When is it safe to return to driving following first-ever seizure?

OBJECTIVES: The risk of recurrence following a first-ever seizure is 40-50%, warranting driving restriction during the early period of highest risk. This restriction must be balanced against the occupational, educational and social limitations that result from patients being ineligible to drive. The recommended duration of non-driving after a first seizure varies widely between jurisdictions, influenced by various factors including the community perception of an acceptable relative level of risk for an accident (the accident risk ratio; ARR). Driving restrictions may be based on individualised risk assessments or across-the-board guidelines, but these approaches both require accurate data on the risk of seizure recurrence. METHODS: 1386 patients with first-ever seizure were prospectively analysed. Seizure recurrence was evaluated using survival analysis. The duration of non-driving required for a range of risks of seizure recurrence and ARRs was calculated. Additionally, the actual occurrence of seizures while driving was prospectively determined during follow-up. RESULTS: For a risk of seizure recurrence to fall to 2.5% per month, corresponding to a monthly risk of a seizure while driving of 1.04 per thousand and an ARR of 2.6, non-driving periods of 8 months are required for unprovoked first-ever seizure, and 5 months for provoked first-ever seizure. Of patients with a seizure recurrence, 14 (2%) occurred while driving, with the monthly risk falling to less than 1/1000 after 6 months. CONCLUSIONS: Our data provide a quantitative approach to decisions regarding a return to driving in patients with first-ever provoked or unprovoked seizure.

First use of alemtuzumab in Balo's concentric sclerosis: a case report.

Balo's concentric sclerosis (BCS) is a rare demyelinating disorder of the central nervous system. The humanised monoclonal antibody alemtuzumab has shown efficacy in another demyelinating disorder, relapsing-remitting multiple sclerosis. We aimed to explore its efficacy in treatment-refractory BCS. A 52-year-old male with radiologically confirmed progressive BCS resistant to steroids, plasmapharesis and cyclophosphamide was administered a standard protocol of alemtuzumab. Treatment failed to slow his decline; he died 6 months after administration. Why alemtuzumab induced no clinical or radiological impact may be multifactorial. We review the evidence directing BCS therapy and propose the next steps for exploring this potentially fatal condition.

Increases in pediatric antiretroviral treatment, South Africa 2005-2010.

BACKGROUND: In South Africa in 2010, about 340,000 children under the age of 15 were infected with HIV. We describe the increase in the treatment of South African pediatric HIV-infected patients assisted by the President's Emergency Plan for AIDS Relief (PEPFAR) from 2004 to 2010. METHODS: We reviewed routine program data from PEPFAR-funded implementing partners among persons receiving antiretroviral treatment age 15 years old and less. Data quality was assessed during the reporting period by program officials through routine analysis of trends and logic checks. Based on UNAIDS estimated mortality rates of untreated HIV-infected children, we calculated the number of deaths averted and life-years gained in children under five receiving PEPFAR-assisted antiretroviral treatment. RESULTS: From October 2004 through September 2010, the number of children newly initiated on antiretroviral treatment in PEPFAR-assisted programs increased from 154 to 2,641 per month resulting in an increase from 2,412 children on antiretroviral treatment in September 2005 to 79,416 children in September 2010. Of those children who initiated antiretroviral treatment before September 2009, 0-4 year olds were 1.4 (95% CI: 1.3-1.5) times as likely to transfer out of the program or die as 5-14 year olds; males were 1.3 (95% CI: 1.0-1.7) times as likely to stop treatment as females. Approximately 27,548 years of life were added to children under-five years old from PEPFAR-assisted antiretroviral treatment. CONCLUSIONS: Pediatric antiretroviral treatment in South Africa has increased substantially. However, additional case-finding and a further acceleration in the implementation of pediatric care and treatment services is required to meet the current treatment need.

Supporting the massive scale-up of antiretroviral therapy: the evolution of PEPFAR-supported treatment facilities in South Africa, 2005-2009.

