Physical therapy in Huntington's disease--toward objective assessments?

BACKGROUND AND PURPOSE: Physical therapy is recommended for the treatment of Huntington's disease, but reliable studies investigating its efficacy are almost non-existent. This may in part be due to the lack of suitable outcome measures. Therefore, we investigated the applicability of novel quantitative and objective assessments of motor dysfunction in the evaluation of physical therapy interventions aimed at improving gait and posture. METHODS: Twelve patients with Huntington disease received a predefined twice-weekly intervention focusing on posture and gait over 6 weeks. The GAITRite mat and a force plate were used for objective and quantitative assessments. The Unified Huntingtons Disease Rating Scale Total Motor Score, the timed Up &Go test, and the Berg Balance Scale were used as clinical outcome measures. RESULTS: Significant improvements were seen in GAITRite measures after therapy. Improvements were also seen in the Up & Go test and Berg Balance Scale, whereas force plate measures and Total Motor Scores did not change. CONCLUSIONS: The results suggest that physical therapy has a positive effect on gait in Huntington's disease. The study shows that objective and quantitative measures of gait and posture may serve as endpoints in trials assessing the efficacy of physical therapy. They should be explored further in larger trials applying a randomized controlled setting.

Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.

Tumor-associated antigens (TAAs) include overexpressed self-antigens (for example, Her2/neu) and tumor virus antigens (for example, HPV-16 E6/E7). Although in cancer patients, TAA-specific CD4+ and CD8+ cells are often present, they are not able to control tumor growth. In recent studies, it became apparent that tumor site-located immune evasion mechanisms contribute to this phenomenon and that regulatory T cells have a major role. We tested in Her2/neu+ breast cancer and HPV-16 E6/E7+ cervical cancer mouse models, whether intratumoral expression of immunostimulatory proteins (ISPs), for example, recombinant antibodies (αCTLA-4, αCD137, αCD3), cyto/chemokines (IL-15, LIGHT, mda-7) and costimulatory ligands (CD80), through adenovirus(Ad)-mediated gene transfer would overcome resistance. In both the breast and cervical cancer model, none of the Ad.ISP vectors displayed a significant therapeutic effect when compared with an Ad vector that lacked a transgene (Ad.zero). However, the combination of Ad.ISP vectors with systemic T regulatory (Treg) depletion, using anti-CD25 mAb (breast cancer model) or low-dose cyclophosphamide (cervical cancer model) resulted in a significant delay of tumor growth in mice treated with Ad.αCTLA4. In the cervical cancer model, we also demonstrated the induction of a systemic antitumor immune response that was able to delay the growth of distant tumors. Ad.αCTLA4-mediated tumor-destructive immune responses involved NKT and CD8+ T cells. In both models no autoimmune reactions were observed. This study shows that Ad.αCTLA4 in combination with systemic Treg depletion has potentials in the immunotherapy of cancer.

Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines.

Predicting the impact of microRNAs (miRNAs) on target proteins is challenging because of their different regulatory effects at the transcriptional and translational levels. In this study, we applied a novel protein lysate microarray (LMA) technology to systematically monitor for target protein levels after high-throughput transfections of 319 pre-miRs into breast cancer cells. We identified 21 miRNAs that downregulated the estrogen receptor-alpha (ERalpha), as validated by western blotting and quantitative real time-PCR, and by demonstrating the inhibition of estrogen-stimulated cell growth. Five potent ERalpha-regulating miRNAs, miR-18a, miR-18b, miR-193b, miR-206 and miR-302c, were confirmed to directly target ERalpha in 3'-untranslated region reporter assays. The gene expression signature that they repressed highly overlapped with that of a small interfering RNA against ERalpha, and across all the signatures tested, was most closely associated with the repression of known estrogen-induced genes. Furthermore, miR-18a and miR-18b showed higher levels of expression in ERalpha-negative as compared with ERalpha-positive clinical tumors. In summary, we present systematic and direct functional evidence of miRNAs inhibiting ERalpha signaling in breast cancer, and demonstrate the high-throughput LMA technology as a novel, powerful technique in determining the relative impact of various miRNAs on key target proteins and associated cellular processes and pathways.

Combining CA 125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma.

