A pilot randomised controlled trial investigating a Mediterranean diet intervention in pregnant women for the primary prevention of allergic diseases in infants.

BACKGROUND: Observational studies suggest a potentially protective role of the Mediterranean diet (MD) in allergic diseases, including asthma. Large scale randomised controlled trials (RCTs) are needed to test the hypothesised allergy-prevention benefits of a MD during pregnancy. The present two-arm pilot RCT in pregnant women at high-risk of having a child who would develop allergic disease investigated maternal recruitment, retention and acceptability of an MD dietary intervention in the UK. The trial also assessed the effect of the intervention on MD adherence scores at 12 and at 24 weeks post-randomisation. METHODS: Thirty women were recruited at around 12 weeks of gestation. Retention was high (28 out of 30; 93%). The intervention was acceptable to participants. Mean (SD) adherence to the MD at baseline was 12.4 (2.9) in the intervention arm (n = 14) and 13.0 (1.9) in the control arm (n = 16), where 24 represents maximal adherence. There was a favourable short-term change in MD score: the adjusted mean difference (intervention - control) in the change in MD score from baseline to 12 weeks post-randomisation was 2.4 (95% confidence interval = 0.6-4.2, P = 0.012). CONCLUSIONS: The trial provides important insights into recruitment, retention and sustaining the dietary intervention, which will be used in the design of a large RCT.

Anxiety, depression and disability across the lifespan.

The authors examined the relationship between anxiety, depression and physical disability, after controlling for demographic and health variables, in a sample of 374 adults aged 18-94. Results indicate that anxiety, depression and comorbid anxiety and depression are associated with higher levels of disability, after controlling for factors such as age, gender, income, self-rated health, number of medical conditions and number of physician visits in the past year. Furthermore, anxiety, depression and comorbid anxiety and depression have a differential effect on disability according to age, with older adults with any of these symptoms reporting higher levels of disability than younger adults. These findings suggest that physicians working with older adults should assess for and treat anxiety as well as depressive symptoms.

Using systems biology to define the essential biological networks responsible for adaptation to endurance exercise training.

We predict that RNA level regulation is as diverse and powerful as protein level regulation when considering physiological adaptation. Non-coding RNA molecules, such as miRNAs (microRNAs), have emerged as a powerful mechanism for post-transcriptional regulation of mRNA. In an effort to define the role of miRNA in human skeletal-muscle biology, we have initiated profiling of muscle RNA before and after endurance exercise training. The robust molecular phenotype of muscle is established using unbiased analysis strategies of the raw data, reflecting the statistical power of gene ontology and network analysis. We can thus determine the structural features of the skeletal-muscle transcriptome, identify discrete networks activated by training and utilize bioinformatics predictions to establish the interaction between non-coding RNA modulation and Affymetrix expression profiles.

Inhibition of antigen-specific T cell trafficking into the central nervous system via blocking PECAM1/CD31 molecule.

Trafficking of antigen-specific T cells into the central nervous system (CNS) is an important initiating step in inflammation in the brain. In spite of the extensive knowledge about the role of adhesion molecules in T cell migration across peripheral vessels, the mechanism of the entry of antigen-specific T cells into the CNS is not known. This work was designed to study the regulatory roles of adhesion molecules in antigen-specific T cell migration into the CNS. Antigen-specific T cells were tracked in an in vivo migration assay using T cell receptor (TCR) transgenic mice having 95% of T cells specific for a defined antigen. pigeon cytochrome c (PCC). TCR transgenic mice were cannulated intraventricularly (IVT) for PCC antigen infusion and cerebrospinal fluid (CSF) sampling. Upon PCC infusion into the CNS, the number of alpha/beta TCR+ Vbeta3+ Mac1- cells in the CSF was characterized in the presence or absence of anti-adhesion molecule reagents. We found that antibodies against VCAM-1 (CD106), VLA-4 (CD49d/CD29), ICAM-1 (CD54), and LFA-1 (CD11a/CD18) did not influence the increased number of antigen-specific T cells in the CSF However, upon intravenous (i.v.) injection, anti-PECAM-1 (CD31) antibody or PECAM-Ig chimeric molecule inhibited the trafficking of alpha/beta TCR+ Vbeta3+ Mac1- cells into the CNS. The expression of PECAM-1 (CD31) was also up-regulated on antigen-specific T cells in a time-dependent manner in vitro upon antigenic stimulation. The antigen-induced activation of T cells in vivo was measured by CD44 and LFA-1 expression and found to be comparable between mPECAMIg-treated mice and wild-type serum control-treated groups. This indicates that CD31 inhibition of antigen-specific T cell accumulation in the CNS is probably not due to a functional inhibition of these cells. Finally, adoptive transfer of CFSE-labeled AND transgenic cells into naïve animals resulted in the accumulation of these cells in the CNS upon PCC IVT immunization that was also inhibited by mPECAMIg treatment. Hence, PECAM-1 (CD31) might play an important role in regulating antigen-specific T cells trafficking in CNS inflammatory diseases.

