Cost-effectiveness of manual therapy versus physiotherapy in patients with sub-acute and chronic neck pain: a randomised controlled trial.

PURPOSE: To evaluate the cost-effectiveness of manual therapy according to the Utrecht School (MTU) in comparison with physiotherapy (PT) in sub-acute and chronic non-specific neck pain patients from a societal perspective. METHODS: An economic evaluation was conducted alongside a 52-week randomized controlled trial, in which 90 patients were randomized to the MTU group and 91 to the PT group. Clinical outcomes included perceived recovery (yes/no), functional status (continuous and yes/no), and quality-adjusted life-years (QALYs). Costs were measured from a societal perspective using self-reported questionnaires. Missing data were imputed using multiple imputation. To estimate statistical uncertainty, bootstrapping techniques were used. RESULTS: After 52 weeks, there were no significant between-group differences in clinical outcomes. During follow-up, intervention costs (ß:€-32; 95 %CI: -54 to -10) and healthcare costs (ß:€-126; 95 %CI: -235 to -32) were significantly lower in the MTU group than in the PT group, whereas unpaid productivity costs were significantly higher (ß:€186; 95 %CI:19-557). Societal costs did not significantly differ between groups (ß:€-96; 95 %CI:-1975-2022). For QALYs and functional status (yes/no), the maximum probability of MTU being cost-effective in comparison with PT was low (≤0.54). For perceived recovery (yes/no) and functional status (continuous), a large amount of money must be paid per additional unit of effect to reach a reasonable probability of cost-effectiveness. CONCLUSIONS: From a societal perspective, MTU was not cost-effective in comparison with PT in patients with sub-acute and chronic non-specific neck pain for perceived recovery, functional status, and QALYs. As no clear total societal cost and effect differences were found between MTU and PT, the decision about what intervention to administer, reimburse, and/or implement can be based on the preferences of the patient and the decision-maker at hand. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00713843.

Speech pathology interventions in patients with neuromuscular diseases: a systematic review.

PURPOSE: A systematic review was conducted to summarize and evaluate the literature on the effectiveness of speech pathology interventions in adults with neuromuscular diseases. METHOD: Databases searched included the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, EMBASE, PsycINFO and PubMed. A total of 1,772 articles were independently screened on title and abstract by 2 reviewers. RESULTS: No randomized controlled trials or clinical controlled trials were found. Four other designs were included. Only one study on oculopharyngeal muscle dystrophy (OPMD) appeared to have sufficient methodological quality. There is evidence indicating that correction of head position in patients with OPMD improves swallowing efficiency (level III evidence). CONCLUSION: Despite 1,772 studies, there is only evidence of level III regarding the effectiveness of speech pathology interventions in patients with OPMD. Recommendations for future research are given.

Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors.

Indibulin (ZIO-301/D-24851) is an orally applied small molecule with antitumor activity based upon destabilization of microtubule polymerization. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) as well as the dose limiting toxicity (DLT), the pharmacokinetics, safety and tolerability of orally administered indibulin as capsule formulation in patients with advanced solid tumors. Patients received a single dose of indibulin. Seven dose-levels were evaluated: 100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part). A total of 28 patients entered the study. Indibulin administered as capsules was generally well tolerated. The MTD was not reached. There was a disproportionate increase of the area under the plasma concentration-time curve (AUC) with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. There was no significant difference in AUC of indibulin after multiple dosing (day 1-14) compared to single administration (day-4). Inter-patient variability in AUC (102% CV) was high. A plateau in drug exposure was observed prior to reaching the MTD. Continued dose-escalation was unlikely to yield any increase in exposure of indibulin. The formulation needs optimization to increase the systemic exposure upon oral administration.

Optimizing referral of patients with neuromuscular disorders to allied health care.

