From State-to-Trait Meditation: Reconfiguration of Central Executive and Default Mode Networks.

While brain default mode network (DMN) activation in human subjects has been associated with mind wandering, meditation practice has been found to suppress it and to increase psychological well-being. In addition to DMN activity reduction, experienced meditators (EMs) during meditation practice show an increased connectivity between the DMN and the central executive network (CEN). However, the gradual change between DMN and CEN configuration from pre-meditation, during meditation, and post-meditation is unknown. Here, we investigated the change in DMN and CEN configuration by means of brain activity and functional connectivity (FC) analyses in EMs across three back-to-back functional magnetic resonance imaging (fMRI) scans: pre-meditation baseline (trait), meditation (state), and post-meditation (state-to-trait). Pre-meditation baseline group comparison was also performed between EMs and healthy controls (HCs). Meditation trait was characterized by a significant reduction in activity and FC within DMN and increased anticorrelations between DMN and CEN. Conversely, meditation state and meditation state-to-trait periods showed increased activity and FC within the DMN and between DMN and CEN. However, the latter anticorrelations were only present in EMs with limited practice. The interactions between networks during these states by means of positive diametric activity (PDA) of the fractional amplitude of low-frequency fluctuations (fALFFs) defined as [Formula: see text] revealed no trait differences but significant increases during meditation state that persisted in meditation state-to-trait. The gradual reconfiguration in DMN and CEN suggest a neural mechanism by which the CEN negatively regulates the DMN and is probably responsible for the long-term trait changes seen in meditators and reported psychological well-being.

Optimizing real time fMRI neurofeedback for therapeutic discovery and development.

While reducing the burden of brain disorders remains a top priority of organizations like the World Health Organization and National Institutes of Health, the development of novel, safe and effective treatments for brain disorders has been slow. In this paper, we describe the state of the science for an emerging technology, real time functional magnetic resonance imaging (rtfMRI) neurofeedback, in clinical neurotherapeutics. We review the scientific potential of rtfMRI and outline research strategies to optimize the development and application of rtfMRI neurofeedback as a next generation therapeutic tool. We propose that rtfMRI can be used to address a broad range of clinical problems by improving our understanding of brain-behavior relationships in order to develop more specific and effective interventions for individuals with brain disorders. We focus on the use of rtfMRI neurofeedback as a clinical neurotherapeutic tool to drive plasticity in brain function, cognition, and behavior. Our overall goal is for rtfMRI to advance personalized assessment and intervention approaches to enhance resilience and reduce morbidity by correcting maladaptive patterns of brain function in those with brain disorders.

Development of pro-apoptotic peptides as potential therapy for peritoneal endometriosis.

Endometriosis is a common gynaecological disease associated with pelvic pain and infertility. Current treatments include oral contraceptives combined with nonsteroidal anti-inflammatory drugs or surgery to remove lesions, all of which provide a temporary but not complete cure. Here we identify an endometriosis-targeting peptide that is internalized by cells, designated z13, using phage display. As most endometriosis occurs on organ surfaces facing the peritoneum, we subtracted a phage display library with female mouse peritoneum tissue and selected phage clones by binding to human endometrial epithelial cells. Proteomics analysis revealed the z13 receptor as the cyclic nucleotide-gated channel ß3, a sorting pathway protein. We then linked z13 with an apoptosis-inducing peptide and with an endosome-escaping peptide. When these peptides were co-administered into the peritoneum of baboons with endometriosis, cells in lesions selectively underwent apoptosis with no effect on neighbouring organs. Thus, this study presents a strategy that could be useful to treat peritoneal endometriosis in humans.

Concomitant chemoradiotherapy versus induction chemotherapy followed by chemoradiotherapy as definitive, first line treatment of squamous cell carcinoma of the head and neck. A retrospective single center analysis.