Interleukin-6 promotes post-traumatic healing in the central nervous system.

The central nervous system (CNS) is an immune-privileged site where the role of immune cells and mediators in traumatic brain injury is poorly understood. Previously we have demonstrated that interleukin (IL)-6, a cytokine that acts on a wide range of tissues influencing cell growth and differentiation, is an agonist for vascular endothelial growth factor (VEGF), in in vitro vascularization assays for brain microvessel endothelial cells. In this present work we focus on the role of IL-6 in promoting tissue repair in the CNS in vivo. An aseptic cerebral injury (ACI) was created in the right parietal cortex, using both wild type (C57Bl/6J) and IL-6-deficient (C57Bl/6J-IL-6-/-) mice to study the consequences of the absence of IL-6 on the pathology of brain injuries. We monitored the immediate, early, and late responses to this traumatic injury by characterizing several histologic features in the CNS at days 1, 4, 7 and 14 following injury. Acellular necrosis, cellular infiltration, and re-vascularization were characterized in the injured tissues, and each of these histologic features was individually graded and totaled to assign a healing index. IL-6-deficient mice were found to have a comparatively slower rate of recovery and healing. Furthermore, fluorescein isothiocyanate (FITC)-dextran intravenous injection demonstrated leaky vessels in IL-6-deficient but not in wild type animals following ACI. Additionally, chronic expression of IL-6 in the CNS using transgenic GFAP-IL-6 mice resulted in more rapid healing following ACI. The accelerated tissue repair in GFAP-IL-6 transgenic animals is primarily due to extensive re-vascularization as detected by endothelial cell markers. Combined, this data suggests an important role of IL-6 in tissue repair processes following traumatic injury in the CNS.

Changes in psychiatric diagnoses from admission to discharge: review of the charts of 159 patients consecutively admitted to a geriatric psychiatry inpatient unit.

The diagnosis of psychopathology among geriatric acute inpatients requires comprehensive evaluation. To our knowledge, no recently published papers in the geriatric psychiatry literature have systematically examined diagnostic changes during single admissions. We reviewed the charts of 159 patients consecutively admitted to an acute geriatric psychiatry unit over 18 months. We recorded admission diagnoses from initial treatment plans, and discharge diagnoses from discharge summaries. Mean patient age was 80 years and average length of stay was 17 days. The most common primary diagnoses were psychotic and depressive disorders. The most common secondary diagnoses were dementias and depressive disorders. Primary diagnoses changed from admission to discharge in 31 patients (20%), and secondary diagnoses changed in 76 patients (48%). There was a significant change involving the diagnosis of dementia, but not that of depressive or psychotic disorders. A large proportion of inpatients had their diagnoses altered, especially those involving dementias, during hospitalization. Inpatient admission may be valuable for clarifying the diagnoses of elderly psychiatric patients.

Two distinct regions of loss on chromosome arm 4q in primary head and neck squamous cell carcinoma.

OBJECTIVE: To more clearly define the frequency and the regions of chromosome arm 4q loss in head and neck squamous cell carcinoma. DESIGN: A retrospective microsatellite analysis of DNA from previously microdissected primary tumor samples. SETTING: Academic medical center. PATIENTS AND METHODS: One hundred primary tumor samples from patients with head and neck squamous cell carcinoma were analyzed for loss of heterozygosity on the long arm of chromosome 4. The Kaplan-Meier method was used to estimate survival for 97 patients for whom clinical data were available. The Cox proportional hazards model was used to compare survival, and logistic regression was used to search for associations between clinical tumor characteristics and 4q status. RESULTS: Analysis of 33 polymorphic microsatellite markers identified 51 samples (51%) exhibiting loss of heterozygosity of 4q in at least 1 locus. Eighteen tumors revealed loss at all informative markers, indicating monosomy or complete deletion of 4q. Thirty-three tumors displayed partial loss of heterozygosity and delineated 2 minimal areas of loss at 4q2324 and 4q2829. Eleven tumors displayed loss solely at the 4q2324 region, 13 tumors displayed deletions confined to the 4q2829 region, and 9 tumors displayed selective loss at both regions. A separate analysis in a subset of 94 primary head and neck tumors was done to further delineate the minimal area of chromosomal loss at 4q2324. Analysis of 8 markers in this region allowed us to identify the smallest region of loss between markers D4S2986 and D4S1564 (a distance of 2 centimorgans). Review of the clinical records of 97 patients revealed no statistically significant association between 4q status and any clinical variable, including survival. CONCLUSION: These results confirm a high frequency of chromosome arm 4q loss in primary head and neck squamous cell carcinoma and might demarcate 2 novel putative suppressor loci involved in progression of this carcinoma.

