High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

White matter abnormalities in gene-positive myoclonus-dystonia.

Myoclonus-dystonia is an autosomal dominantly inherited movement disorder clinically characterized by myoclonic jerks and dystonic movements of the upper body. Functional imaging and structural gray matter imaging studies in M-D suggest defective sensorimotor integration and an association between putaminal volume and severity of dystonia, possibly because of neuronal plasticity. As we expect changes in the connections between the cortical and subcortical regions, we performed a combination of white matter voxel-based morphometry (wVBM) and diffusion tensor imaging (DTI) to detect macro- and microstructural white matter changes, respectively, in DYT-11 mutations carriers (M-D). Sixteen clinically affected DYT-11 mutation carriers and 18 control subjects were scanned with 3-Tesla MRI to compare white matter volume, fractional anisotropy, and mean diffusivity between groups. In DYT11 mutation carriers, increased white matter volume and FA and decreased mean diffusivity were found in the subthalamic area of the brain stem, including the red nucleus. Furthermore, decreased mean diffusivity was found in the subgyral cortical sensorimotor areas. The white matter changes found in the subthalamic area of the brain stem, connecting the cerebellum with the thalamus, are compatible with the hypothesis that abnormal function in M-D involves a network that includes the cerebellum, brain stem, and basal ganglia. Whether these changes are causative or an effect of M-D requires further study.

Severity of dystonia is correlated with putaminal gray matter changes in myoclonus-dystonia.

BACKGROUND: Myoclonus-dystonia (M-D) is an autosomal dominantly inherited movement disorder characterized by myoclonic jerks and dystonic postures or movements. Morphometric studies have been performed in other, mainly heterogenous, types of dystonia producing conflicting results. However, all these studies agree on abnormalities in sensorimotor structures, mainly in the basal ganglia. We aimed to study gray matter (GM) volumes in sensorimotor brain structures with magnetic resonance imaging (MRI) in a genetically homogeneous form of dystonia, M-D. METHODS: Twenty-five clinically affected DYT11 mutation carriers (MC) and 25 matched control subjects were studied using T1-weighted 3D anatomical images of the entire brain, obtained with a 3.0 Tesla MRI. MC were clinically scored using the Burke Fahn Marsden dsytonia rating scale (BFMDRS) and the unified myoclonus rating scale (UMRS). GM volumes in sensorimotor cortices and basal ganglia of patients and controls were compared, and multiple regression analyses were used to correlate the GM volumes of patients with the clinical rating scales BFMDRS and UMRS. RESULTS: No significant differences were found between groups, but dystonia severity in MC was strongly correlated with increased GM volume in bilateral putamina. CONCLUSIONS: This study provides further evidence for the involvement of putamina as important motor structures in the pathophysiology of (myoclonus-) dystonia. Changes in these structures are associated with the severity of dystonia.

Normal cortical excitability in Myoclonus-Dystonia--a TMS study.

OBJECTIVE: The aim of the present study is to investigate cortical excitability in patients with DYT 11 positive Myoclonus-Dystonia (M-D), using transcranial magnetic stimulation (TMS). METHODS: Silent period, motor evoked potential (MEP) recruitment curve, short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF), with short interstimulus intervals (ISIs) ranging from 1.2 to 3.2 ms, were studied in 15 DYT 11-positive M-D patients and their matched controls. In four patients and matched controls peripheral double pulse electrical nerve stimulation was performed. RESULTS: All TMS parameters of cortical excitability were normal compared to healthy controls. In the SICF protocol we observed more variable and polyphasic MEPs in M-D patients. Cross-covariance analysis of MEP area revealed a significant correlation difference at ISI 2.2 and 2.8 ms. This increased variability was not seen in other TMS protocols or with peripheral nerve stimulation. CONCLUSIONS: In contrast with other types of dystonia, no changes in cortical excitability were found in DYT 11 patients. Our findings suggest that M-D is both clinically and pathophysiologically a separate entity from other dystonic disorders. Polyphasic MEPs during the SICF protocol in M-D patients could reflect central neuron membrane instability. Application of the SICF protocol in other patient groups has to prove its value in movement disorders.

Interleukin-2/interferon-alpha2a/13-retinoic acid-based chemoimmunotherapy in advanced renal cell carcinoma: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN).

We performed a prospectively randomised clinical trial to compare the efficacy of four subcutaneous interleukin-2-(sc-IL-2) and sc interferon-alpha2a (sc-IFN-alpha2a)-based outpatient regimens in 379 patients with progressive metastatic renal cell carcinoma. Patients with lung metastases, an erythrocyte sedimentation rate < or =70 mm h(-1) and neutrophil counts < or =6000 microl(-1) (group I) were randomised to arm A: sc-IL-2, sc-IFN-alpha2a, peroral 13-cis-retinoic acid (po-13cRA) (n=78), or arm B: arm A plus inhaled-IL-2 (n=65). All others (group II) were randomised to arm C: arm A plus intravenous 5-fluorouracil (iv-5-FU) (n=116), or arm D: arm A plus po-Capecitabine (n=120). Median overall survival (OS) was 22 months (arm A; 3-year OS: 29.7%) and 18 months (arm B; 3-year OS: 29.2%) in group I, and 18 months (arm C; 3-year OS: 25.7%) and 16 months (arm D; 3-year OS: 32.6%) in group II. There were no statistically significant differences in OS, progression-free survival, and objective response between arms A and B, and between arms C and D, respectively. Given the known therapeutic efficacy of sc-IL-2/sc-INF-alpha2a/po-13cRA-based outpatient chemoimmunotherapies, our results did not establish survival advantages in favour of po-Capecitabine vs iv-5-FU, and in favour of short-term inhaled-IL-2 in patients with advanced renal cell carcinoma receiving systemic cytokines.