PURPOSE: Despite the lack of evidence to support its implementation in the clinical practice, induction chemotherapy (IC) before chemoradiotherapy (CRT) is often used in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). We retrospectively examined the tolerability, feasibility, and clinical outcome of both concepts in a single center analysis. PATIENTS AND METHODS: In all, 83 patients were treated between 2007 and 2010 with IC + CRT (n = 42) or CRT alone (n = 41). IC consisted of docetaxel, cisplatin and 5-fluorouracil (TPF), or cisplatin and 5-fluorouracil (PF). All patients were scheduled to receive 2 cycles of PF during concurrent CRT. Adverse events were assessed according to the common toxicity criteria of adverse events (CTCAE v. 3.0). Associations were tested using the χ² test, and survival estimates were calculated according to Kaplan-Meier. RESULTS: The median follow-up was 30.35 months (range 2.66-61.25 months). At 2 years, the overall survival rate was significantly higher for primary CRT compared to IC + CRT group (74.8 % vs. 54 %, respectively; p = 0.041). Significantly more treatment-related overall grade 4 toxicities were documented in the IC + CRT group compared to the CRT group (42.9% vs. 9.8%; p = 0.001). Renal toxicity ≥ grade 2 occurred in 52.4 % vs. 7.3 % (p < 0.001), respectively. In all, 93 % of the patients with primary CRT compared to 71 % with IC + CRT received the planned full radiotherapy dose (p = 0.012). CONCLUSION: This is, to our knowledge, the largest retrospective study to compare IC + CRT with primary CRT. IC showed high acute toxicity, compromised the feasibility of concurrent CRT, and was associated with reduced overall survival rates compared to primary CRT. The lack of clinical benefit in conjunction with the increased toxicity does not support implementation of IC.

German national consensus recommendations on nutrition and lifestyle in pregnancy by the 'Healthy Start - Young Family Network'.

Diet and physical activity before and during pregnancy affect short- and long-term health of mother and child. The energy needs at the end of pregnancy increase only by about 10% compared to nonpregnant women. An excessive energy intake is undesirable since maternal overweight and excessive weight gain can increase the risks for a high birth weight and later child overweight and diabetes. Maternal weight at the beginning of pregnancy is especially important for pregnancy outcome and child health. Women should strive to achieve normal weight already before pregnancy. Regular physical activity can contribute to a healthy weight and to the health of pregnant women. The need for certain nutrients increases more than energy requirements. Before and during pregnancy, foods with a high content of essential nutrients should be preferentially selected. Supplements should include folic acid and iodine, iron (in case of suboptimal iron stores), the ω-3 fatty acid docosahexaenoic acid (in case of infrequent consumption of ocean fish) and vitamin D (in case of decreased sun exposure and decreased endogenous vitamin D synthesis). Pregnant women should not smoke and not stay in rooms where others smoke or have smoked before (passive smoking). Alcohol consumption should be avoided, since alcohol can harm unborn children.

[Nutrition in pregnancy - Practice recommendations of the Network "Healthy Start - Young Family Network"]. / Ernährung in der Schwangerschaft - Teil 2. Handlungsempfehlungen des Netzwerks "Gesund ins Leben - Netzwerk Junge Familie".

Nutrition, physical activity and lifestyle in pregnancy influence maternal and child health. The "Healthy start - Young Family Network" supported by the German Government with the national action plan IN FORM developed recommendations on nutrition in pregnancy. Folic acid supplements (400 µg/day) should be started before pregnancy and continue for at least the first trimester. Iodine rich foods and salt and an iodine supplement (100-150 µg/day) are recommended. Long-chain omega-3 fatty acids should be provided with ≥ 1 weekly portion of oily sea fish, or a DHA-supplement if regular fish consumption is avoided. Vitamin D supplementation is advisable unless there is regular exposure to sunlight. Iron supplements should be used based on medical history and blood testing. Vegetarian diets with nutritional supplements can provide adequate nutrition, but counselling is recommended. In contrast, a vegan diet is inadequate and requires additional micronutrient supplementation. For risk reduction of listeriosis and toxoplasmosis, raw animal foods, soft cheeses and packed fresh salads should be avoided; fresh fruit, vegetables and salad should be washed well and consumed promptly. Pregnant women should remain physically active and perform sports with moderate intensity. They should avoid alcohol, active and passive smoking. Up to 3 daily cups of coffee are considered harmless, but energy drinks should be avoided. Childhood allergy is not reduced by avoiding certain foods in pregnancy whereas oily sea fish is recommended. Health care professions should lead parents to health-promoting lifestyles. Subjects of part 1 of the article are practice recommendations on nutrition, on energy needs, micronutrient needs and body weight/weight gain in pregnancy.

[Nutrition in pregnancy - Practice recommendations of the Network "Healthy Start - Young Family Network"]. / Ernährung in der Schwangerschaft - Teil 1.