Dietary creatine supplementation does not affect some haematological indices, or indices of muscle damage and hepatic and renal function.

BACKGROUND: The use of creatine (Cr) as a nutritional supplement to aid athletic performance has gained widespread popularity among athletes. However, concerns have recently been expressed over potentially harmful effects of short and long term Cr supplementation on health. METHODS: Forty eight young healthy subjects were randomly allocated to three experimental protocols aimed at elucidating any potential health risks associated with five days (20 g/day) to nine weeks (3 g/day) of Cr supplementation. Venous blood samples were collected before and after periods of Cr supplementation and were analysed for some haematological indices, and for indices of hepatic, muscular, and renal dysfunction. FINDINGS: All measured indices were well within their respective normal range at all times. Serum creatinine concentration tended to be increased the day after Cr supplementation. However, values had returned to baseline six weeks after the cessation of supplementation. These increases were probably attributable to increased creatinine production rather than renal dysfunction. No indication of impairment to the haematological indices measured, hepatic function, or muscle damage was apparent after Cr supplementation. INTERPRETATION: These data provide evidence that there are no obvious adverse effects of acute or more chronic Cr supplementation on the haematological indices measured, nor on hepatic, muscle, and renal function. Therefore there is no apparent health risk associated with Cr supplementation to healthy people when it is ingested in quantities that have been scientifically proven to increase muscle Cr stores.

Antigen-specific T cell trafficking into the central nervous system.

The initiation step of cell-mediated immune responses in the central nervous system (CNS) involves the trafficking of the antigen-specific T cells into the brain. To study this trafficking, we developed an in vivo system for studying antigen-specific responses in the CNS. In this assay, T cell receptor (TCR) transgenic mice having 95% of T cells specific for a defined antigen-pigeon cytochrome c (PCC) were cannulated intraventricularly for PCC antigen infusion and cerebrospinal fluid (CSF) sampling. Upon PCC infusion into the CNS, the number of alpha/beta TCR(+) Vbeta3(+) Mac1(-) cells in the CSF was characterized. We found that infusion of antigen into the CSF induced an increased number of antigen-specific T cells in the CNS and activation of antigen-specific T cells in the peripheral blood. Hence, the drainage of CNS antigen into the periphery might play an important role in sustaining autoimmune reactivity in CNS inflammatory diseases.

EMT domestic violence knowledge and the results of an educational intervention.

The objective of this study was to determine levels of knowledge regarding domestic violence (DV), and the effectiveness of formal instruction about DV. A general knowledge survey of DV was given before and approximately 4 to 6 months after 3 hours of instruction given by Emergency Medicine and Law Enforcement faculty. A Emergency medical service (EMS) consisting of 73% paramedic-level providers in a metropolitan urban/suburban area. Differences in DV knowledge before and after the instruction were the main outcome measures. In the preinstruction series, 46 emergency medical technicians (EMTs) participated. After the instruction 19 EMTs participated (42%). Thirty-five percent of EMTs before instruction and 37% after instruction correctly identified the prevalence of DV against women as 15% to 30%. Thirty-five percent of EMTs before instruction and 63% after instruction (P < .05) correctly identified the prevalence of DV against men as 0% to 15%. Before instruction 54% knew that DV is equal among races, and 79% after instruction (P < .05). Before instruction 37% of EMTs knew that DV is equal in different socioeconomic groups and 68% after instruction (P < .05). The percent of EMTs who knew that the victim is not responsible for the abuse was 50% before instruction and 89% after instruction (P < .05). Before instruction, the results on a knowledge questionnaire were 54% correct, after instruction, results improved to 71% correct. Improvement in understanding of DV was shown for 4 of 11 questions after 3 hours of instruction. These results indicate the need for more instruction on DV for EMTs.

Head and neck cancer in nonsmokers: a distinct clinical and molecular entity.