BACKGROUND: South Africa has an estimated 1.5 million persons in need of antiretroviral therapy (ART). In 2004, the South African government began collaborating with the United States President's Emergency Plan for AIDS Relief (PEPFAR) to increase access to ART. We determined how PEPFAR treatment support changed from 2005-2009. METHODS: In order to describe the change in number and type of PEPFAR-supported ART facilities, we analyzed routinely collected program-monitoring data from 2005-2009. The collected data included the number, type and province of facilities as well as the number of patients receiving ART at each facility. RESULTS: The number of PEPFAR-supported facilities providing ART increased from 184 facilities in 2005 to 1,469 facilities in 2009. From 2005-2009 the number of PEPFAR-supported government facilities increased 10.1 fold from 54 to 546 while the number of PEPFAR-supported NGO facilities (including general practitioner and NGO facilities) increased 6.2 fold from 114 to 708. In 2009 the total number of persons treated at PEPFAR-supported NGO facilities was 43,577 versus 501,089 persons at PEPFAR-supported government facilities. Overall, the median number of patients receiving ART per site increased from 81 in 2005 to 136 in 2009. CONCLUSIONS: To mitigate the gap between those needing and those receiving ART, more facilities were supported. The proportion of government facilities supported and the median number of persons treated at these facilities increased. This shift could potentially be sustainable as government sites reach more individuals and receive government funding. These results demonstrate that PEPFAR was able to support a massive scale-up of ART services in a short period of time.

Two RNA-binding sites in plant fibrillarin provide interactions with various RNA substrates.

Fibrillarin, one of the major proteins of the nucleolus, plays several essential roles in ribosome biogenesis including pre-rRNA processing and 2'-O-ribose methylation of rRNA and snRNAs. Recently, it has been shown that fibrillarin plays a role in virus infections and is associated with viral RNPs. Here, we demonstrate the ability of recombinant fibrillarin 2 from Arabidopsis thaliana (AtFib2) to interact with RNAs of different lengths and types including rRNA, snoRNA, snRNA, siRNA and viral RNAs in vitro. Our data also indicate that AtFib2 possesses two RNA-binding sites in the central (138-179 amino acids) and C-terminal (225-281 amino acids) parts of the protein, respectively. The conserved GCVYAVEF octamer does not bind RNA directly as suggested earlier, but may assist with the proper folding of the central RNA-binding site.

Effects of a mass media intervention on HIV-related stigma: 'Radio Diaries' program in Malawi.

HIV-related stigma has been recognized as a significant public health issue, yet gaps remain in development and evaluation of mass media interventions to reduce stigma. The Malawi 'Radio Diaries' (RD) program features people with HIV telling stories about their everyday lives. This study evaluates the program's effects on stigma and the additional effects of group discussion. Thirty villages with 10 participants each were randomized to listen to RD only, to the program followed by group discussion or to a control program. Post-intervention surveys assessed four stigma outcomes: fear of casual contact, shame, blame and judgment and willingness to disclose HIV status. Regression analyses indicated that fear of casual contact was reduced by the intervention. Shame was reduced by the radio program, but only for those reporting prior exposure to the radio program and for those who did not have a close friend or relative with HIV. Shame was not reduced when the radio program was followed by discussion. The intervention reduced blame for men and not women and for younger participants but not older participants. Including people with HIV/AIDS in mass media interventions has potential to reduce stigma.

Scale-up and continuation of antiretroviral therapy in South African treatment programs, 2005-2009.