BACKGROUND AND PURPOSE: To report the predictive validity of the perceived limitations in activities and need questionnaire (PLAN-Q), a screening instrument to support neurologists to select patients with neuromuscular disorders (NMD) for referral for a one-off consultation by occupational therapist (OT), physical therapist (PT) and speech therapist (ST). METHODS: In a cross-sectional validation study, 102 patients with various NMD participated. Patients received a one-off consultation by an expert OT, PT and ST and filled out the PLAN-Q. Therapists rated the appropriateness of the one-off consultations based on need, available treatment and patient's motivation. Receiver Operation Characteristic analysis and multivariate logistic regression analysis were used to obtain a PLAN-Q based prediction model for the appropriateness of the one-off consultations. RESULTS: Probability for a one-off OT consultation increased from 64% to 78% (95% CI: 69-85%). Prior test probability for a one-off ST consultation increased from 44% to 61% (95% CI: 48-73%). Prior test probability for one-off PT consultation could not be increased. CONCLUSION: Screening patients with NMD using the PLAN-Q may assist neurologists in selecting the appropriate patients for a one-off consultation by OT and ST. Unlike our expectations the screening did not guide referral for a one-off consultation by PT.

Bioequivalence study of a new oral topotecan formulation, relative to the current topotecan formulation, in patients with advanced solid tumors.

OBJECTIVE: The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients with advanced solid tumors. PATIENTS AND METHODS: This was a multi-center, pharmacological Phase I, multiple-dose, randomized, open-label, cross-over bioequivalence study. In the bioequivalence part, 85 patients were randomized to receive either a 4 mg (4 x 1 mg) dose of the new or current formulation on Days 1 or 8. In the food-effect part, 23 patients received a 4 mg (4 x 1 mg) dose of the new formulation in a fasted and fed state. Total topotecan and topotecan lactone were determined and pharmacokinetic data were analyzed by non-compartmental method. RESULTS: Bioequivalence was demonstrated as the 90% confidence intervals of the ratio of the new to current formulation for both the area under the plasma concentration-time curve (AUC) and the maximal drug concentration (Cmax) for topotecan lactone were contained within the 0.8 - 1.25 boundary. The AUC and Cmax were similar in the fed and fasted state whilst food delayed the tmax for topotecan lactone and total topotecan. Safety data were collected on all subjects enrolled (n = 108) and were consistent with observations from previous studies of oral topotecan. All subjects experienced at least one adverse event, the majority of which were graded as mild to moderate in severity. CONCLUSION: The new oral topotecan formulation demonstrated bioequivalence to the current formulation and demonstrated it can be administered to patients with solid tumors in the fed or fasted state with similar systemic exposure.

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon alpha/beta.

Type I interferon (IFN) is shown to control the reversible quiescence of a primitive human bone marrow mesenchymal stem cell (MSC) subpopulation. A 24 h pre-treatment of Stro1+/GlycoA- or CD45-/GlycoA- subpopulations with a monoclonal antibody (mAb) against the IFNAR1 chain of the human type I IFN receptor (64G12), or with a polyclonal anti-IFNalpha antibody, resulted in a marked increase in the number of very large colonies (CFU-F >3000 cells) obtained in the presence of low, but necessary, concentrations of bFGF. Over a 2-month culture period, this short activation promoted a faster and greater amplification of mesenchymal progenitors for adipocytes and osteoblasts. Activation correlated with inhibition of STAT1 and STAT2 phosphorylation and of STAT1 nuclear translocation. A non-neutralizing anti-IFNAR1 mAb was ineffective. We demonstrate that control and activated MSCs express ST3GAL3, a sialyltransferase necessary to produce the embryonic antigens SSEA-3 and -4. Interestingly, activated MSC progeny expressed SSEA-3 and -4 at a higher level than control cultures, but this was not correlated with a significant expression of other embryonic markers. As MSCs represent an essential tool in tissue regeneration, the use of 64G12, which rapidly recruits a higher number of primitive cells, might increase amplification safety for cell therapy.

Influence of behaviour and risk factors on motor performance in preterm infants at age 2 to 3 years.