Nutrition, physical activity and lifestyle in pregnancy influence maternal and child health. The "Healthy start - Young Family Network" supported by the German Government with the national action plan IN FORM developed recommendations on nutrition in pregnancy. Energy needs increase by only ≈10 % by the end of pregnancy whereas micronutrient needs increase much more. Normal weight should preferably be achieved before pregnancy. Dietary recommendations follow those for the general population. Folic acid supplements (400 µg/day) should be started before pregnancy and continue for at least the first trimester. Iodine rich foods and salt and an iodine supplement (100-150 µg/day) are recommended. Long-chain omega-3 fatty acids should be provided with ≥ 1 weekly portion of oily sea fish, or a DHA-supplement if regular fish consumption is avoided. Vitamin D supplementation is advisable unless there is regular exposure to sunlight. Health care professions should lead parents to health-promoting lifestyles. Subjects of part 2 of the article are practice recommendations on nutrition in pregnancy, especially vegetarian diets, recommendations on micronutrient supplementation, risk reduction of listeriosis and toxoplasmosis, alcohol, tobacco, caffeine and physical activity in pregnancy.

A comparison of the effects of isoflurane and ketamine anesthesia on auditory brainstem response (ABR) thresholds in rats.

The auditory brainstem response (ABR) is an acoustically evoked potential commonly used to determine hearing sensitivity in laboratory animals. Both isoflurane and ketamine/xylazine anesthesia are commonly used to immobilize animals during ABR procedures. Hearing threshold determination is often the primary interest. Although a number of studies have examined the effect of different anesthetics on evoked potential waveforms and growth functions, none have directly compared their effect on ABR hearing threshold estimates. The present study used a within-subject comparison and typical threshold criteria, to examine the effect of isoflurane and ketamine/xylazine on ABR thresholds for clicks and pure-tone stimuli extending from 8 to 32 kHz. At comparable physiological doses, hearing thresholds obtained with isoflurane (1.7% in O(2)) were on average elevated across a broad frequency range by greater than 27 dB compared to ketamine/xylazine (ketamine HCl, 50mg/kg; xylazine, 9 mg/kg). This highly significant threshold effect (F(1,6) = 158.3403, p = 3.51 × 10(-22)) demonstrates a substantial difference between general anesthetics on auditory brainstem sensitivity. Potential mechanisms and implications for ABR threshold determination under anesthesia are discussed.

Abnormal functioning of the thalamocortical system underlies the conscious awareness of the phantom limb phenomenon.

Phantom limb (PL), a phenomenon experienced by most patients after amputation, has mostly served as a paradigm to study experiences that appear to be associated with neural plasticity within the CNS. However, the subjective nature of PL experiences has had no definitive means of reliable assessment other than using patients' direct reports, nor was there a way to study the neural mechanisms involved in the conscious awareness of this mental phenomenon. Here we obtained patients' indirect responses to PL experiences for an objective evaluation using functional magnetic resonance imaging (fMRI). Six control subjects and six lower limb (LL) amputees participated in a motor imagery task for both the intact and the particular phantom toes. While all subjects shared neural processing of distinctive regional cerebral activations during motor imagery of the intact toes (prefrontal (PF), supplementary motor area (SMA), primary motor cortex (M1), superior temporal gyrus (STG)), it was only during motor imagery of the amputated toes in amputees that we observed an increased blood oxygen level-dependent (BOLD) signal in the contralateral basal ganglia at the medial globus pallidus (MGP), substantia nigra (SN), and thalamus. This increased BOLD signal in the basal ganglia-thalamus-cortex pathway during imaginary movement of the phantom toes may reflect an abnormal open loop functioning of the thalamocortical system underlying the conscious awareness of the phantom phenomenon. We suggest that the reduction in afferent information contributes to and coalesces with the higher-level reorganization resulting in the subjective conscious awareness of the phantom limb.

Safety and tolerability of seasonal ultra-rush, high-dose sublingual-swallow immunotherapy in allergic rhinitis to grass and tree pollens: an observational study in 193 children and adolescents.