BACKGROUND: South Africa has the greatest burden of HIV-infection in the world with about 5.2 million HIV-infected adults. In 2003, the South African Government launched a comprehensive HIV and AIDS care treatment program supported by the United States in 2004 through the President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: To describe the scale-up and continuation of antiretroviral therapy in South African Government and PEPFAR-supported sites in South Africa, we conducted a retrospective analysis of routinely collected program reporting data, 2005-2009. RESULTS: From 2005 through 2009, the average rate of persons initiated on antiretroviral therapy in PEPFAR-supported South African Government treatment programs increased nearly four-fold from 6,327 a month in 2005-2006 to 24,622 a month in 2008-2009 resulting in an increase from 33,543 patients on continued treatment in April-June 2005 to 631,985 patients in July-September 2009. Of those 631,985 patients receiving treatment, 65% were women. Men were more likely to be lost to follow-up (9.2% vs. 7.8%, PR 1.18, 95% CI 1.17-1.19) and more likely to die (5.6% vs. 4.1%, PR 1.36, 95% CI 1.35-1.37) than women. CONCLUSIONS: Scale-up and continuation of antiretroviral therapy in South Africa has been a remarkable medical accomplishment. Because more women receive and continue treatment, more efforts are needed to treat and retain men.

Involvement of the plant nucleolus in virus and viroid infections: parallels with animal pathosystems.

The nucleolus is a dynamic subnuclear body with roles in ribosome subunit biogenesis, mediation of cell-stress responses, and regulation of cell growth. An increasing number of reports reveal that similar to the proteins of animal viruses, many plant virus proteins localize in the nucleolus to divert host nucleolar proteins from their natural functions in order to exert novel role(s) in the virus infection cycle. This chapter will highlight studies showing how plant viruses recruit nucleolar functions to facilitate virus translation and replication, virus movement and assembly of virus-specific ribonucleoprotein (RNP) particles, and to counteract plant host defense responses. Plant viruses also provide a valuable tool to gain new insights into novel nucleolar functions and processes. Investigating the interactions between plant viruses and the nucleolus will facilitate the design of novel strategies to control plant virus infections.

Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues.

Peptide analogues targeting various neuropeptide receptors have been used effectively in cancer therapy. A hallmark of adrenocortical tumor formation is the aberrant expression of peptide receptors relating to uncontrolled cell proliferation and hormone overproduction. Our microarray results have also demonstrated a differential expression of neuropeptide hormone receptors in tumor subtypes of human pheochromocytoma. In light of these findings, we performed a comprehensive analysis of relevant receptors in both human adrenomedullary and adrenocortical tumors and tested the antiproliferative effects of peptide analogues targeting these receptors. Specifically, we examined the receptor expression of somatostatin-type-2 receptor, growth hormone-releasing hormone (GHRH) receptor or GHRH receptor splice variant-1 (SV-1) and luteinizing hormone-releasing hormone (LHRH) receptor at the mRNA and protein levels in normal human adrenal tissues, adrenocortical and adrenomedullary tumors, and cell lines. Cytotoxic derivatives of somatostatin AN-238 and, to a lesser extent, AN-162, reduced cell numbers of uninduced and NGF-induced adrenomedullary pheochromocytoma cells and adrenocortical cancer cells. Both the splice variant of GHRH receptor SV-1 and the LHRH receptor were also expressed in adrenocortical cancer cell lines but not in the pheochromocytoma cell line. The GHRH receptor antagonist MZ-4-71 and LHRH antagonist Cetrorelix both significantly reduced cell growth in the adrenocortical cancer cell line. In conclusion, the expression of receptors for somatostatin, GHRH, and LHRH in the normal human adrenal and in adrenal tumors, combined with the growth-inhibitory effects of the antitumor peptide analogues, may make possible improved treatment approaches to adrenal tumors.

Dynamic behavior of Arabidopsis eIF4A-III, putative core protein of exon junction complex: fast relocation to nucleolus and splicing speckles under hypoxia.