The aim of this cross-sectional study was to determine the influence of test-taking behaviour and risk factors for delayed motor performance in 437 preterm infants (244 males, 193 females; < or = 32 weeks of gestation) at the corrected age of 2 to 3 years (mean 29mo [SD 3.3]). Other mean (SD) sample demographics were: postmenstrual age 29(+5) weeks (1(+5)), range 25(+0)-32(+0); birthweight 1213.7g (331.7), range 468-2350; and days in the neonatal intensive care unit 21.1 (21.3), range 1-165. Children (n=23) with a severe disability were excluded. We assessed motor performance and behaviour during testing with the Motor Scale and the Behaviour Rating Scale (BRS) of the Bayley Scales of Infant Development, 2nd edition (BSID-II). Risk factors were tested against delayed motor performance as the dependent variable in binary logistic regression analysis. Median score on the Motor Scale in terms of the BSID-II Psychomotor Developmental Index (PDI) was 86. 'Delayed' motor performance was observed in 46.5% of the children tested, and behaviour was 'not-optimal' in 31.4%. The Motor Scale and BRS scores were significantly correlated (r(s)=0.62, p<0.01). Risk factors for delayed motor performance were: neonatal convulsions (odds ratio [OR] 4.5; 95% confidence interval [CI] 1.6-12.9), low maternal educational level (OR 3.3; 95% CI 1.7-6.5), male sex (OR 2.8; 95% CI 1.8-4.3), and chronic lung disease (OR 2.1; 95% CI 1.1- 4.1). We conclude that preterm infants are at high risk of delayed motor performance and non-optimal test-taking behaviour.

Construct validity of instruments measuring impairments in body structures and function in rheumatic disorders: which constructs are selected for validation? A systematic review.

PURPOSE: This paper focuses on the construct validity of instruments measuring impairments in body structures and function in rheumatic disorders. The objective is: 1) to make an inventory of constructs, based on the domains of the International Classification of Functioning, Disabilities and Health problems (ICF), against which instruments measuring impairments in body structures and function were validated; 2) to analyse whether validation against a similar construct resulted in higher correlation coefficients than validation against a dissimilar construct. METHODS: In a systematic review papers were identified in which instruments measuring impairments in body structures and function for patients with rheumatic disorders were validated. The instruments identified were assessed on their methodological properties and the constructs against which they were validated. Subsequently, pooled (interclass) correlations of similar constructs and dissimilar constructs against which was validated were compared. An instrument was decided to have good construct validity, if the correlation coefficient was 0.50 or higher, and the measurement instrument in question is validated against similar constructs. RESULTS: In total 216 papers were identified analysing the validity of 42 different instruments. Only 16% of these instruments were validated against instruments that represent the most similar construct. In general, estimates of construct validity were lower when validated against dissimilar constructs, except for instruments measuring impairments in mental functions. CONCLUSION: There is a trend that validation against a similar construct yields higher correlation coefficients than validation against a dissimilar construct. If an instrument measuring impairments is validated against the most similar construct, and a criterion of r > 0.50 is applied, only 10 out of the 42 identified instruments turned out to be valid.

New monoclonal antibodies against the putative immunosuppressive site of retroviral p15E.

Both retroviral infections as well as human tumors may cause immunosuppression. One of the factors involved in immunosuppression in patients with squamous cell carcinoma of the head and neck (SCC-HN) is a protein related to the retroviral protein p15E. A conserved, 17-amino acid sequence represents the immunosuppressive epitope of retroviral p15E. In order to study the relationship between SCC-HN associated immunosuppression and retroviral p15E, we produced three new monoclonal antibodies (MAbs; ER-IS1, ER-IS2, and ER-IS5) directed against the immunosuppressive synthetic CKS-17 peptide. These MAbs react with the immunosuppressive peptide (in enzyme-linked immunosorbent assay), with human tumor cell lines (in FACScan analysis), with retroviral p15E (on Western blot), and with cryostat sections of SCC-HN tumor tissue. In addition, the MAbs neutralize the immunosuppressive low molecular weight factors present in sera of patients with SCC-HN. These results show that retroviral p15E and the immunosuppressive factors associated with SCC-HN share a conserved immunosuppressive epitope and that MAbs against this epitope can be used for detection and neutralization of the tumor-associated immunosuppressive protein(s).

Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients.

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

Effect on the process of care of an active strategy to implement clinical guidelines on physiotherapy for low back pain: a cluster randomised controlled trial.