OBJECTIVE: We conducted a large observational study in 193 children and adolescents with allergic rhinitis due to grass or tree pollens to evaluate the safety and tolerability of an ultrarush high-dose sublingual immunotherapy (SLIT) regimen reaching a maintenance dose of 300 index of reactivity within 90 minutes. METHODS: Children and adolescents aged 5 to 17 years with at least a 1-year medical history of allergic rhinitis with or without mild to moderate asthma due to tree pollens (birch, alder, hazel) or grass pollens (cocksfoot, meadow grass, rye grass, sweet vernal grass, timothy) were recruited. Standardized grass and tree pollen allergen extracts were used for ultrarush titration and subsequent coseasonal maintenance. RESULTS: During ultrarush titration, 60 patients (31%) reported 117 predominantly mild and local adverse events, which resolved within 150 minutes. During the maintenance phase, 562 adverse events were reported; the most frequent local events were oral pruritus, burning sensation, lip or tongue swelling, and gastrointestinal symptoms, and the most frequent systemic events were rhinoconjunctivitis and asthma. There was 1 clinically significant asthma event in an 11-year old boy with known asthma in whom SLIT was resumed after an interval of 4 days. CONCLUSION: Ultrarush titration was safe and well tolerated. Pediatric patients with asthma should be carefully monitored and adequately trained to use their rescue medications.

Dog ownership and contact during childhood and later allergy development.

The effect of dog ownership during childhood on the development of allergy has been investigated in few studies with conflicting results. The association between dog contact and indoor endotoxin exposure during infancy and the development of allergic sensitisation and atopic disease up to age 6 yrs was investigated. Two ongoing birth cohorts, the German Infant Nutrition Intervention Programme (GINI; n = 1,962) and the Influences of Lifestyle Related Factors on the Human Immune System and Development of Allergies in Children (LISA; n = 1,193), were analysed. In both studies, information on children's contact with dogs and their allergic symptoms and doctor-diagnosed allergic disease were collected during follow-up using questionnaires. Specific immunoglobulin E to common aeroallergens was measured at age 6 yrs. House dust samples were collected at age 3 months and the amount of endotoxin was determined. Dog ownership in early childhood was associated with a significantly lower rate of mixed pollen and inhalant sensitisation but not with dog sensitisation or allergic symptoms and diseases up to age 6 yrs. Regular contact with dogs, without ownership, during childhood was not associated with those health outcomes. No associations were found between house dust endotoxin exposure during infancy and sensitisation outcomes. In conclusion, dog ownership in early childhood protects against the development of inhalant sensitisation and this effect cannot be attributed to the simultaneous exposure to endotoxin.

A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen.

BACKGROUND: Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available. METHODS: In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38). RESULTS: The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026). CONCLUSION: Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo.

Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas with psychophysical evidence of tinnitus.

Chinchillas with psychophysical evidence of chronic tinnitus were shown to have significantly elevated spontaneous activity and stimulus-evoked responses in putative fusiform cells of the dorsal cochlear nuclei (DCN). Chinchillas were psychophysically trained and tested before and after exposure to a traumatic unilateral 80 dB (sound pressure level) 4 kHz tone. Before exposure, two groups were matched in terms of auditory discrimination performance (noise, and 1, 4, 6, and 10 kHz tones). After exposure, a single psychophysical difference emerged between groups. The exposed group displayed enhanced discrimination of 1 kHz tones (p = 0.00027). Postexposure discrimination of other stimuli was unaffected. It was hypothesized that exposed animals experienced a chronic subjective tone (i.e., tinnitus), resulting from their trauma, and that features of this subjective tone were similar enough to 1 kHz to affect discrimination of 1 kHz objective signals. After psychophysical testing, single-unit recordings were obtained from each animal's DCN fusiform cell layer. Putative fusiform cells of exposed animals showed significantly (p = 0.0136) elevated spontaneous activity, compared with cells of unexposed animals. Putative fusiform cells of exposed animals showed a greater stimulus-evoked response to tones at 1 kHz (p = 0.0000006) and at characteristic-frequency (p = 0.0000009). This increased activity was more pronounced on the exposed side. No increase in stimulus-evoked responses was observed to other frequencies or noise. These parallel psychophysical and electrophysiological results are consistent with the hypothesis that chronic tonal tinnitus is associated with, and may result from, trauma-induced elevation of activity of DCN fusiform cells.

Prandial glucose regulation with repaglinide: its clinical and lifestyle impact in a large cohort of patients with Type 2 diabetes.