Here, we identify the Arabidopsis thaliana ortholog of the mammalian DEAD box helicase, eIF4A-III, the putative anchor protein of exon junction complex (EJC) on mRNA. Arabidopsis eIF4A-III interacts with an ortholog of the core EJC component, ALY/Ref, and colocalizes with other EJC components, such as Mago, Y14, and RNPS1, suggesting a similar function in EJC assembly to animal eIF4A-III. A green fluorescent protein (GFP)-eIF4A-III fusion protein showed localization to several subnuclear domains: to the nucleoplasm during normal growth and to the nucleolus and splicing speckles in response to hypoxia. Treatment with the respiratory inhibitor sodium azide produced an identical response to the hypoxia stress. Treatment with the proteasome inhibitor MG132 led to accumulation of GFP-eIF4A-III mainly in the nucleolus, suggesting that transition of eIF4A-III between subnuclear domains and/or accumulation in nuclear speckles is controlled by proteolysis-labile factors. As revealed by fluorescence recovery after photobleaching analysis, the nucleoplasmic fraction was highly mobile, while the speckles were the least mobile fractions, and the nucleolar fraction had an intermediate mobility. Sequestration of eIF4A-III into nuclear pools with different mobility is likely to reflect the transcriptional and mRNA processing state of the cell.

Role of the oestrogen receptors GPR30 and ERalpha in peripheral sensitization: relevance to trigeminal pain disorders in women.

Oestrogen increases facial allodynia through its actions on activation of the MAPK extracellular-signal regulated kinase (ERK) in trigeminal ganglion neurons. This goal of study was to determine which oestrogen receptor is required for behavioural sensitization. Immunohistochemical studies demonstrated the presence of oestrogen receptor alpha (ERalpha) in nuclei of larger neurons and cytoplasm of smaller neurons, and the novel oestrogen receptor G-protein coupled receptor 30 (GPR30) in small diameter neurons that also contained peripherin, a marker of unmyelinated C-fibres. Specific agonists for ERalpha (PPT) and GPR30 (G-1), but not ERbeta (DPN), activated ERK in trigeminal ganglion neurons in vitro. Both G-1 and PPT treatment increased allodynia after CFA injections into the masseter of ovariectomized Sprague-Dawley rats. Treatment with oestrogen increased expression of ERalpha but not GPR30, while masseter inflammation increased GRP30 but not ERalpha. Differential modulation of these ERK-coupled receptors by oestrogen and inflammation may play a role in painful episodes of temporomandibular disorder and migraine.

Oestrogen increases nociception through ERK activation in the trigeminal ganglion: evidence for a peripheral mechanism of allodynia.

The mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), is activated in experimental models of chronic pain, and is also activated by oestrogen. We used an established model of inflammatory trigeminal pain, injection of Complete Freund's Adjuvant (CFA) into the masseter muscle, to determine whether ERK activation may play a role in hormone-related trigeminal pain disorders. We measured withdrawal responses to stimulation of the masseter (V3, primary allodynia) and whisker pad (V2, secondary allodynia) using graded monofilaments. Oestrogen treatment in the presence of inflammation increased withdrawal response to stimulation of both masseter and whisker pad compared with inflammation alone, indicating an additive effect of inflammation and oestrogen on both primary and secondary allodynia. We examined ERK activation in trigeminal ganglia from each treatment group using western blot and immunohistochemistry. Both masseter inflammation and oestrogen treatment increased ERK activation, and combined treatment had an additive effect. Both masseter inflammation and oestrogen increased the percentage of pERK immunoreactive neurons in divisions 1 and 2 (V1/2), and combined treatment increased pERK immunoreactivity in V1/2 compared with inflammation alone. We stereotactically administered ERK antagonist U0126, or inactive control U0124, to the trigeminal ganglion of CFA+E2-treated rats. U0126 decreased withdrawal responses to mechanical stimulation of the whisker pad compared with U0124-treated rats. Because the secondary allodynia in V2 after inflammation in V3 was reduced by antagonizing ERK activation in the periphery, these data suggest a peripheral component to secondary allodynia mediated through ERK activation.

Integrative practices of Canadian oncology health professionals.