Transforming growth factor-beta is an autocrine mitogen for a novel androgen-responsive murine prostatic smooth muscle cell line, PSMC1.

A prostatic smooth muscle cell line (PSMC1) was established from the dorsolateral prostate of p53 null mice. The cell line is nontumorigenic when inoculated subcutaneously, under the renal capsule or intraprostatically in syngeneic mice. These cells express alpha-smooth muscle actin (alpha-SMA), indicating their smooth muscle origin, and TGF-beta significantly enhances expression of alpha-SMA. The cells express both androgen receptor (AR) mRNA and protein, and respond mitogenically to physiological concentrations of androgens. PSMC1 cells produce significant amounts of TGF-beta, which stimulates growth by an autocrine mechanism. Dihydrotestosterone (DHT) increases proliferation of PSMC1 cells by promoting TGF-beta secretion. Considering the significant inhibitory effect of TGF-beta on prostatic epithelial cells and its stimulatory effect on the PSMC1 cells, we postulate that TGF-beta produced by prostatic smooth muscle cells may have a paracrine effect on the prostatic epithelium. We also postulate that TGF-beta may be involved in the etiology of benign prostatic hyperplasia (BPH) by stimulating excessive stromal proliferation. Line PSMC1 is the first reported androgen-responsive murine smooth muscle cell line. It will be useful for in vivo and in vitro experiments to study the mechanisms of androgen action on prostatic stroma and for delineating the interactions that occur between prostatic smooth muscle and epithelium that may lead to prostatic diseases such as BPH.

Generation of active TGF-beta by prostatic cell cocultures using novel basal and luminal prostatic epithelial cell lines.

Two prostatic epithelial lines, one of basal origin and one of luminal origin, were established from the dorsolateral prostates of p53 null mice. The cell lines are nontumorigenic when inoculated subcutaneously under the renal capsule or intraprostatically in syngeneic mice. The luminal cell line (PE-L-1) expresses cytokeratins 8 and 18 and the basal cell line (PE-B-1) expresses cytokeratins 5 and 14. The basal cells require serum for growth, whereas the luminal cells grow only in serum-free medium. Both cell lines require the presence of growth factors for optimal growth in culture, with EGF and FGF-2 having the greatest effect on the growth rate. Both lines express androgen receptor (AR) mRNA and protein. Androgen stimulates growth of the basal cell line, indicating that the ARs are functional, whereas growth of the luminal cells is unaffected by androgens. The luminal line is significantly inhibited by exogenous TGF-beta and produces low levels of endogenous TGF-beta. In contrast, the basal cell line produces significant amounts of TGF-beta and its growth is not influenced by this cytokine. Coculture of luminal cells with prostatic smooth muscle cells results in the generation of increased levels of biologically active TGF-beta, indicating a paracrine mechanism of TGF-beta activation that may be involved in the maintenance of normal prostatic function. To our knowledge this is the first report describing both basal and luminal prostatic cell lines from a single inbred animal species and the first indication that prostatic epithelial and stromal cells interact to generate the biologically active form of TGF-beta. These lines will provide an important model for determining basal/luminal interactions in both in vitro and in vivo assays.

Identification of P gene mutations in individuals with oculocutaneous albinism in sub-Saharan Africa.

Oculocutaneous albinism (OCA) is an inherited disorder resulting in hypopigmentation of the skin, hair, and eyes. OCA type 2 (tyrosinase-positive) is the most common recessively inherited disorder among southern African Blacks. OCA2 is also seen in southern African Caucasoids, but is less frequent. The gene responsible for this type of albinism, P, is the human homolog of the mouse pink-eyed dilution gene. Mutations at this locus are also responsible for the milder hypopigmentation phenotype seen in individuals with brown oculocutaneous albinism (BOCA). A common African P mutation was identified in Black OCA2 individuals, and has since been shown to occur in Black individuals with brown OCA as well. This mutation is a 2.7 kb interstitial deletion. In this study, we undertook to screen the coding region of the P gene for mutations in the non-2.7 kb deletion alleles of OCA2 patients who did not carry the deletion allele in either one or both of their P genes. We identified four mutations (A334V, 614delA, 683insG [corrected], 727insG) in a group of 39 unrelated Black OCA2 patients with a total of 52 non-2.7 kb deletion OCA2 genes. When taking all OCA2 cases into consideration, including those homozygous for the 2.7 kb deletion mutation, these account for a further 1.7% of OCA2 mutations in southern African Blacks, increasing the overall mutation detection rate to 78.7%. Three mutations (E678K, L688F, I370T) were identified in a group of 15 Black patients with an initially unclassified type of OCA and another three mutations (IVS 14-2 (a-->g), V350M, P743L) were identified in nine Caucasoid OCA patients. Relatively few mutations, all with low frequency, were identified in the non-2.7 kb deletion OCA genes. We propose that other mutations may lie either within intronic sequence or within the promoter region of the gene.

