Anti-HIV type 1 activity of 3'-fluoro-3'-deoxythymidine for several different multidrug-resistant mutants.

The objective of this work was to test the antiviral activity of a potent nucleoside reverse transcriptase inhibitor, 3'-fluoro-3'-deoxythymidine (FLT), on both a wild-type human immunodeficiency virus (HIV-1) isolate and multidrug-resistant HIV-1 patient isolates. Drug-resistant viral isolates were selected on the basis of four different categories of well-characterized and representative multidrug-resistant mutants. The isolates included three variants containing 151M alone or in combination; three variants containing 215Y and 41L, 67N, 184V, 210W, and 219N in combination; two insertion mutant viruses (69 + EA and 69 + SA); and two deletion mutant viruses (del67NG and del67GS), the latter two groups both also containing other significant mutations. The activity of FLT and AZT against these isolates was determined by drug susceptibility assays and by measuring viral antigen p24 by ELISA. The cytotoxicity of FLT and AZT was assessed in PHA-stimulated PBMCs. Development of resistant mutants under FLT pressure was attempted by passaging HIV-1 isolates in SupT1 cells and stepwise increasing the concentration of FLT. The multidrug-resistant mutant HIV-1 isolates exhibited 7-fold to >100-fold increased resistance to AZT, but showed IC(50) values for FLT of 0.0014-0.0168 microM, which were lower than or similar to that of wild type (0.0075 microM). The cellular cytotoxicities of FLT and AZT fell into a similar range in PBMCs. The development of HIV mutants resistant to FLT appeared to be slower than for other RT inhibitors. HIV isolates with mutations resulting in multidrug resistance had no evidence of resistance to FLT. FLT may be useful in salvage therapies for patients harboring resistant strains and a reassessment of its therapeutic potential seems required.

A critical analysis of randomised clinical trials on neck pain and treatment efficacy. A review of the literature.

The efficacy of physiotherapy or chiropractic treatment for patients with neck pain was analysed by reviewing 27 randomised clinical trials published 196-1995. Three different methods were employed: systematic analyses of; methodological quality; comparison of effect size; analysis of inclusion criteria, intervention and outcome according to The Disablement Process model. The quality of most of the studies was low; only one-third scored 50 or more of a possible 100 points. Positive outcomes were noted for 18 of the investigations, and the methodological quality was high in studies using electromagnetic therapy, manipulation, or active physiotherapy. High methodological quality was also noted in studies with traction and acupuncture, however, the interventions had either no effect or a negative effect on outcome. Pooling data and calculation of effect size showed that treatments used in the studies were effective for pain, range of motion, and activities of daily living. Inclusion criteria, intervention, and outcome were based on impairment in most of the analysed investigations. Broader outcome assessments probably would have revealed relationships between treatment effect and impairment, functional limitation and disability.

One-year follow-up comparison of the cost and effectiveness of chiropractic and physiotherapy as primary management for back pain. Subgroup analysis, recurrence, and additional health care utilization.

STUDY DESIGN: A randomized trial was conducted in which patients with back and neck pain, visiting a general practitioner, were allocated to chiropractic or physiotherapy. OBJECTIVES: To compare outcome and costs of chiropractic and physiotherapy as primary treatment for patients with back and neck pain, with special reference to subgroups, recurrence rate, and additional health care use at follow-up evaluation 12 months after treatment. SUMMARY OF BACKGROUND DATA: Earlier studies on the effect of spinal manipulation have shown inconsistent results. Mostly they include only short-term follow-up periods, and few cost-effectiveness analyses have been made. METHODS: A group of 323 patients aged 18-60 years who had no contraindications to manipulation and who had not been treated within the previous month were included. Outcome measures were changes in Oswestry scores, pain intensity, and general health; recurrence rate; and direct and indirect costs. RESULTS: No differences were detected in health improvement, costs, or recurrence rate between the two groups. According to Oswestry score, chiropractic was more favorable for patients with a current pain episode of less than 1 week (5%) and physiotherapy for patients with a current pain episode of greater than 1 month (6.8%). Nearly 60% of the patients reported two or more recurrences. More patients in the chiropractic group (59%) than in the physiotherapy group (41%) sought additional health care. Costs varied considerably among individuals and subgroups; the direct costs were lower for physiotherapy in a few subgroups. CONCLUSIONS: Effectiveness and costs of chiropractic or physiotherapy as primary treatment were similar for the total population, but some differences were seen according to subgroups. Back problems often recurred, and additional health care was common. Implications of the result are that treatment policy and clinical decision models must consider subgroups and that the problem often is recurrent. Models must be implemented and tested.