OBJECTIVE: Cancer patients are increasingly known to use complementary medicine (CAM) during conventional treatment, but data are limited on how Canadian oncology health professionals attempt to assist patients with their use of cam in the context of conventional cancer care. As part of a larger qualitative study assessing the perceptions of Canadian oncology health professionals regarding integrated breast cancer care, we undertook an exploration of current integrative practices of oncology health professionals. DESIGN: Using an interpretive description research design and a purposive sampling, we conducted a series of in-depth qualitative interviews with various oncology health professionals recruited from provincial cancer agencies, hospitals, integrative clinics, and private practice settings in four Canadian cities: Vancouver, Winnipeg, Montreal, and Halifax. A total of 16 oncology health professionals participated, including medical and radiation oncologists, nurses, and pharmacists. RESULTS: Findings highlighted two main strategies used by oncology health professionals to create a more integrative approach for cancer patients: acting as an integrative care guide, and collaborating with other health professionals. CONCLUSIONS: Although few clear standards of practice or guidance material were in place within their organizational settings, health professionals discussed some integrative roles that they had adopted, depending on interest, knowledge, and skills, in supporting patients with cam decisions. Given that cancer patients report that they want to be able to confer with their conventional health professionals, particularly their oncologists, about their cam use, health professionals who elect to adopt integrative practices are likely offering patients much-welcomed support.

Impact and outcomes of an Iyengar yoga program in a cancer centre.

BACKGROUND: Individuals have increasingly sought complementary therapies to enhance health and well-being during cancer, although little evidence of their effect is available. OBJECTIVES: We investigated how an Iyengar yoga program affects the self-identified worst symptom in a group of participants. Whether quality of life, spiritual well-being, and mood disturbance change over the Iyengar yoga program and at 6 weeks after the program. How, from a participant's perspective, the Iyengar yoga program complements conventional cancer treatment. PATIENTS AND METHODS: This pre-post instrumental collective case study used a mixed methods design and was conducted at a private Iyengar yoga studio. The sample consisted of 24 volunteers (23 women, 1 man; 88% Caucasian; mean age: 49 years) who were currently on treatment or who had been treated for cancer within the previous 6 months, and who participated in ten 90-minute weekly Iyengar yoga classes. The main outcome measures were most-bothersome symptom (Measure Your Medical Outcome Profile 2 instrument), quality of life and spiritual well-being (Functional Assessment of Chronic Illness Therapy-General subscale and Spiritual subscale), and mood disturbance (Profile of Mood States-Short Form). Participant perspectives were obtained in qualitative interviews. RESULTS: Statistically significant improvements were reported in most-bothersome symptom (t((23)) = 5.242; p < 0.001), quality of life (F((2,46)) = 14.5; p < 0.001), spiritual well-being (F((2,46)) = 14.4; p < 0.001), and mood disturbance (F((2,46)) = 10.8; p < 0.001) during the program. At follow-up, quality of life (t((21)) = -3.7; p = 0.001) and mood disturbance (t((21)) = 2.4; p = 0.025) significantly improved over time. Categorical aggregation of the interview data showed that participants felt the program provided them with various benefits not included on the outcomes questionnaires. CONCLUSIONS: Over the course of the Iyengar Yoga for Cancer program, participants reported an improvement in overall well-being. The program was also found to present participants with a holistic approach to care and to provide tools to effectively manage the demands of living with cancer and its treatment.

U12-dependent intron splicing in plants.