OBJECTIVES/HYPOTHESIS: Clinical and molecular patterns of head and neck squamous cell carcinoma (HNSCC) in nonsmokers and smokers may be different. Analysis of these patterns may improve understanding and management of this disease. STUDY DESIGN: three hundred five subjects were included (46 nonsmokers, 29 former smokers, and 230 smokers). Subsets were analyzed for p53 mutation, human papillomavirus (HPV), and loss of heterozygosity (LOH) at 10 chromosomal loci. METHODS: Clinical information was analyzed for common patterns of disease among the groups. The p53 gene was sequenced, and polymerase chain reaction was used to detect HPV DNA and LOH at two microsatellite markers for each loci. The chi2 test was used to assess differences in genetic alterations between groups, logistic regression to examine the independence of association of tobacco exposure with each alteration, and Kaplan Meier estimates and the log-rank statistic to assess differences in survival. RESULTS: Nonsmokers included a disproportionate number of women, oral cavity (especially tongue) tumors, and very young or old individuals. Smokers had more tumors of the larynx, hypopharynx, and floor of mouth. The rate of p53 mutation was much greater in smokers; the percentage with HPV was marginally lower. The percentage of LOH at 3p, 4q, and 11q13, and the overall average number of chromosomal losses, was significantly lower in nonsmokers' tumors. Survival did not vary with smoking or age. CONCLUSIONS: The clinical and genetic features of HNSCC are distinct between groups defined by tobacco use. Tumors of nonsmokers contain a lower frequency of common genetic alterations, suggesting that the underlying changes in these tumors may remain undiscovered.

Role of submaximal exercise in promoting creatine and glycogen accumulation in human skeletal muscle.

We examined the effect of glycogen-depleting exercise on subsequent muscle total creatine (TCr) accumulation and glycogen resynthesis during postexercise periods when the diet was supplemented with carbohydrate (CHO) or creatine (Cr) + CHO. Fourteen subjects performed one-legged cycling exercise to exhaustion. Muscle biopsies were taken from the exhausted (Ex) and nonexhausted (Nex) limbs after exercise and after 6 h and 5 days of recovery, during which CHO (CHO group, n = 7) or Cr + CHO (Cr+CHO group, n = 7) supplements were ingested. Muscle TCr concentration ([TCr]) was unchanged in both groups 6 h after supplementation commenced but had increased in the Ex (P < 0.001) and Nex limbs (P < 0.05) of the Cr+CHO group after 5 days. Greater TCr accumulation was achieved in the Ex limbs (P < 0.01) of this group. Glycogen was increased above nonexercised concentrations in the Ex limbs of both groups after 5 days, with the concentration being greater in the Cr+CHO group (P = 0.06). Thus a single bout of exercise enhanced muscle Cr accumulation, and this effect was restricted to the exercised muscle. However, exercise also diminished CHO-mediated insulin release, which may have attenuated insulin-mediated muscle Cr accumulation. Ingesting Cr with CHO also augmented glycogen supercompensation in the exercised muscle.

Confirmatory factor analysis of the Competitive State Anxiety Inventory-2.

The aim of this study was to evaluate the factor structure of the Competitive State Anxiety Inventory-2 (CSAI-2) using confirmatory factor analysis. Volunteer participants (n = 1213) completed the CSAI-2 approximately 1 h before competition and the data were analysed in two samples. The hypothesized model showed poor fit indices in both samples independently (Robust Comparative Fit Index: sample A = 0.82, sample B = 0.84) and simultaneously (Comparative Fit Index = 0.83), suggesting that the factor structure proposed by Martens et al. is flawed. Our findings suggest that a limitation of the Cognitive Anxiety scale derives from phrasing items around the word 'concerned' rather than 'worried'. We suggest that being concerned about an impending performance does not necessarily mean that an athlete is experiencing negative thoughts, but that the athlete is acknowledging the importance and difficulty of the challenge and is attempting to mobilize resources to cope. The present results question the use of the CSAI-2 as a valid measure of competitive state anxiety.

Condyloma acuminata: a fatal disease?

Condyloma acuminata is a virally mediated epithelial overgrowth caused by the human papilloma virus. Its simplest form is the common wart, which may occur almost anywhere on the body surface. Its papillary lesion forms are commonly seen in the genital, perineal, and anal areas, though it also infects the conjunctiva, nose, mouth, larynx, and tracheo-bronchial tree. Malignant degeneration may occur in any of these areas. Diagnosis is established by clinical impression and biopsy. Immunoassay methods exist but are simply indicative of the presence of infection and are not useful in predicting the course of the disease. Many treatment modalities exist and all work well for minor lesions. For large lesions such as the giant condyloma acuminata, also known as the Buschke-Lowenstein lesion, only radical surgical extirpation is considered to be appropriate treatment. This case report, as well as others referenced in this study, documents the extreme complexity of management of many of these lesions and the fatal outcome of this disease process in a significant number of cases.

Safety of in vivo adenovirus-mediated thymidine kinase treatment of oral cancer.