OBJECTIVE: Prandial glucose regulation has the potential for achieving good metabolic control with a low risk of hypoglycaemia and increased flexibility with regard to eating patterns. Comparative studies have suggested that the prandial glucose regulator repaglinide is at least equivalent to sulphonylureas in terms of efficacy, but incurs a lower risk of major hypoglycaemia. However, these trials employed fixed dosing and mealtime regimens, so repaglinide was not used as intended. This prospective investigation in a daily clinical setting aimed to assess the efficacy and tolerability profile of flexible prandial glucose regulation with repaglinide in Type 2 diabetes. DESIGN: 5,985 patients with Type 2 diabetes in Germany were surveyed prospectively. These patients were assessed before and after a mean of 46 days treatment with repaglinide. At baseline, available data showed that 64% of patients had previously received therapy with conventional oral antidiabetic drugs, 22% were on diet alone, and 13% were naive to any treatment. RESULTS: Overall, mean HbA1c decreased from 8.6 to 7.4%, fasting blood glucose from 183.9 to 134.2 mg/dl (10.2 to 7.4 mmol/l), blood glucose prior to main meals from 198.5 to 141.4 mg/dl (11 to 7.8 mmol/l), and blood glucose 2 hours after main meals from 219.3 mg/dl to 153.2 mg/dl (12.2 to 8.5 mmol/l). Subgroup analysis showed significant improvements in each of these parameters (P<0.0001) in therapy-naive patients, in patients switched from other oral antidiabetic drugs, and in patients receiving repaglinide as combination therapy. Body weight decreased slightly (1.2+/-2.7 kg). Only 49 hypoglycaemic episodes were reported, of which 38 cases were mild and no adverse sequelae to these events have been reported. Repaglinide also led to a liberating effect on lifestyle when patients were switched from other oral hypoglycaemic agents (OHAs), with 80% reporting a sense of relief at the prospect of being able to miss meals. The proportion of these patients reporting lifestyle restrictions as a result of fixed mealtimes declined from 36% to 7%. Before switching, 38% of the patients admitted to eating when not hungry for fear of hypoglycaemia, but only 10% continued this behaviour and patients took fewer supplementary snacks after switching to repaglinide. CONCLUSION: Prandial glucose regulation with repaglinide improves metabolic control in patients with Type 2 diabetes without causing weight gain and with few hypoglycaemic episodes. This beneficial effect is seen in patients who are therapy-naive, have switched from alternative OHAs, or are in need of combination therapy. The prandial approach to treatment has a liberating effect with regard to eating behaviour that is welcomed by most patients switched from alternative therapies.

Development of seasonal allergic rhinitis during the first 7 years of life.

BACKGROUND: Against the background of the controversial discussion about an increase in allergic rhinitis in recent years, intraindividual longitudinal data is lacking for IgE-mediated seasonal allergic rhinitis (SAR). Little is known about the development of SAR in terms of prevalence and incidence rates from birth to school age. OBJECTIVE: In a prospective birth cohort, we investigated the development of sensitization and symptoms of SAR. SAR should be defined with high specificity, and associated risk factors should be determined. METHODS: Annual longitudinal data about seasonal allergic symptoms and sensitization was available for 587 children from birth to their seventh birthday. The definition of SAR was based on a combination of exposure-related symptoms and sensitization. RESULTS: Up to 7 years of age, SAR developed in 15% of the children. Incidence and prevalence of symptoms and sensitization were low during early childhood (<2%) and increased steadily with age. Children in which SAR had already developed in the second year all were born in spring or early summer, resulting in at least two seasons of pollen exposure before manifestation of SAR. Risk factors assessed by multiple logistic regression analysis were male sex (odds ratio [OR] = 2.4), atopic mothers (OR = 2.6) and fathers (OR = 3.6) having allergic rhinitis themselves, first-born child (OR = 2.0), early sensitization to food (OR = 3.3), and atopic dermatitis (OR = 2.5), whereas early wheezing was not associated with SAR. CONCLUSION: The development of SAR is characterized by a marked increase in prevalence and incidence after the second year of life. Our longitudinal data further indicate that in combination with the risk of allergic predisposition, at least 2 seasons of pollen allergen exposure are needed before allergic rhinitis becomes clinically manifest.