Swahili women since the nineteenth century: theoretical and empirical considerations on gender and identity construction.

PIP: This paper provides an analysis and update on the theoretical discussion about the link between gender and identity and uses a group of Swahili women in eastern Africa as an example of how this link works in practice. The first part of the study provides a brief overview of gender theory related to the terms "gender" and "identity." It is noted that gender is only one aspect of identity and that the concept of gender has undergone important changes such as the reconceptualization of the terms "sex" and "gender." The second part of the study synthesizes the experiences of Swahili women in the 19th century when the convergence of gender and class was very important. The status of Muslim women is reviewed, and it is noted that even influential women practiced purdah and that all Swahili women experienced discrimination, which inhibited their opportunities for socioeconomic mobility. Slavery and concubinage were widespread during this period, and the participation of Islamic women in spirit possession cults was a way for women to express themselves culturally. The separation of men and women in Swahili culture led to the development of two distinct subcultures, which excluded women from most aspects of public life. The third part of the study looks at the experiences of Swahili women since the 19th century both during and after the colonial period. It is shown that continuity exists in trends observed over a period of 200 years. For example, the mobility of Swahili women remains limited by Islam, but women do exert influence behind the scenes. It is concluded that the socioeconomic status of Swahili woman has been shaped more by complex forces such as class, ethnic, religious, and geographic area than by the oppression of Islam and colonialism. This study indicates that gender cannot be studied in isolation from other salient variables affecting identity.^ieng

Molecular cloning and nucleotide sequencing of the 3'-terminal region of a South African isolate of ryegrass mosaic virus RNA and in vitro expression of the coat protein gene.

The 2094 nucleotides at the 3'-terminus of a South African isolate of ryegrass mosaic virus (RGMV) was cloned and sequenced. Two putative polyprotein cleavage sites were found: Q/L and E/A, both of which are novel in the Potyviridae. The RGMV-SA cDNA was cloned into an expression vector, pUEX, and a fusion protein of 185 kDa was obtained which reacted strongly to anti-RGMV-SA antiserum. Alignment of the predicted amino acid sequence of RGMV-SA with those of other Potyviridae members showed limited identity, indicating that RGMV-SA is a definite and distinct virus.

Molecular cloning and nucleotide sequencing of the partial genomes of Agropyron and Hordeum mosaic viruses, two members of the Rymovirus genus in the taxonomic family Potyviridae.

Complementary DNAs encompassing the coat protein coding and adjacent regions of Agropyron mosaic virus (AgMV) and Hordeum mosaic virus (HoMV) were cloned and sequenced. Comparison with other sequenced potyviruses indicated that each clone contained the 3'-non-coding region (3'NCR), the coat protein (CP) gene and part of the nuclear inclusion protein (NIb) gene. Nucleotide and amino acid sequence comparisons of the 3'-terminal regions of these and other rymoviruses indicate that distinct groups exist. Ryegrass mosaic virus (RGMV) strains share sequence similarity with AgMV and HoMV. Wheat streak mosaic virus (WSMV) and brome streak mosaic virus (BrSMV) form a separate group, sharing limited sequence similarity with the other rymoviruses. It is proposed that subgroups occur within the Rymovirus genus, depending on the vector species involved in transmission and on sequences.

Phylogenetic justification for splitting the Rymovirus genus of the taxonomic family Potyviridae.

The Potyviridae family has been divided into four genera on the basis of vector transmission, as follows: Potyvirus genus (aphid), Rymovirus genus (mite), Bymovirus genus (fungus) and Ipomovirus genus (whitefly). However recent sequence comparisons of the coat protein and 3' NCR regions of the potyviruses have demonstrated that the rymoviruses appear to be a group of two unrelated clusters namely Ryegrass Mosaic Virus (RGMV), Agropyron Mosaic Virus (AgMV) and Hordeum Mosaic Virus (HoMV) in one group and Wheat Streak Mosaic Virus (WSMV) and Brome Streak Mosaic Virus (BrSMV) in the second group. We therefore propose that RGMV, AgMV and HoMV remain in the genus Rymovirus and WSMV and BrSMV form a separate genus, possibly the Whestrevirus genus.

Range of motion after total condylar knee arthroplasty.

In this study the function of the knee measured at a medium-follow-up of 5-6 years was correlated with influencing factors concerning the implant of total condylar knee prosthesis in 90 patients. The only variable affecting postoperative extension was the preoperative range of extension whereas postoperative flexion was influenced by the preoperative flexion, valgus deviation of the preoperative AP tibial-femoral angle, position of the patella, and thickness of the resection of the distal femur cut.