matter ADC ratio (rADC: 1.198±0.19 vs. 1.59±0.30), mean T23D (T23Dmean: 142.91±19.9 vs. 218.72±84.73), and tumor:adipose T23D ratio (rT23d: 0.19±0.06 vs. 0.30±0.28) Cutoff, sensitivity (Se), and specificity (Sp) values were ADCmin, 0.856×10-3 mm2/s (Se: 96.6%, Sp: 100%); ADCmean, 0.963×10-3 mm2/s (Se: 96.6%, Sp: 95.5%); rADC, 1.3189 (Se: 93.1%, Sp: 81.8%), T23Dmean (Se: 96.6%, Sp: 100%); rT23D, 0.1951 (Se: 89.7%, Sp: 100%), Vtumor, 14828.65 mm3 (Se: 75.0%, Sp: 66.7%), and EI, 1.1025 (Se: 47.2%, Sp: 100%). CONCLUSIONS: ADCmin, ADCmean, rADC, T23Dmean, rT23D, Vtumor, and EI, effectively discriminated meningioma from VS.

Temperature dependence studies of tissue-mimicking phantoms for ultra-wideband microwave breast tumor detection.

Microwave imaging (MWI) systems are being investigated for breast cancer diagnostics as an alternative to conventional x-ray mammography and breast ultrasound. This work aims at a next generation of tissue-mimicking phantoms modelling the temperature-dependent dielectric properties of breast tissue over a large frequency bandwidth. Such phantoms can be used to develop a novel kind of MWI systems that exploit the temperature-dependent permittivity of tissue as a natural contrast agent. Due to the higher water content in tumor tissue, a temperature increase leads to a different change in the complex permittivity compared to surrounding tissue. This will generate a tumor dominated scattering response when the overall tissue temperature increases by a few degrees, e.g. through the use of microwave hyperthermia systems. In that case a differential diagnostic image can be calculated between microwave measurements at reference (around 37 °C) and elevated temperature conditions. This work proposes the design and characterization of agar-oil-glycerin phantoms for fatty, glandular, skin and tumor tissue. The characterization includes measurements with an open-ended coaxial probe and a network analyzer for the frequency range from 50 MHz to 20 GHz in a temperature-controlled environment covering the temperature range from 25 °C to 46 °C. The phantoms show an unique temperature response over the considered frequency bandwidth leading to significant changes in the real and imaginary part of the complex permittivity. Comparative studies with porcine skin and fat tissue show a qualitative agreement.

Discrimination between glioblastoma and solitary brain metastasis: a quantitative analysis based on FLAIR signal intensity.

OBJECTIVE: This study determined the diagnostic performance of fluid-attenuated inversion recovery (FLAIR) signal intensity (SI) in discriminating between glioblastoma (GBM) and solitary brain metastasis (SBM). PATIENTS AND METHODS: We recruited 40 patients with a histologically confirmed diagnosis of GBM or SBM who underwent conventional 3 Tesla magnetic resonance imaging before surgery or biopsy between August 2020 and January 2022. Three regions of interest were placed to assess FLAIR SI: the enhancing region (eFLAIR), the peritumoral region (pFLAIR), and the contralateral normal white matter (nFLAIR). The diagnostic performance of significantly different parameters between the two tumor entities was analyzed by receiver operating characteristic (ROC) curve analysis. RESULTS: The pFLAIR SI was significantly lower in GBM than in SBM (p < 0.05). The eFLAIR SI and the SI ratio eFLAIR and nFLAIR (e/nFLAIR) were significantly higher in GBM than in SBM (p < 0.05). On ROC curve analysis, the e/nFLAIR ratio provided the highest area under the curve value of 81%, with a sensitivity of 80.8% and a specificity of 85.7%, for distinguishing between the two tumor types. CONCLUSIONS: The eFLAIR, pFLAIR, and e/nFLAIR parameters are useful for differentiating between GBM and SBM.

Simultaneously Both Expression of LMP-1 and Methylation of E-cadherin: Molecular Biomarker in Stage IV of Nasopharyngeal Carcinoma Patients.