Vitamin A supplementation for extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Vitamin A supplementation may reduce the risk of chronic lung disease and sepsis in extremely-low-birth-weight infants. The results of our pilot study suggested that a dose of 5000 IU administered intramuscularly three times per week for four weeks was more effective than the lower doses given in past trials. METHODS: We performed a multicenter, blinded, randomized trial to assess the effectiveness and safety of this regimen as compared with sham treatment in 807 infants in need of respiratory support 24 hours after birth. The mean birth weight was 770 g in the vitamin A group and 769 g in the control group, and the respective gestational ages were 26.8 and 26.7 weeks. RESULTS: By 36 weeks' postmenstrual age, 59 of the 405 infants (15 percent) in the vitamin A group and 55 of the 402 infants (14 percent) in the control group had died. The primary outcome - death or chronic lung disease at 36 weeks' postmenstrual age - occurred in significantly fewer infants in the vitamin A group than in the control group (55 percent vs. 62 percent; relative risk, 0.89; 95 percent confidence interval, 0.80 to 0.99). Overall, 1 additional infant survived without chronic lung disease for every 14 to 15 infants who received vitamin A supplements. The proportions of infants in the vitamin A group and the control group who had signs of potential vitamin A toxicity were similar. The proportion of infants with serum retinol values below 20 microg per deciliter (0.70 micromol per liter) was lower in the vitamin A group than in the control group (25 percent vs. 54 percent, P<0.001). CONCLUSIONS: Intramuscular administration of 5000 IU of vitamin A three times per week for four weeks reduced biochemical evidence of vitamin A deficiency and slightly decreased the risk of chronic lung disease in extremely-low-birth-weight infants.

RERG is a molecular correlate of the inward-rectifying K current in clonal rat pituitary cells.

The rat homologue of the human ether-ä-go-go-related gene (r-erg) was cloned from rat brain using homology screening. RERG has a 96% amino acid identify to HERG. Membrane currents recorded in CHO cells after previous injection of r-erg showed that the voltage- and time-dependent properties are indistinguishable from h-erg-induced currents expressed in the same system. RT-PCR revealed the presence of r-erg mRNA in clonal rat pituitary cells (GH3/B6 cells). These cells exhibit a voltage-dependent inward-rectifying K current (IK, IR) which is highly sensitive to the class III antiarrhythmic E-4031. IK, IR recorded in GH3/B6 cells and ERG currents in CHO cells were compared using similar experimental conditions (same pulse protocols and isotonic KCl as extracellular solution). The voltage- and time-dependent properties of both currents were found to be almost identical. These results strongly suggest that RERG channels mediate IK, IR in GH3/B6 cells.

Recombinant N-terminal fragment of bactericidal/permeability increasing protein (rBPI21) prevents shock-induced microcirculatory alterations in the liver.

OBJECTIVE: To investigate the effects of the recombinant 21-kilodalton N-terminal fragment of recombinant bactericidal and permeability increasing protein (rBPI21) on leukocyte adhesion and the hepatic microcirculation after hemorrhagic shock. DESIGN: Prospective, randomized, blinded, and placebo-controlled experimental study. SETTING: University research laboratory. SUBJECTS: Anesthetized Sprague-Dawley rats, weighing 220 to 250 g. INTERVENTIONS: Rats were subjected to 60 mins of hemorrhagic shock and subsequent resuscitation to sufficiently restore systemic circulation. The microcirculation of the liver was investigated by intravital fluorescence microscopy 5 hrs after hemorrhagic shock. Four shock groups were compared with a sham-control group. Shock groups received either rBPI21 (10 mg/kg) or placebo either before or after shock period. MEASUREMENTS AND MAIN RESULTS: No differences were observed in hemodynamic, respiratory, or metabolic parameters between the shock groups. However, the hepatic microcirculation showed severe deterioration 5 hrs after shock, indicated by significantly narrowed sinusoids in all shock groups compared with controls (8.5 +/- 0.3 microm vs. 10.0 +/- 0.4 pm). Leukocyte adhesion was markedly increased to comparable values in both placebo groups (619 cells/mm2 and 644 cells/mm2; sham, 168 cells/mm2). Neutralization of endotoxin by administration of rBPI21 before or after shock resulted in plain reduction of pathologic leukocyte-endothelial interaction (138 cells/mm2 and 85 cells/mm2). CONCLUSION: The results support the hypothesis that endotoxin induces microcirculatory alterations after shock, and further suggest a potentially beneficial role of rBPI21 in the treatment of posttraumatic endotoxin-induced inflammatory reactions.