OBJECTIVES: To evaluate the effect on the process of care of an active strategy to implement clinical guidelines on physiotherapy for low back pain. DESIGN: A cluster randomised controlled trial comparing an active strategy with standard dissemination. SETTING: Primary care physiotherapy practices. PARTICIPANTS: 113 physiotherapists were randomly allocated to receive the guidelines by mail (control group) or to receive an additional active strategy (intervention group) which consisted of a multifaceted programme including education, discussion, role playing, feedback, and reminders. MAIN OUTCOME MEASURES: Adherence to the guidelines was measured by means of individual patients' forms recording the treatment completed by the physiotherapist. The forms were assessed using an algorithm based on the number of treatment sessions, treatment goals, interventions, and patient education. RESULTS: Physiotherapists in the intervention group more often correctly limited the number of treatment sessions for patients with a normal course of back pain (OR 2.39; 95% CI 1.12 to 5.12), more often set functional treatment goals (OR 1.99; 95% CI 1.06 to 3.72), more often used mainly active interventions (OR 2.79; 95% CI 1.19 to 6.55), and more often gave adequate patient education (OR 3.59; 95% CI 1.35 to 9.55). They also adhered more to all four criteria (OR 2.05; 95% CI 1.15 to 3.65). CONCLUSIONS: The active strategy moderately improved adherence to the guidelines. Active strategies are recommended to implement the clinical guidelines on physiotherapy for low back pain.

Cell division tracking and expansion of hematopoietic long-term repopulating cells.

The combined use of rigorous assays for quantitating transplantable stem cell numbers and precise cell labeling and tracking procedures have provided definitive evidence that stem cell self-renewal divisions can occur in vitro in the absence of stromal feeder layers. These findings set the stage for defining conditions that may alter the ability of these cells to maintain their primitive status when mitogenically activated.

Stromal cells from murine embryonic aorta-gonad-mesonephros region, liver and gut mesentery expand human umbilical cord blood-derived CAFC(week6) in extended long-term cultures.

The first definitive long-term repopulating hematopoietic stem cells (HSCs) emerge from and undergo rapid expansion in the embryonic aorta-gonad-mesonephros (AGM) region. To investigate the presumptive unique characteristics of the embryonic hematopoietic microenvironment and its surrounding tissues, we have generated stromal clones from subdissected day 10 and day 11 AGMs, embryonic livers (ELs) and gut mesentery. We here examine the ability of 19 of these clones to sustain extended long-term cultures (LTCs) of human CD34(+) umbilical cord blood (UCB) cells in vitro. The presence of in vitro repopulating cells was assessed by sustained production of progenitor cells (extended LTC-CFC) and cobblestone area-forming cells (CAFC). The embryonic stromal clones differed greatly in their support for human HSCs. Out of eight clones tested in the absence of exogenous cytokines, only one (EL-derived) clone was able to provide maintenance of HSCs. Addition of either Tpo or Flt3-L + Tpo improved the long-term support of about 50% of the tested clones. Cultures on four out of 19 clones, ie the EL-derived clone mentioned, two urogenital-ridge (UG)-derived clones and one gastrointestinal (GI)-derived clone, allowed a continuous expansion of primitive CAFC and CFU-GM with over several hundred-fold more CAFC(week6) produced in the 12th week of culture. This expansion was considerably higher than that found with the FBMD-1 cell line, which is appreciated by many investigators for its support of human HSCs, under comparable conditions. This stromal cell panel derived from the embryonic regions may be a powerful tool in dissecting the factors mediating stromal support for maintenance and expansion of HSCs.

Synthetic hexapeptides derived from the transmembrane envelope proteins of retroviruses suppress N-formylpeptide-induced monocyte polarization.

Retroviral infections are frequently associated with immunosuppression. Retroviral transmembrane envelope proteins (TM proteins) play an important role in this phenomenon. CKS-17, a synthetic heptadecapeptide, represents the immunosuppressive site of these retroviral TM proteins. Here we support on the further delineation of this immunosuppressive site using CKS-17-derived hexapeptides. The N-formyl-methionyl-leucyl-phenylalanine-induced monocyte polarization assay was used throughout this study because this monocyte function has been shown to be highly sensitive to TM protein p15E-related immunosuppression. We found that in addition to CKS-17 one CKS-17-derived hexapeptide, LDLLFL, reversibly inhibited monocyte polarization, with 50% inhibitory concentrations of 20 and 2 microM respectively. LDLLFL-mediated inhibition was sequence specific because the reverse peptide LFLLDL and scrambled peptides were not inhibitory. Hexapeptides corresponding to LDLLFL, but derived from various retroviruses other than murine leukemia virus, also inhibited monocyte polarization. Peptides most homologous to LDLLFL-LDILFL (feline leukemia virus) and LDLLFW (human T lymphotropic virus types I and II)--were the most potent inhibitors. Peptides homologous to primate and human endogenous proviruses were not suppressive. LDLLFL and some of its homologous also inhibited polarization of neutrophilic granulocytes. These findings lend further support to the view that conserved retroviral TM protein-related peptides can play an important role in suppression of inflammatory cell function as encountered in retrovirus-associated immunosuppression.