The phenome of E-cadherin gene methylation and the expression of latent membrane protein 1 (LMP-1) gene are associated with nasopharyngeal carcinoma (NPC). In order to determine whether cooperative LMP-1 expression or methylation of E-cadherin could serve as the potential molecule biomarker target for diagnosis and therapy of NPC, a case-control study including 93 NPC biopsy samples and 100 non cancerous nasopharyngeal swab samples were examined, as well as the strength of association among them by the quantitative polymerase chain reaction (qPCR) and nested-methylation-specific PCR methods. The significantly higher frequency of LMP-1 expression and E-cadherin methylation in NPC biopsy samples, accounting for 76.34 and 73.12%, respectively, compared to non cancerous samples, accounting for 0.00 and 30.00%, respectively, were observed. The significant correlation between the LMP-1 expression and E-cadherin methylation in NPC samples was reported. In detail, in the stage IV of NPC, in case of LMP-1-positive samples, 35 of 37 samples (accounting for 94.60%) were positive for methylation of E-cadherin. It was demonstrated that cooperative LMP-1 expression and E-cadherin gene methylation could serve as a molecular biomarker in NPC.

Intercellular bridges coordinate the transition from pluripotency to meiosis in mouse fetal oocytes.

Meiosis is critical to generating oocytes and ensuring female fertility; however, the mechanisms regulating the switch from mitotic primordial germ cells to meiotic germ cells are poorly understood. Here, we implicate intercellular bridges (ICBs) in this state transition. We used three-dimensional in toto imaging to map meiotic initiation in the mouse fetal ovary and revealed a radial geometry of this transition that precedes the established anterior-posterior wave. Our studies reveal that appropriate timing of meiotic entry across the ovary and coordination of mitotic-meiotic transition within a cyst depend on the ICB component Tex14, which we show is required for functional cytoplasmic sharing. We find that Tex14 mutants more rapidly attenuate the pluripotency transcript Dppa3 upon meiotic initiation, and Dppa3 mutants undergo premature meiosis similar to Tex14 Together, these results lead to a model that ICBs coordinate and buffer the transition from pluripotency to meiosis through dilution of regulatory factors.

A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

Fiducial marker implantation in prostate radiation therapy: complication rates and technique.

PURPOSE: This study aims to report the complication rate from the transrectal ultrasound-guided implantation of gold seed markers in prostate radiotherapy, as well as describing the technique used. MATERIALS AND METHODS: Between May 2010 and December 2012, 169 patients with localized prostate cancer had an intraprostatic fiducial marker implantation under transrectal ultrasound guidance. The procedure included prophylactic antibiotic therapy, fleet enema, implantation performed by trained radiation oncologists at our center prior to image-guided radiotherapy. Toxicity occurring between implantation and subsequent radiotherapy start date was assessed. The following parameters were analyzed via medical chart review: antibiotic therapy, anticoagulant interruption, bleeding, pain, prostate volume, number of markers implanted, post-implantation complications and delay before starting radiotherapy. RESULTS: Of the 169 men, 119 (70.4%) underwent insertion of 4 fiducial markers and the other 50 (29.6%) had 3. The procedure was well-tolerated. There was no interruption of the implantation with regards to pain or hemorrhage. No grade 3 or 4 complications were observed. Seed migration rate was 0.32%, for the migration of 2 markers on 626 implanted. Mean prostate volume was 38 cm(3) (range: 10-150 cm(3)). Two patients (1.18%) developed a urinary tract infection following the procedure: prostate volume of 25 and 65 cm(3), four gold seed markers implanted, urinary tract infection resistant to prophylactic antibiotherapy, and treated with antibiotics specific to their infection as determined on urine culture. CONCLUSION: Transrectal fiducial marker implantation for image-guided radiotherapy in prostate cancer is a well-tolerated procedure without major associated complications.

Laser and light-based treatment of Keloids--a review.

BACKGROUND: Keloids are an overgrowth of fibrotic tissue outside the original boundaries of an injury and occur secondary to defective wound healing. Keloids often have a functional, aesthetic, or psychosocial impact on patients as highlighted by quality-of-life studies. OBJECTIVES: Our goal is to provide clinicians and scientists an overview of the data available on laser and light-based therapies for treatment of keloids, and highlight emerging light-based therapeutic technologies and the evidence available to support their use. METHODS: We employed the following search strategy to identify the clinical evidence reported in the biomedical literature: in November 2012, we searched PubMed.gov, Ovid MEDLINE, Embase and Cochrane Reviews (1980-present) for published randomized clinical trials, clinical studies, case series and case reports related to the treatment of keloids. The search terms we utilized were 'keloid(s)' AND 'laser' OR 'light-emitting diode' (LED) OR 'photodynamic therapy' (PDT) OR 'intense pulsed light' OR 'low level light' OR 'phototherapy.' RESULTS: Our search yielded 347 unique articles. Of these, 33 articles met our inclusion and exclusion criteria. CONCLUSION: We qualitatively conclude that laser and light-based treatment modalities may achieve favourable patient outcomes. Clinical studies using CO2 laser are more prevalent in current literature and a combination regimen may be an adequate ablative approach. Adding light-based treatments, such as LED phototherapy or PDT, to laser treatment regimens may enhance patient outcomes. Lasers and other light-based technology have introduced new ways to manage keloids that may result in improved aesthetic and symptomatic outcomes and decreased keloid recurrence.