Intensified regimen for advanced head and neck squamous cell carcinomas.

OBJECTIVE: To devise an intensified treatment regimen for patients with advanced, resectable head and neck squamous cell carcinomas. DESIGN: Phase I/II clinical trial consisting of perioperative cisplatin chemoradiotherapy, surgical resection, intraoperative radiotherapy, and postoperative cisplatin chemoradiotherapy. SETTING: The Ohio State University Comprehensive Cancer Center, Columbus. PATIENTS: Thirty-seven patients (median age, 63 years) with advanced oral cavity, oropharyngeal, or hypopharyngeal carcinomas. RESULTS: The range of time at risk was 1 to 30 months (median, 21 months). Thirty of the 37 registered patients were analyzable; 11 have died (5 with distant metastases; 1 of lung carcinoma; and 5 were cancer-free); 2 experienced second primary tumors in the oral cavity (out of or adjacent to the previous radiotherapy portals). Treatment compliance was excellent (92%), morbidity was low, and excellent locoregional control was achieved. CONCLUSIONS: The initial results are encouraging; the future strategy will intensify the systemic component of therapy based on results from concurrent laboratory studies.

Pilot study of intraoperative high dose rate brachytherapy for head and neck cancer.

PURPOSE: To develop a new technique, intraoperative high dose rate brachytherapy (IOHDR), to deliver localized radiation therapy intraoperatively to head and neck tumors at sites inaccessible to intraoperative electron beam radiotherapy (IOEBRT) in the skull base region. METHODS: After maximal surgical resection, afterloading catheters spaced 1 cm apart embedded in custom surface applicators made of foam or silicone were placed on resected tumor beds. IOHDR was delivered in a shielded operating room using preplanned dosimetry with a nominal 10 Ci iridium-192 source in an HDR micro-Selectron afterloader. Twenty-nine patients (20 males, 9 females) ranging in age from 9 to 80 years (median = 61) were irradiated intraoperatively for advanced head and neck tumors at sites inaccessible to IOEBRT. Six patients who had previously received external beam radiation (EBRT) ranging from 50 to 75 Gy, were given 15 Gy of IOHDR only. Twenty-three patients who had no prior radiation received 7.5 to 12.5 Gy IOHDR, and 45 to 50 Gy EBRT was planned post-operatively; however, six of these patients did not complete the planned EBRT. Doses to normal tissues were reduced whenever possible by shielding with lead or by displacement with gauze or retractors. Treatment time ranged from 3.8 to 23 min (median = 6.5 min). Five patients received concurrent cis-platinum based chemotherapy. RESULTS: Twenty-nine patients treated to 30 sites had local tumor control of 67% and crade survival of 72%, with the follow-up ranging from 3 to 33 months (median = 21 months). In the group of 17 previously unirradiated patients who had completed full treatment (IOHDR and EBRT) to 18 sites, the local tumor control was 89%, and all of these patients survived. Tumor control in the six previously unirradiated patients who did not complete EBRT was 50% with a crude survival of 50%. In the group of six previously irradiated patients treated by IOHDR only, the local tumor control was 17% with a crude survival of 17%. No intraoperative complications were noted. The delayed morbidity included cerebrospinal fluid (CSF) leak with bone exposure (1), chronic subdural hematoma (1), septicemia (1), otitis media (1), and severe xerostomia (1). We cannot comment on long-term morbidity due to the relatively short follow-up period of 21 months. CONCLUSIONS: It is feasible to deliver IOHDR, with acceptable toxicity, to skull base tumors at sites inaccessible to IOEBRT. The use of IOHDR as a pre-radiotherapy boost produced excellent local control and survival in the selected group of patients who had no previous radiation therapy. The use of exclusive IOHDR in the previously irradiated group resulted in poor outcome, possibly due to the limitations on re-irradiation doses and/or volumes determined by normal tissue tolerance or because these patients have inherently radioresistant tumors. Higher IOHDR doses, additional EBRT, and/or chemotherapy should be considered for this group. The use of IOHDR as a pre-EBRT boost to maximize local control has a promising future in the treatment of carefully selected patients with advanced skull base tumor.