BACKGROUND: Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene (tk) is one of the most effective gene therapy strategies for solid tumors in experimental animal studies. Foundational animal studies in an oral cancer model have demonstrated significant antitumor effects and improved animal survival using this treatment strategy. OBJECTIVE: To assess the safety of adenovirus-mediated transfer of the herpes simplex virus tk gene for the treatment of oral cancer. DESIGN: Oral tumors were established in C3H/HeJ mice and were treated with tk followed by systemic ganciclovir administration. Polymerase chain reaction amplification techniques were used to screen local surrounding tissues and distant organs for the presence of the adenoviral construct. Microscopic examination of the tissues was performed to determine the cytopathic effects of the vector. Blood samples were obtained from the animals to test for liver, renal, and bone marrow function after treatment. RESULTS: The adenoviral vector was present in the livers, lungs, and kidneys of animals treated with the maximal single injection dose of 2 x 10(9) plaque forming units (pfu). No vector was noted systemically after delivery of an equally effective low dose of 1 x 10(8) pfu. Microscopic examination revealed no cytopathic effects in distant organs despite the presence of vector. Results of liver and renal function tests revealed no differences between treated and control animals. There was no statistical difference in white blood cell count, hematocrit, or platelet count between animals treated with ganciclovir and control animals. CONCLUSIONS: Based on these results, the direct delivery of adenovirus-tk followed by ganciclovir administration appears both efficacious and safe in an animal model. However, serum evaluation for adenovirus vector and screening organ function studies should be included in human protocols using this gene therapy scheme.

Functional analysis of wild-type and malignant glioma derived CDKN2Abeta alleles: evidence for an RB-independent growth suppressive pathway.

The tumor suppressor gene CDKN2A (p16/MTS1/INK4A), which encodes the cyclin-dependent kinase inhibitor p16(INK4a), is a target of 9p21 deletions during the malignant progression of human gliomas. This gene also encodes a second protein product (human p16beta, murine p19ARF), which originates from an unrelated exon of CDKN2A (exon 1beta) spliced onto exon 2 in an alternate reading frame. Cell cycle arrest by p16beta is caused by an as yet unidentified pathway. In order to test the candidacy of p16beta as a glioma suppressor, we replaced p16(INK4a), p15(INK4b) and p16beta wild-type as well as a series of seven glioma-derived p16beta alleles (R87H, A112V, R120H, A121V, G125R, A128A and A128V), into glioma cell lines that had either CDKN2A-/RB+ (U-87MG and U-251MG) or CDKN2A+/RB- (LN-319) endogenous backgrounds and demonstrated that p16beta can act as a functional glioma cell growth suppressor. Moreover, p16beta, but not p16(INK4a) or p15(INK4b) inhibited the growth of RB-negative LN-319 cells, indicating that p16beta likely exerts its effects through an RB-independent pathway. In vitro and in vivo assays of pRB phosphorylation were consistent with this interpretation. Since none of the glioma-derived p16beta mutations inactivated their growth suppressive activities, it appears that mutations in CDKN2A exon 2 (which is shared in the coding sequences of p16(INK4a) and p16beta) likely exclusively target p16(INK4a).

Optimizing suicide gene therapy for head and neck cancer.

An effective "suicide gene" therapy strategy in experimental studies has been the use of the herpes simplex virus thymidine kinase gene (HSV-tk) to sensitize tumors to the cytotoxic effects of ganciclovir administration. Previous studies using this model have focused on utilizing maximal viral titers and high levels of ganciclovir that are not compatible with human dosing. Because of the high ganciclovir doses and the maximal viral titers, this strategy has limited application to actual clinical scenarios. In the following studies the authors investigate tumor regression in an oral squamous cell carcinoma animal model as a function of variable adenoviral titers and more physiologic ganciclovir dosing. Using adenoviral titers ranging from 1 x 10(8) to 2 x 10(9) plaque forming units (pfu) to treat oral tumors, they found no statistical difference in tumor regression among the different viral doses, despite differences in mitotic activity. Each treatment group, however, demonstrated a significant effect on tumor regression when compared with controls. Furthermore, the authors were able to reduce the level of ganciclovir administration to 10 mg/kg twice daily from established levels of 100 to 150 mg/kg twice daily while maintaining significant tumor responses to the HSV-tk therapy. Mean survival of animals treated with this lower ganciclovir dose was significantly higher than in controls and was equal to established means based on previous studies using higher ganciclovir doses. The optimization of this suicide gene therapy strategy is imperative in order to minimize theoretical and known viral and ganciclovir toxicities while establishing a foundation upon which to design appropriate and effective clinical trials.