OBJECTIVES: The serum tumor marker CA 125 is elevated in most clinically advanced ovarian carcinomas. Because these elevations may precede clinical detection by a year or more, CA 125 is potentially useful for early detection as part of an ovarian cancer screening program. However, CA 125 is often not elevated in clinically detected cancer and is frequently elevated in women with benign ovarian tumors. CA 125 may be more useful in conjunction with one or more other tumor biomarkers. Additional markers could play a role if, when used with CA 125, they identify some carcinomas missed by CA 125 (i.e., they improve sensitivity), rule out false positives (i.e., improve specificity), or are able to detect the same cancers earlier. METHODS: We have evaluated a composite marker (CM) that combines CA 125 and a previously described soluble mesothelin related (SMR) marker in sera from 52 ovarian cancer cases, 43 controls with benign ovarian tumors, and 220 normal risk controls who participated in a screening program, including 25 healthy women having two serum samples collected 1 year apart. CA 125, SMR, and CM were evaluated for their ability to identify clinical disease and for their temporal stability, which assesses their ability to obtain even greater sensitivity when used in a longitudinal screening program. RESULTS: CM has the best sensitivity, with specificity equal to CA 125. Importantly, CM has temporal stability at least as high as CA 125. CONCLUSION: The CM may outperform CA 125 alone in a longitudinal screening program as well as in a diagnostic setting.

C-reactive protein levels following standard neurosurgical procedures.

BACKGROUND: The aim of the present study was to establish the magnitude and time-course of C-reactive protein increases following routine neurosurgical procedures in the absence of clinical and laboratory signs of infection. METHOD: C-reactive protein levels were studied daily following ventriculo-peritoneal shunt implantation, anterior cervical fusion, vestibular schwannoma operation, supratentorial glioma surgery, endovascular intracranial aneurysm treatment and open cerebral aneurysm surgery. FINDINGS: The magnitude of the C-reactive protein increase depended on the extent of surgical trauma and peak-levels were recorded between postoperative day one and four after which the levels tapered off. INTERPRETATION: Increases occurring after the fourth postoperative day are likely to be caused by complications of surgery, e.g. infection.

One-Session treatment of specific phobias in youths: a randomized clinical trial.

Sixty children, ages 7-17 years, who fulfilled Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) diagnosis for various specific phobias were randomized to (a) 1-session exposure treatment alone, (b) 1-session treatment with a parent present, or (c) wait-list control group for 4 weeks. After the waiting period, the wait-list patients were rerandomized to the active treatments. The patients' phobias were assessed with behavioral approach tests (approach behavior, experienced anxiety, and physiological reactions), whereas general anxiety, depression, phobic tendencies, and anxiety sensitivity were assessed with self-report inventories. Assessments were done pre-, post-, and 1-year following treatment. Results showed that both treatment conditions did significantly better than the control condition, whereas the treatment groups did equally well on most measures, and the effects were maintained at follow-up. The implications of these results are discussed.

Walking training of patients with hemiparesis at an early stage after stroke: a comparison of walking training on a treadmill with body weight support and walking training on the ground.

OBJECTIVE: To compare the effect of walking training on a treadmill with body weight support (BWS) and walking training on the ground at an early stage of rehabilitation in patients with hemiparesis after stroke. DESIGN: Randomized controlled experimental study. SETTING: Multicentre design; three departments of rehabilitation medicine. SUBJECTS: Seventy-three consecutive first stroke patients admitted to a rehabilitation clinic were randomized into a treatment group and a control group. INTERVENTIONS: The treatment group received walking training on a treadmill with BWS for 30 minutes, 5 days a week. The control group received walking training according to the Motor Relearning Programme (MRP) on the ground for 30 minutes 5 days a week, not including treadmill training. During the time in the rehabilitation department (about two months), all patients in the study also received professional stroke rehabilitation besides the walking training in the two groups. MAIN OUTCOME MEASURES: Functional Independence Measure (FIM), walking velocity for 10 m, Functional Ambulation Classification (FAC), Fugl-Meyer Stroke Assessment and Berg's Balance Scale. The assessments were performed at admission, at discharge and at 10-month follow-up. RESULTS: There were no statistically significant differences between the groups at discharge or at the 10-month follow-up with regard to FIM, walking velocity, FAC, Fugl-Meyer Stroke Assessment, and Berg's Balance Scale. Patients in both groups improved in these variables from admission to the 10-month follow-up. CONCLUSIONS: Treadmill training with BWS at an early stage of rehabilitation after stroke is a comparable choice to walking training on the ground.

Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia.