Cost and effectiveness analysis of chiropractic and physiotherapy treatment for low back and neck pain. Six-month follow-up.

STUDY DESIGN: A randomized, clinical trial was conducted in which patients with back/neck problems, visiting a general practitioner, were allocated to chiropractic or physiotherapy as primary management. OBJECTIVES: To compare outcome and costs of chiropractic and physiotherapy in managing patients with low back or neck pain. SUMMARY OF BACKGROUND DATA: Earlier studies on the treatment of back pain by spinal manipulation have shown inconsistent results. When a "new" strategy--chiropractic--in the treatment of back pain was introduced in public health care in Sweden, there was a need to compare the effects and costs of chiropractic with the established physiotherapy. METHODS: Three hundred twenty-three patients aged 18 to 60 years who had no contraindications to manipulation and who had not been treated within the previous month were included in the study. Treatment was carried out at the discretion of the therapist. Outcome measures were primarily changes in pain intensity and general health, both assessed with visual analog scale and Oswestry pain disability questionnaire. Direct and indirect costs were measured. RESULTS: For patients with low back or neck pain visiting the general practitioner in primary care, both chiropractic and physiotherapy as primary treatment reduced the symptoms. No difference in outcome or direct or indirect costs between the two groups could be seen, nor in subgroups defined as duration, history, or severity. CONCLUSIONS: The effectiveness and total costs of chiropractic or physiotherapy as primary treatment were similar to reach the same result after treatment and after 6 months.

Pelvic floor exercises for children: a method of treating dysfunctional voiding.

OBJECTIVE: To evaluate the clinical effect of a pelvic floor exercise programme developed for children. PATIENTS AND METHODS: Sixteen girls with non-neurogenic dysfunctional voiding were treated by a physiotherapist, mostly in small groups. The exercises were designed to increase the child's awareness of their pelvic floor musculature and to teach them how to contract and relax these muscles at will. The emphasis on pelvic floor relaxation served to improve the child's voiding pattern. RESULTS: After 1 year, nine girls were cured and seven improved. Another three girls were cured at the 3-4 year follow-up, giving a total cure rate of 12/16. CONCLUSION: This non-invasive method seems to be a useful alternative or complement to other treatments of children with dysfunctional voiding.

Prevention of HIV-2 and SIV infections in cynomolgus macaques by prophylactic treatment with 3'-fluorothymidine.

The aim of this study was to determine the usefulness of human immunodeficiency virus type 2 (HIV-2) for in vivo evaluation of antiviral drugs in monkeys and to study if prophylactic treatment with 3'-fluorothymidine (FLT) could prevent infection against a low challenge dose of HIV-2 or simian immunodeficiency virus (SIV). Protection against infection was assessed by virus isolation and polymerase chain reaction (PCR) on monkey peripheral blood mononuclear cells (PBMC) as well as by antibody and viral antigen assays. Prophylactic treatment with FLT 3 x 5 mg/kg/day, starting 8 h prior to virus inoculation, prevented HIV-2 infection in 3 of 8 monkeys. In another experiment 2 of 4 monkeys resisted 2-10 monkey infectious doses (MID50) of SIV with the same prophylactic treatment. All control animals (HIV-2 n = 8, SIV n = 4) became infected. Thus, FLT treatment prevented HIV-2 and SIV infection in 5 of 12 animals.

Antiviral effects of 3'-fluorothymidine and 3'-azidothymidine in cynomolgus monkeys infected with simian immunodeficiency virus.