Antibodies to the beta 1-integrin chain, CD44, or ICAM-3 stimulate adhesion of blast colony-forming cells and may inhibit their growth.

Early hematopoietic progenitor cells adhere to bone marrow stromal cells (BMSCs) mainly through VLA-4/VCAM-1 interactions. However, many adhesion molecules are expressed by these cell types. Cell adhesion molecules not only mediate adhesion; some are also capable of triggering cellular signaling events. These signals can be induced by several anti-adhesion molecule antibodies. In this study, we investigated the effects of several of such stimulatory antibodies against alpha L (CD11a), alpha 4 (CD49d), and beta 1 (CD29) integrin chains, ICAM-3 (CD50), CD34, CD44, and CD45. All antibodies reacted strongly with CD34-positive bone marrow (BM) cells, but only those against beta 1 integrin (TS2/16, Lia1/2) or CD44 (NKI-P2) reacted with BMSCs. To test the ability of these antibodies to stimulate adhesive interactions, we analyzed their effect on stroma-adherent blast colony-forming cells (Bl-CFCs). We found that TS2/16 (anti-beta 1 integrin), NKI-P2 (anti-CD44), and 152-2D11 (anti-ICAM-3) enhanced adhesion of BM mononuclear cells to stroma (TS2/16:3.4-fold, NKI-P2: 3.8-fold, 152-2D11: 2.6-fold) when compared with isotype-control-treated cells. The increase in stroma-adherent cells was accompanied by an increase in Day 5-7 blast colonies of 3.8-, 2.6-, and 1.9-fold, respectively. One antibody against CD29:Lia1/2 strongly inhibited the formation of blast colonies, an effect that was at least partially caused by its growth-inhibitory activity. Of the other antibodies tested, none displayed growth-modulatory activity. We have found previously that Bl-CFCs depend strongly on VLA-4 and VCAM-1. However, in TS2/16- or 152-2D11-treated cultures, we observed not only these, but also VLA-5-dependent adhesive interactions. In contrast, VLA-5 did not appear to be involved in NKI-P2-treated cultures. Our data indicate that interactions mediated by beta 1-integrins are involved in the growth of Bl-CFCs. Furthermore, interactions mediated by beta 1-integrins, CD44, and ICAM-3 differentially modulate VLA-4- and VLA-5-dependent progenitor/BMSC interactions.

Constitutive and modulated cytokine expression in two permanent human bone marrow stromal cell lines.

We present a detailed analysis of cytokine expression patterns of the two permanent human bone marrow stromal cell lines, L87/4 and L88/5. These cell lines, previously established in our laboratory, are highly radiotolerant without cell detachment and support long-term cultures of CD(34+)-enriched human cord blood cells. RT-PCR analysis of 22 different cytokines or cytokine receptor mRNAs showed an almost identical expression pattern in the two stromal cell lines compared to primary human Dexter-type stroma. Since stromal feeder lines employed in long-term cultures usually are irradiated and grown in media containing corticosteroids, we analyzed the impact of irradiation and dexamethasone on cytokine production in the two cell lines by RT-PCR, Northern blot analysis, bioassays, and RIAs. By RT-PCR analysis, constitutive mRNA expression of c-kit, G-CSF, GM-CSF, IL-1 beta, IL-6, IL-7, IL-8, IL-11, Kit ligand (KL), LIF, M-CSF, MIP-1 alpha, TGF-beta, and TNF-alpha was demonstrated in both cell lines, with L87/4 a more potent cytokine producer than L88/5. Northern blot data showed an increase in mRNA levels for GM-CSF, IL-1 beta, and LIF by irradiation and IL-1 alpha treatment in both cell lines. IL-1 alpha-induced GM-CSF, IL-1 beta, IL-6, IL-11, and LIF mRNA levels were reduced by the addition of dexamethasone, whereas dexamethasone had no influence on the amounts of IL-1 alpha-induced G-CSF mRNA. L87/4 and, to a lower extent, L88/5 cells showed dexamethasone-dependent increases in KL mRNA, while KL mRNA levels were not stimulated by IL-1 alpha.

Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors.

Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCF(Skp2)) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin-Sca-1+Kit+ (LSK) HSC, and the loss resulted in accumulation of the SCF(Skp2)/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1(-/-) HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr-Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCF(Skp2)/Cks1 complex that controls CKI abundance and cancer cell proliferation.

Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy.

There are no adequate comparative studies on physical therapy (PT) versus occupational therapy (OT) in patients with complex regional pain syndrome I (CRPS I). Therefore, we conducted a prospective randomised clinical trial to assess their effectiveness. The outcomes regarding reducing pain and normalising active range of motion (AROM) are discussed. Included in the study were 135 patients who had been suffering from CRPS I of one upper extremity for less than one year. They were randomly assigned to one of three groups: PT, OT, or control (social work, CT). Measurements were taken at base-line (t0), after 6 weeks, and after 3, 6 and 12 months (t1 to t4). Pain was measured on four visual analogue scales (VAS) and the McGill Pain Questionnaire, Dutch Language Version (MPQ-DLV). The AROM was recorded relative to the contralateral side. Explorative statistical evaluations were performed (Wilcoxon; alpha=0.05). PT and to a lesser extent OT, resulted in more rapid improvement in the VAS scores than CT, especially for the VAS during or after effort (P<0.05 at t1 to t3). PT was superior to CT and OT according to the MPQ-DLV particularly at t4. Improvement on the MPQ-DLV over the year was significantly greater for PT than for OT and CT (P<0.05). PT -and to a lesser degree OT- led to better results than CT for the AROM of the wrist, fingers and thumb at t1 to t3 (most-times P<0.05 for PT), but the improvements over the year were not significantly different. Our results indicated that PT, and to a lesser extent OT, were helpful for reducing pain and improving active mobility in patients with CRPS I of less than one year duration, localised in one upper extremity.

A rapid and simple hapten conjugation method for monoclonal antibodies to be used in immunoenzyme single and double staining procedures.

A rapid and simple method was developed for the haptenization of monoclonal antibodies (MAbs), to be used in immunoenzyme single and double staining techniques. Using this method minute amounts of MAbs can be haptenized without purification of the antibody or removal of the excess hapten. The haptenized MAb can be ready for use with 2.5 h. The method consists of a direct incubation of the antibody with the haptenizing agent and subsequent addition of an amino acid solution to stop the reaction. Commonly available reagents were tested, of which dinitrofluorobenzene, trinitrobenzene sulfonic acid and an oxazolone derivative gave the best results. The procedure was evaluated by using MAbs directed against lymphoid cell surface membrane antigens in an indirect immunoenzyme staining on frozen sections using peroxidase or alkaline phosphatase-conjugated anti-hapten antibodies as second step antibody. It was found that those MAbs, which show good staining results in conventional indirect immunoenzyme procedures, can also be used successfully after haptenization in single as well as double staining procedures. Combination of haptenized and biotynilated MAbs gave good results when weakly reactive MAbs had to be included in immunoenzyme double staining.

Nephrotoxicity and hepatotoxicity of 1,1-dichloro-2,2-difluoroethylene in the rat. Indications for differential mechanisms of bioactivation.

1,1-Dichloro-2,2-difluoroethylene (DCDFE) produced marked nephrotoxicity in rats upon an i.p. dose of 150 mumole/kg. At doses higher than 375 mumole/kg, DCDFE also produced hepatotoxicity. Aminooxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, appeared to be slightly nephrotoxic in Wistar rats. Nevertheless it exerted an inhibitory effect on the nephrotoxicity of DCDFE. The N-acetylcysteine conjugate of DCDFE was identified as a major urinary metabolite of DCDFE. When administered as such, this conjugate appeared to be a potent nephrotoxin, without any effect on the liver, indicating that glutathione conjugation of DCDFE is most likely a bioactivation step for nephrotoxicity. The appearance of traces of chlorodifluoroacetic acid in urine of rats treated with higher doses of DCDFE indicates the existence of an oxidative pathway of metabolism of DCDFE, probably involving epoxidation by hepatic mixed-function oxidases. It is speculated that the latter route might account for the hepatotoxicity at higher doses of DCDFE. The nephro- and hepatotoxicity of DCDFE, therefore, most likely are the result of two different mechanisms of bioactivation.