BACKGROUND: No controlled trial of treatment of generalised social phobia has been conducted in general practice. AIMS: To examine the efficacy of sertraline or exposure therapy, administered alone or in combination in this setting. METHOD: Study was of a randomised, double-blind design. Patients (n = 387) received sertraline 50-150 mg or placebo for 24 weeks. Patients were additionally randomised to exposure therapy or general medical care. RESULTS: Sertraline-treated patients were significantly more improved than non-sertraline-treated patients (chi(2)=12.53, P<0.001; odds ratio=0.534; 95% Cl 0.347-0.835). No significant difference was observed between exposure- and non-exposure-treated patients (chi(2)=2.18, P=0.140; odds ratio=0.732; 95% Cl 0.475-1.134). In the pairwise comparisons, combined sertraline and exposure (chi(2)=12.32; P<0.001) and sertraline (chi(2)=10.13; P=0.002) were significantly superior to placebo. CONCLUSIONS: Sertraline is an effective treatment for generalised social phobia. Combined treatment with sertraline and exposure therapy, conducted by the general practitioner, may enhance the treatment efficacy in primary care.

CD3-mediated activation of tumor-reactive lymphocytes from patients with advanced cancer.

Lymphocytes from blood or tumors of patients with advanced cancer did not proliferate and produced very low levels of tumor necrosis factor and IFN-gamma when cultured with autologous tumor cells. Proliferation and lymphokine production dramatically increased in the presence of beads conjugated with mAbs to CD3 plus mAbs to CD28 and/or CD40, and the lymphocytes destroyed the tumor cells. Expression density of CD3 concomitantly increased from low to normal levels. Furthermore, beads providing a CD3 signal (in combination with CD28 or CD28 plus CD40) gave partial protection against the inhibitory effect of transforming growth factor type beta1 on lymphocyte proliferation and production of tumor necrosis factor and IFN-gamma. MHC class I-restricted cytolytic T cells lysing autologous tumor cells in a 4-h Cr(51) release assay were generated when peripheral blood leukocytes were activated in the presence of autologous tumor cells and anti-CD3/CD28 or anti-CD3/CD28/CD40 beads. Experiments performed in a model system using anti-V-beta1 or anti-V-beta2 mAbs to activate subsets of T cells expressing restricted T cell receptor showed that lymphocytes previously activated by anti-V-beta can respond to CD3 stimulation with vigorous proliferation and lymphokine production while retaining their specificity, also in the presence of transforming growth factor type beta1. Our results suggest that T lymphocytes from cancer patients can proliferate and form Th1 type lymphokines in the presence of autologous tumor cell when properly activated, and that antigen released from killed tumor cells and presented by antigen-presenting cells in the cultures facilitates the selective expansion of tumor-directed, CD8(+) cytolytic T cells.

Overexpression of HER-2 in ovarian carcinomas.

The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. Shown by immunohistology, <25% of newly diagnosed ovarian carcinomas express the HER-2 protein. However, now we report that this protein was expressed in all 20 tumor cell lines derived from stage III and IV ovarian cancers as well as in tumor cells harvested from patients with malignant ascites and in tumor samples taken at a second surgery, suggesting that cells with excess expression may have a selective growth advantage. HER-2-positive ovarian carcinoma cells were shown to be sensitive to antibody-dependent cellular cytotoxicity, and their in vitro proliferation was inhibited by anti-HER-2 MAb Herceptin. We postulate, therefore, that therapy which targets HER-2 may be more efficacious in patients with ovarian carcinoma than indicated by the commonly low expression of HER-2 in tumors removed at the time of primary surgery.

CD83 is an I-type lectin adhesion receptor that binds monocytes and a subset of activated CD8+ T cells [corrected].

To help determine CD83 function, a cDNA encoding a soluble protein containing the CD83 extracellular domain was fused with a mutated human IgG1 constant region (CD83Ig) and expressed by stable transfection of Chinese hamster ovary cells. Purified CD83Ig bound to peripheral blood monocytes and a subset of activated CD3(+)CD8(+) lymphocytes but did not bind to FcR. Monocytes that had adhered to plastic lost their ability to bind to CD83Ig after 90 min of in vitro incubation. CD83Ig bound to two of five T cell lines tested, HPB-ALL and Jurkat. The binding to HPB-ALL cells significantly increased when they were grown at a low pH (pH 6.5), whereas binding to Jurkat cells increased after apoptosis was induced with anti-Fas mAb. B cell and monocytic lines did not bind CD83Ig and neither did CD56(+) NK cells or granulocytes. Full-length CD83 expressed by a transfected carcinoma line mediated CD83-dependent adhesion to HPB-ALL cells. CD83Ig immunoprecipitated and immunoblotted a 72-kDa protein from HPB-ALL cells. Binding of CD83Ig to HPB-ALL cells was eliminated by neuraminidase treatment of the cells. We conclude that CD83 is an adhesion receptor with a counterreceptor expressed on monocytes and a subset of activated or stressed T lymphocytes, and that interaction between CD83 and its counterreceptor is dependent upon the state of glycosylation of a 72-kDa counterreceptor by sialic acid residues. In view of the selectivity of the expression of CD83 and its ligand, we postulate that the interaction between the two plays an important role in the induction and regulation of immune responses.