Sickle cell disease and complex congenital cardiac surgery: a case report and review of the pathophysiology and perioperative management.

Sickle cell anemia and thalassemia are hemoglobinopathies rarely encountered in the United States. Compounded with congenital heart disease, patients with sickle cell disease (SCD) requiring cardiopulmonary bypass and open-heart surgery represent the proverbial "needle in the haystack". As such, there is some trepidation on the part of clinicians when these patients present for complex cardiac surgery. SCD is an autosomal, recessive condition that results from a single nucleotide polymorphism in the ß-globin gene. Hemoglobin SS molecules (HgbSS) with this point mutation can polymerize under the right conditions, stiffening the erythrocyte membrane and distorting the cellular structure to the characteristic sickle shape. This shape change alters cellular transit through the microvasculature. As a result, circumstances such as hypoxia, hypothermia, acidosis or diminished blood flow can lead to aggregation, vascular occlusion and thrombosis. Chronically, SCD can give rise to multiorgan damage secondary to hemolysis and vascular obstruction. This review and case study details an 11-year-old African-American male with known SCD who presented to the cardiothoracic surgical service with congenital heart disease consisting of an anomalous, intramural right coronary artery arising from the left coronary sinus for surgical consultation and subsequent surgical correction. This case report will include a review of the pathophysiology and current literature regarding preoperative, intraoperative and postoperative management of SCD patients.

Tumor necrosis factor-related apoptosis-inducing ligand translates neonatal respiratory infection into chronic lung disease.

Respiratory infections in early life can lead to chronic respiratory disease. Chlamydia infections are common causes of respiratory disease, particularly pneumonia in neonates, and are linked to permanent reductions in pulmonary function and the induction of asthma. However, the immune responses that protect against early-life infection and the mechanisms that lead to chronic lung disease are incompletely understood. Here we identify novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infection-induced pathology in early life, and subsequent chronic lung disease. By infecting TRAIL-deficient neonatal mice and using neutralizing antibodies against this factor and its receptors in wild-type mice, we demonstrate that TRAIL is critical in promoting infection-induced histopathology, inflammation, and mucus hypersecretion, as well as subsequent alveolar enlargement and impaired lung function. This suggests that therapeutic agents that target TRAIL or its receptors may be effective treatments for early-life respiratory infections and associated chronic lung disease.

Applying the transtheoretical model to cervical cancer screening in Vietnamese-American women.

BACKGROUND: Low levels of Papanicolaou (Pap) screening participation in Vietnamese-American women remain a significant public health problem. The transtheoretical model (TTM) suggests that individuals adopting Pap smear behaviour move through a series of stages of readiness to change. Determining a woman's level of readiness for regular Pap testing and identifying the screening behaviour that an individual already performs is important in the development of successful intervention programmes that address the specific needs of Vietnamese-American women in different stages. AIMS: To describe Pap smear screening behaviours of Vietnamese-American women, and to examine whether constructs (stages of change, self-efficacy and perceived benefits/barriers) from the TTM are applicable to Vietnamese-American women relative to Pap testing. METHODS: A descriptive, cross-sectional design with snowball sampling was used to recruit participants. A total of 80 Vietnamese-American women completed the self-administered questionnaire. RESULTS: Most respondents (62.5%) reported previous Pap testing and only 46.3% receiving regular Pap testing. Compared with those in the pre-contemplation stage of the TTM, participants in maintenance reported significantly less self-efficacy (F (3, 73) = 4.85, P = 0.00), a lower level of perceived barriers (F (3, 75) = 5.99, P = 0.00) and a higher level of perceived benefits (F (3, 76) = 3.91, P = 0.01) relative to Pap smear. CONCLUSIONS: The results support some of the assumptions of the TTM but raise questions about the predicted relationships between stages of change and self-efficacy. Continued research is needed to identify the most effective theory-based interventions for evidence-based nursing practice in this population.