U12-dependent (U12) introns have persisted in the genomes of plants since the ancestral divergence between plants and metazoans. These introns, which are rare, are found in a range of genes that include essential functions in DNA replication and RNA metabolism and are implicated in regulating the expression of their host genes. U12 introns are removed from pre-mRNAs by a U12 intron-specific spliceosome. Although this spliceosome shares many properties with the more abundant U2-dependent (U2) intron spliceosome, four of the five small nuclear RNAs (snRNAs) required for splicing are different and specific for the unique splicing of U12 introns. Evidence in plants so far indicates that splicing signals of plant U12 introns and their splicing machinery are similar to U12 intron splicing in other eukaryotes. In addition to the high conservation of splicing signals, plant U12 introns also retain unique characteristic features of plant U2 introns, such as UA-richness, which suggests a requirement for plant-specific components for both the U2 and U12 splicing reaction. This chapter compares U12 and U2 splicing and reviews what is known about plant U12 introns and their possible role in gene expression.

The role of the plant nucleolus in pre-mRNA processing.

The nucleolus is a multifunctional compartment of the eukaryotic nucleus. Besides its well-recognised role in transcription and processing of ribosomal RNA and the assembly of ribosomal subunits, the nucleolus has functions in the processing and assembly of a variety of RNPs and is involved in cell cycle control and senescence and as a sensor of stress. Historically, nucleoli have been tenuously linked to the biogenesis and, in particular, export of mRNAs in yeast and mammalian cells. Recently, data from plants have extended the functions in which the plant nucleolus is involved to include transcriptional gene silencing as well as mRNA surveillance and nonsense-mediated decay, and mRNA export. The nucleolus in plants may therefore have important roles in the biogenesis and quality control of mRNAs.

Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture.

Adrenocortical carcinoma is an uncommon malignancy that is usually fatal within a short time after diagnosis. We have investigated the effects on the growth and survival of SW-13 human adrenal carcinoma cells in culture of some currently used and some potentially new agents in the treatment of adrenal cancer. Established drugs tested were mitotane, cisplatin, etoposide, 5-fluorouracil, and suramin. Other agents studied included adenine arabinofuranoside, cytosine arabinofuranoside, 2-methoxyestradiol, and paclitaxel. The most potent chemotherapeutic agents in this system were paclitaxel and 2-methoxyestradiol, with EC (50) of 1.8x10 (-8) and 3.3x10 (-7) M, respectively. Cytosine arabinofuranoside and cisplatin both had the same EC (50) of 7.0x10 (-7) M, and etoposide 1.1x10 (-6) M. All the other agents tested required much higher doses for effect, including mitotane, the current most commonly used chemotherapy for adrenal cancer, with an EC (50) of 3.3x10 (-4) M. These data suggest that paclitaxel, 2-methoxyestradiol, and cytosine arabinofuranoside should be further evaluated for their potential in the chemotherapy of adrenal carcinoma.

Estrogen and progesterone lower cyclin B1 AND D1 expression, block cell cycle in G2/M, and trigger apoptosis in human adrenal carcinoma cell cultures.

The effects of 17 beta-estradiol and progesterone were evaluated separately and in combination, on the growth, survival, and cell cycle dynamics of SW-13 human adrenal carcinoma cells in culture. Both hormones significantly decreased cell survival, with dose response curves at four days demonstrating EC (50)s estimated at 1.2 x 10 (-5) M for 17 beta-estradiol and 4.8 x 10 (-6) M for progesterone. Flow cytometry studies of these cultures indicated a strong G2/M blocking effect of both steroids, either individually or in combination; the effects of progesterone and of both agents together were substantially greater than the effect with 17 beta-estradiol alone. The sub-G1 region of the flow cytometry profile was significantly enhanced by exposure to 17 beta-estradiol and even more by progesterone. Sub-G1 "apoptosis" was confirmed by fragmented and condensed nuclear chromatin staining using a standard DAPI fluorescence assay. The expression of the critical cell cycle regulatory proteins cyclin B1 and D1 were significantly decreased by each hormone, with the influence of progesterone again predominating. These data demonstrate that high doses of 17 beta-estradiol and progesterone have inhibitory and apoptotic effects on SW-13 human adrenal carcinoma cells IN VITRO. The observed effects are associated with declines in cyclin B1 and D1 expression as well as a block in G2/M.