An acute infection with simian immunodeficiency virus (SIVSM) in cynomolgus monkeys was used to evaluate the antiviral effects of 3'-fluorothymidine (FLT) and 3'-azidothymidine [zidovudine (ZDV)]. Neither compound prevented the infection despite dosing prior to virus inoculation. FLT was about ten times more potent than ZDV in delaying the appearance of SIVSM antigen in the monkeys. The serum half-life of FLT was longer than that of ZDV and ZDV was bound to plasma proteins to about 60% while FLT was virtually unbound. It is proposed that the in vivo difference in potency between ZDV and FLT could, at least partly, be explained as the combined effects of a longer plasma half-life and a higher free concentration of FLT and possibly a higher intracellular concentration of the triphosphate of FLT.

Influence of twenty potentially antiviral substances on in vitro multiplication of hepatitis A virus.

A multiwell tissue culture system was developed to study the influence of various substances on hepatitis A virus (HAV) propagation. A panel of 20 substances of different structure types, each with known effect against at least some viruses, was studied at a concentration of 100 microM. Three substances showed reproducible inhibition. The strongest inhibitor, arabinosylcytosine, also produced cytotoxic changes in cells down to a concentration of 1 microM, and its effect was considered as nonspecific. Amantadine and ribavirin showed a moderate effect at 100 microM. A stronger inhibition was seen at 250 and 500 microM, doses that are toxic and impractical for clinical use. Although no promising candidates for antiviral treatment of hepatitis A have emerged from the present study, the assay model described here would seem useful in the screening of substances with inhibitory effects on HAV.

Effects of warming up, massage, and stretching on range of motion and muscle strength in the lower extremity.

The effects of general warming up, massage, and stretching on ranges of motion (ROM) and strength of quadriceps and hamstring muscles were measured in eight male volunteers. Thigh muscle strength was not influenced by the experimental procedures. Stretching resulted in a significantly increased range of hip flexion/extension, hip abduction, knee flexion, and ankle dorsiflexion; the effect was significantly greater than that obtained by massage and warming up separately or combined. Only ankle dorsiflexion was influenced by massage or warming up, whereas stretching affected all muscle groups tested. Stretching was, therefore, superior to the other methods tested for increasing flexibility in the lower extremity.

Interaction between the hypothalamic defence reaction and cardiac ventricular receptor reflexes.

The interference with regard to the cardiovascular and gastric motility responses which follows stimulation of the hypothalamic defence area (D.A.) and a simultaneous afferent input from cardiac ventricular receptors was analysed in chloralose-anesthetized cats. In spinalized animals with only the vagal efferent innervation of autonomic effectors from supraspinal structures intact, a D.A. stimulation increased the heart rate to the same level irrespective whether the cardiac receptor afferents were stimulated or not. This suggests that the vagal component of the reflex bradycardia of cardiac receptor origin was completely suppressed by the D.A. stimulation. The reflex gastric relaxation to cardiac receptor activation, mediated via vagal efferent non-adrenergic fibres, was similarly completely blocked by D.A. stimulation. In contrast, the reflex inhibition of the sympathetic outflow to the heart and vessels from cardiac receptors was still effective during a D.A. stimulation, a phenomenon which seems compatible with a simple summation of excitatory D.A. and inhibitory cardiac receptor influences on the sympathetic neurons. The modifying influence from ventricular receptors on D.A. responses closely resembles that exerted by the arterial baroreceptors. The two reflex mechanisms thus work in concert and synergistically with the hypothalamic influences to produce maximal cardiac output and skeletal muscle perfusion without undue increases of pressure load on the pump during a defence reaction.

Identification of the in vitro translation products of adenovirus mRNA by immunoprecipitation.

Adenovirus type 2 mRNA was translated in S30 extracts from Ehrlich ascites and wheat embryo cells. The in vitro products were identified by sodium dodecyl sulfate-gel electrophoresis after immunoprecipitation with specific antisera in the presence of urea. Seven virion polypeptides could be identified by immunoprecipitation. Three of these appear to be precursors to polypeptides of the virion. mRNA isolated late in adenovirus infection was separated into three size classes by zonal sedimentation. Material sedimenting at 26S was translated into polypeptides corresponding to the largest virion polypeptides II to IV, a 22S fraction corresponding to polypeptide V, and smaller polypeptides and a 15S fraction corresponding to polypeptide IX. A significant amount of polypeptide IX was also synthesized by the 26S and 22S RNA.