Practical management of avian influenza in humans.

There has been much alarm about avian influenza and its potential for a global pandemic ever since the current epidemic of avian influenza infections in humans began in 2003. While there have been a number of published reports on the clinical features of avian influenza, there are few guidelines on the practical management of patients with avian influenza. A symposium organised by the Society of Infectious Disease (Singapore), Society of Intensive Care Medicine and the Singapore General Hospital was held in Singapore to gather the views of experts from Turkey, Thailand, Vietnam and Indonesia who collectively had first-hand experience of the management of the majority (more than 100 of 192) of cases of avian influenza worldwide. The experts emphasised the importance of adapting international guidelines to the practicalities of situations on the ground. There was stress on wide screening using clinical criteria primarily, molecular diagnostic techniques (with reference laboratory confirmation) for diagnosis, and rational use of antiviral prophylaxis as well as infection control using at least surgical masks, gowns and gloves. A detailed analysis of data from a pooled database from these and other affected countries is critical to building up the evidence base for practical internationally applicable guidelines.

Lack of effect of 10 kV/m 60 Hz electric field exposure on pregnant dairy heifer hormones.

Sixteen pregnant Holstein heifers weighing 521 +/- 46 kg, at 3.3 +/- 0.7 months of gestation and 2.2 +/- 2.0 months of age were confined to wooden metabolism cages and were exposed to a vertical electric field (EF) of 10.0 +/- 0.4 kV/m and an artificial light cycle of 12 h light-12 h dark. The heifers were divided into two replicates of eight each. Each replicate was divided into two groups of four animals each, one group becoming the non-exposed and the second, the EF exposed group. The exposed group were housed in metabolism cages in an area where EF were generated, and the non-exposed group, in metabolism cages located in the adjacent area where the EF was less than 2% of that present in the exposed area. The test animals were subject to the different treatments for 4 weeks continuously. After 4 weeks, the animals switched treatment, the exposed group becoming the non-exposed group and vice-versa. Then the treatment continued for 4 more weeks. Catheters were inserted into the jugular vein of the animals, and blood samples were collected on twice a week to estimate the serum concentration of progesterone (P4), melatonin (MLT), prolactin (PRL), and insulin-like growth factor-1 (IGF-1). Feed consumption was measured daily and feed samples were collected twice a week. The results indicated that exposure of dairy cattle to EF similar to those encountered directly underneath a 735 kV high tension electrical power line carrying a maximum load of current, cannot be associated with any variation in the experimental variables mentioned above. An exception to this, is the variation in MLT, which was associated with the EF exposure. Due to the inconsistency of the MLT response in the different replicates, caution should be exercised in the interpretation of this phenomenon.

Responses of the estrous cycle in dairy cows exposed to electric and magnetic fields (60 Hz) during 8-h photoperiods.

To study the effects of exposure to extremely low frequency (ELF) electric and magnetic fields (EMF) on the estrous cycle of dairy cows under short-day photoperiod, 16 non-lactating, non-pregnant Holstein cows were exposed to a vertical electric field of 10 kV/m and a horizontal magnetic field of 30 microT for 16 h per day in a cross-over design consisting of two sequences. Each sequence included three periods, and each period corresponded to the duration of one estrous cycle. All animals were maintained under short photoperiod (8 h light/16 h dark) during the trial. Exposure to EMF had an impact on the duration of a complete estrous cycle (P<0.01) and on the duration of the luteal phase (P<0.01). The mean duration of one cycle was 19.5+/-0.4 for the control and 21.3+/-0.4 days for the exposed animals, respectively. The mean duration of the luteal phase was 15.4+/-0.4 days for the control and 17.2+/-0.4 days for the exposed group. The total area under the progesterone (P(4)) curve, the amplitude of the curve or the slope of the P(4) rise at the onset of the luteal phase were not affected by EMF exposure. Results indicate that exposure to EMF may increase the duration of the estrous cycle.

Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry.