Balance function and fall-related efficacy in patients with newly operated hip fracture.

OBJECTIVE: To investigate the relation between fall-related efficacy in daily-life activities and functional as well as instrumental tests of balance in patients with hip fracture. DESIGN: Analysis of different aspects of balance using the Falls Efficacy Scale, Swedish version FES(S), questions on fear of falling, Functional Reach (FR) and tests on a balance platform (Chattanooga). SUBJECTS: Fifty-five elderly inpatients (mean age 82.3) with newly operated hip fracture who were assessed during the last week in hospital before discharge. RESULTS: The results showed a significant relationship between the subjective ability measured with the FES(S) and the objectively measured balance in the Functional Reach test and also between fall-related efficacy measured with FES(S) and fear of falling. Very few significant correlations were found between the results from balance tests on the force platform and those obtained with FES(S) and FR. CONCLUSIONS: Both the Falls Efficacy Scale, Swedish version, and the Functional Reach have been shown to be useful in analysing balance function in elderly patients newly operated on for hip fracture. The Falls Efficacy Scale also indicates which of the daily activities the patient perceives as troublesome and thus require further training.

The treatment of social phobia in general practice. is exposure therapy feasible?

BACKGROUND: Exposure therapy is an effective treatment for generalized social phobia. Most patients with social phobia are treated in primary care, but family doctors are not usually trained to perform exposure therapy. We have conducted a study in primary care of the effect of exposure therapy alone or in combination with sertraline on generalized social phobia. OBJECTIVES: The purpose of this article is to describe the training of GPs and the application of the treatment programme in general practice. METHOD: Forty-five GPs were trained for approximately 30 h in assessing patients with social phobia and conducting exposure therapy. The training programme included scoring of videotaped interviews of five patients on several social phobia scales, and a videotape demonstrating different steps of an exposure therapy was used as a model for role play in group training. RESULTS: All of the GPs completed the training programme. The doctors expressed satisfaction with the programme and also found it useful in the treatment of patients with conditions other than social phobia. There was a significant difference in response between the treatment groups (P = 0.001), and the combination of exposure therapy and sertraline seemed to be particularly beneficial.

Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model.

OBJECTIVE: To evaluate dose intensification with osmotic blood-brain barrier disruption (BBBD) and the potential use of drug targeting with monoclonal antibody (MAb) BR96 conjugated to doxorubicin (BR96-DOX, now called SGN15) for treatment of intracerebral and subcutaneous human LX-1 small cell lung carcinoma xenografts in rats. METHODS: LX-1 tumors with high, low, or heterogeneous levels of the Lewis(y) antigen for BR96 were evaluated. Rats were treated with intracarotid or intravenous BR96-DOX, with or without osmotic BBBD. RESULTS: Both BR96-DOX and MAb BR96 treatment resulted in significant regression of subcutaneous tumors, in contrast to control groups including doxorubicin alone, saline, or nonbinding doxorubicin immunoconjugate. BR96-DOX delivered with BBBD to brain tumors with low antigen expression resulted in significantly (P < 0.001) increased rat survival time compared with animals that received intravenous or intra-arterial BR96-DOX. CONCLUSION: The combination of an effective drug such as doxorubicin with a MAb to facilitate tumor-selective localization and osmotic BBBD to increase tumor delivery may have practical application in the clinic, because an increased delivery of drug to tumor can be obtained without increasing the dose of systemic drug.

Enhanced antitumor activity of paclitaxel in combination with the anticarcinoma immunoconjugate BR96-doxorubicin.

The efficacy of chemotherapy has been improved by regimens that combine several cytotoxic drugs with different mechanisms of action and/or different dose-limiting toxicities. Here we demonstrate clearly, and for the first time, that combined therapy using an anticarcinoma immunoconjugate, BR96-doxorubicin, and the cytotoxic drug paclitaxel results in a significant increase in antitumor activity over that of either agent alone. Synergistic activity was seen at doses of BR96-doxorubicin that were minimally active as single agents. A dramatic increase in regression rates was seen when a regimen that combined BR96-doxorubicin and paclitaxel was used to treat both paclitaxel-sensitive and paclitaxel-insensitive carcinomas. Importantly, combined therapy resulted in increased antitumor activity against lung, colon, and breast tumors xenografted in athymic mice and large, paclitaxel-insensitive colon tumors xenografted in athymic rats that also express the Lewis(y) target antigen in normal tissues.