BACKGROUND: The axolemmal distribution and density of voltage-gated sodium channels largely determines the electrical excitability of sprouting neurites. Recent evidence suggests that accumulation of sodium channels at injured axonal tips may be responsible for ectopic axonal hyperexcitability and the resulting abnormal sensory phenomena of pain and paresthesias. For future improvement in pain management it is necessary to identify structurally significant generators of autorhythmicity. A first step in this regard will be to determine the predominant types of sodium channels in injured axons. The opportunity to test human specimens from painful and non-painful neuroma is of great value. METHODS: We employed immunocytochemical methods to investigate if two types of highly specific voltage-gated sodium channel subtypes could be detected in sections of human neuroma. FINDINGS: Both subtypes of sodium channels PN1 and PN3 accumulated abnormally in human neuromas. The immunoreactive pattern was more pronounced in painful neuromas. This is in contrast to previous reports that focused either on PN1 or PN3 as main generators of hyperexcitability induced pain. INTERPRETATION: Both, PN1 and PN3 seem to be involved in hyperexcitability induced pain. It can be expected that a variety of other highly specific voltage gated sodium channel subtypes will be detected in regenerating peripheral nerve in the near future, which contribute to the development of neuropathic pain states. Thus, in order to therapeutically control hyperexcitability induced neuropathic pain, it might be worthwhile to develop pharmaceuticals that can selectively block different sodium channel subtypes and subunits.A review of the role of sodium channels in neuropathic pain is implemented in the discussion.

Lipid rafts and HIV pathogenesis: host membrane cholesterol is required for infection by HIV type 1.

In a previous study we showed that budding of HIV-1 particles occurs at highly specialized membrane microdomains known as lipid rafts. These microdomains are characterized by a distinct lipid composition that includes high concentrations of cholesterol, sphingolipids, and glycolipids. Since cholesterol is known to play a key role in the entry of some other viruses, our observation of HIV budding from lipid rafts led us to investigate the role in HIV-1 entry of cholesterol and lipid rafts in the plasma membrane of susceptible cells. We have used 2-OH-propyl-beta-cyclodextrin (beta-cyclodextrin) to deplete cellular cholesterol and disperse lipid rafts. Our results show that removal of cellular cholesterol rendered primary cells and cell lines highly resistant to HIV-1-mediated syncytium formation and to infection by both CXCR4- and CCR5-specific viruses. beta-Cyclodextrin treatment of cells partially reduced HIV-1 binding, while rendering chemokine receptors highly sensitive to antibody-mediated internalization. There was no effect on CD4 expression. All of the above-described effects were readily reversed by incubating cholesterol-depleted cells with low concentrations of cholesterol-loaded beta-cyclodextrin to restore cholesterol levels. Cholesterol depletion made cells resistant to SDF-1-induced binding to ICAM-1 through LFA-1. Since LFA-1 contributes significantly to cell binding by HIV-1, this latter effect may have contributed to the observed reduction in HIV-1 binding to cells after treatment with beta-cyclodextrin. Our results indicate that cholesterol may be critical to the HIV-1 coreceptor function of chemokine receptors and is required for infection of cells by HIV-1.

The clinical utility of multimarker RT-PCR in the detection of occult metastasis in patients with melanoma.

Cutaneous melanoma is characterized by a high propensity for metastasis. Currently, surgical intervention remains the mainstay of therapy. This approach has proven most beneficial when the diagnosis is of early stage primary lesions. Likewise, patients undergoing resection for a solitary site of metastasis have shown a survival advantage. Identification of metastatic disease depends predominantly on radiographic techniques requiring the presence of significant tumor burdens for successful imaging. However, at that time, the role of surgery and/or biochemotherapy may be of limited value. Techniques to identify minimal disease states may permit more accurate assessment of prognosis. The detection of occult tumor cells by RT-PCR in the blood, lymph nodes, and bone marrow of melanoma patients provides one such approach to monitor tumor progression. Single-marker RT-PCR has been used as one such approach but is noted to have limitations in sensitivity and specificity based on the heterogeneity of tumor marker expression among tumors as well as within an individual tumor lesion or among multiple lesions in individual patients. We employed a multimarker reverse transcriptase polymerase chain reaction assay that demonstrates improved sensitivity over a single-marker approach. Currently, the consequences of detecting systemic subclinical metastasis remain unknown pending longer-term follow-up. The detection of occult melanoma cells using molecular techniques in conjunction with known clinicopathologic prognostic factors may provided a novel and efficient approach in monitoring tumor progression and further identify high-risk patients diagnosed early in the disease course.