Fear of falling in patients with stroke: a reliability study.

OBJECTIVE: To examine the scaling properties and test-retest reliability of an expanded version of the Falls Efficacy Scale (FES) and to compare group differences in the scores. The expanded version focuses on more basic, primary activities of daily living (ADL), which makes the scale more suitable for subjects with moderate to low functional ability, e.g. patients with stroke. DESIGN: A test-retest reliability study with one group convenience sample. SETTING: Two day-care units: a rehabilitation unit and a geriatric rehabilitation unit. SUBJECTS: A volunteer sample of 30 patients (mean age 65 years, SD 11 years) who had sustained stroke between 5 and 84 months prior to the investigation. MAIN OUTCOME MEASURE: A 13-activity questionnaire (the Swedish modification of the Falls Efficacy Scale (FES(S)) comprising the 10 activities of the original FES and three additional activities was used. Falls efficacy was rated on a 10-point visual analogue scale for each activity on two occasions, 5-22 (mean 10, Md 7) days apart. RESULTS: The overall test-retest reliability of the FES(S) was high (intraclass correlation coefficient (ICC) = 0.97). The ICC for the personal ADL (items 1-6) scores was 0.93 and for the instrumental ADL (items 8-13) 0.97. ICC for the individual items ranged from 0.76 to 0.97. CONCLUSIONS: On the basis of these preliminary findings, the FES(S) appears to have acceptable test-retest reliability. The test may be a reasonable addition for assessing stroke patients with balance disturbances and risk for falls.

Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma.

mAb OV569 was made by immunizing mice with ovarian carcinoma cells. It binds to cells from ovarian carcinomas and, to a lesser extent, to cells from certain other carcinomas whereas the binding to normal tissues is low to nondetectable. It also binds to soluble molecule(s) in culture supernatants from antigen-positive carcinomas. OV569 recognizes a protein(s) of 42-45 kDa with the same N-terminal amino acid sequence as the membrane-bound portion of mesothelin and megakaryocyte potentiating factor (MPF). Binding assays with fusion proteins comprising either the N-terminal part of mesothelin/MPF (D1Ig), reported to be easily cleaved off, or a noncleavable, membrane-associated part (D2Ig) showed that OV569 only binds to D2hIg. A new member of the mesothelin/MPF family was discovered, which has an 82-bp insert in the membrane-associated part, leading to a frameshift of 212 bp, and whose predicted molecular structure indicates that it is soluble. To test patient sera for soluble tumor antigen, antigen was isolated from cell-free tumor culture supernatants via immunoadsorption with OV569 and used to generate murine mAbs to an epitope different from the one to which OV569 binds, after which mAbs to two different epitopes were used to develop a "sandwich ELISA." Using this assay, the level of circulating antigen was elevated significantly in 23 of 30 sera from patients with ovarian carcinoma, as compared with 0 of 68 sera from healthy controls, 0 of 3 sera from patients with nonneoplastic diseases, and 25 of 75 sera from patients with other tumors. Soluble molecules of the mesothelin/MPF family may provide useful new marker(s) for diagnosis of ovarian carcinoma and/or monitoring its response to therapy.

Evaluation of refractory epilepsy treated with vagus nerve stimulation for up to 5 years.

We assessed the long-term efficacy of vagus nerve stimulation (VNS) in 64 refractory epilepsy patients. After implantation, intermittent stimulation was delivered and seizure frequency and severity were counted. Average treatment time was 20 months. Nineteen of 47 patients with partial seizures, five of nine patients with idiopathic generalized seizures, and five of eight patients with Lennox-Gastaut syndrome had >50% seizure reduction. Side effects were mild. VNS is a safe and effective treatment for refractory epilepsy.

Monoclonal antibody conjugates of doxorubicin prepared with branched linkers: A novel method for increasing the potency of doxorubicin immunoconjugates.

Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series of branched hydrazone linkers. Since each linker bound to the mAb carries two DOX molecules, the DOX/mAb molar ratios of these conjugates were approximately 16, twice that of those previously prepared with single-chain hydrazone linkers. The conjugates were stable at a physiological pH of 7, but released DOX rapidly at lysosomal pH 5. The branched series of BR96 conjugates demonstrated antigen-specific cytotoxicity, and were more potent in vitro than the single-chain conjugate on both a DOX (4-14-fold) and mAb (7-23-fold) basis. The results suggest that, by using the branched linker methodology, it is possible to significantly reduce the amount of mAb required to achieve antigen-specific cytotoxic activity. In this paper, the synthesis and in vitro biology of branched chain immunoconjugates are described.