Spinal manipulation for low-back pain.

PURPOSE: To review the use, complications, and efficacy of spinal manipulation as a treatment for low-back pain. DATA IDENTIFICATION: Articles were identified through a MEDLINE search, review of articles' bibliographies, and advice from expert orthopedists and chiropractors. STUDY SELECTION: All studies reporting use and complications of spinal manipulation and all controlled trials of the efficacy of spinal manipulation were analyzed. Fifty-eight articles, including 25 controlled trials, were retrieved. DATA ANALYSIS: Data on the use and complications of spinal manipulation were summarized. Controlled trials of efficacy were critically appraised for study quality. Data from nine studies were combined using the confidence profile method of meta-analysis to estimate the effect of spinal manipulation on patients' pain and functional outcomes. RESULTS OF DATA SYNTHESIS: Chiropractors provide most of the manipulative therapy used in the United States for patients with low-back pain. Serious complications of lumbar manipulation, including paraplegia and death, have been reported. Although the occurrence rate of these complications is unknown, it is probably low. For patients with uncomplicated, acute low-back pain, the difference in probability of recovery at 3 weeks favoring treatment with spinal manipulation is 0.17 (for example, increase in recovery from 50% to 67%; 95% probability limits of estimate, 0.07 to 0.28). For patients with low-back pain and sciatic nerve irritation, the difference in probabilities of recovery at 4 weeks is 0.098 (probability limits, -0.016 to 0.209). CONCLUSIONS: Spinal manipulation is of short-term benefit in some patients, particularly those with uncomplicated, acute low-back pain. Data are insufficient concerning the efficacy of spinal manipulation for chronic low-back pain.     

Interleukin-1 is both morphogenic and cytotoxic to cultured rat ovarian cells: obligatory role for heterologous, contact-independent cell-cell interaction.

An increasing body of information now suggests that intraovarian interleukin-1 (IL-1) may play an intermediary role in the ovulatory process. Given that follicular rupture inevitably requires marked tissue remodeling and possibly cell death, we set out to examine the morphogenic potential of IL-1 under in vitro circumstances. Treatment of freshly plated whole ovarian dispersates from immature rats with any one of several batches of IL-1 (10 ng/ml) for up to 96 h produced marked time-dependent morphological alterations, including cellular retraction, rounding, clumping, aggregation, blebbing, swelling, and, ultimately, irreversible detachment. Evidence of (asynchronous) cell death consisted of reduced total cell number, diminished cellular protein content, enhanced cellular release of lactic dehydrogenase, failure to exclude trypan blue, and attenuated reduction of the tetrazolium dye 3-[4,5-dimethylthiazol-2-y]2,5-diphenyltetrazolium bromide to spectrophotometrically detectable formazan. Comparable results were obtained when using established day 4 cultures, arguing against a possible critical action of IL-1 at the time of plating. Dose-response curves revealed IL-1 beta (EC50, 0.2-0.4 ng/ml) to be substantially more potent than IL-1 alpha (EC50, 2.7-2.8 ng/ml). Importantly, the concurrent provision of an IL-1 beta-directed polyclonal antibody yielded complete immunoneutralization of the IL-1 beta effect, arguing against the possible involvement of a non-IL-1 contaminant. An unrelated polyclonal antiserum raised against insulin-like growth factor-I was without effect. IL-1 action proved relatively specific, in that tumor necrosis factor-alpha (10 ng/ml), a putative cytotoxic principle, as well as IL-1-inducible ILs (IL-2 and -6; 100 U/ml) were without effect. Although minimally effective at the level of the isolated granulosa or theca-interstitial cell, IL-1 proved highly potent in heterologous (but not homologous), contact-dependent and independent cocultures of these somatic cell types, strongly suggesting obligatory cell-cell cooperation. These observations further indicate that IL-1 action is indirect and may require the induction of an intermediary soluble principle to serve as the final effector. Taken together, these findings indicate that relatively low concentrations of IL-1 (beta > alpha), possible of somatic ovarian cell or resident ovarian macrophage origin, are capable of exerting specific dose- and time-dependent (immunoneutralizable) morphogenic as well as cytotoxic effects at the level of ovarian cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Bone mineral density varies as a function of the rate of joint space narrowing in the hip

OBJECTIVE: To determine whether patients with a rapid rate of joint space narrowing (JSN) in the hip have higher initial bone mineral density (BMD) in the proximal femur and/or lumbar spine than corresponding patients with a slow rate of JSN. METHODS: Twenty-eight patients undergoing unilateral total hip replacement (THR) for osteoarthritis (OA), but whose contralateral hips were asymptomatic and had minimal or no radiographic OA, were evaluated. The contralateral proximal femur (i.e., non-operated hip) and lumbar spine were scanned by dual energy x-ray absorptiometry at baseline (prior to THR) and at 2 years. The rate of JSN was determined by serial longitudinal quantification of the joint spaces over the 2 year period following THR from conventional radiographs, and the patients were divided into a group with a slow rate of JSN (< or = 0.2 mm/yr, n = 20) and a group with a rapid rate of JSN (> 0.2 mm/yr, n = 8). RESULTS: The baseline BMD z and t scores at the femoral neck, Ward's triangle, and lumbar spine of the patients with subsequent rapid rates of JSN were significantly higher than those of patients with slower rates (p < 0.05). There was no difference between the rapid and slow narrowers at the greater trochanter (p > 0.2). Age, sex, weight, height, body mass index, Kellgren- Lawrence scores, and initial joint space width were not significantly different between the 2 groups. CONCLUSION: Patients with a rapid rate of JSN of the asymptomatic hip after unilateral THR are characterized by elevated local and remote BMD. The local elevation in BMD implies that increased local bone density may contribute to or serve as a marker for increased risk of development of OA (assuming that JSN can be used as a predictive marker). The presence of elevated BMD in the spine suggests that there are systemic as well as local aspects of OA pathogenesis, at least in patients with one THR and rapid JSN in the contralateral hip.     

Age‐dependent differences in morphine‐induced taste aversions

Adolescence is a developmental period of particular importance given the host of neurobiological changes that occur during this stage of development. Drug use and abuse is said to be a function of the balance of its rewarding and aversive effects, and any age‐dependent differences in morphine's aversive effects could impact drug intake. The present experiments examined the ability of morphine sulfate (0, 3.2, 10, and 18 mg/kg) to induce taste aversions in adolescent and adult rats under high (20‐min fluid access each day; Experiment 1A/B) and low (50% of ad libitum access; Experiment 2A/B) deprivation conditions. In both studies, adolescent and adult rats were given a novel saccharin solution to drink and were subsequently injected with morphine. Independent of the deprivation condition, adults acquired stronger aversions than adolescents and did so at a faster rate. On a subsequent two‐bottle aversion test, all morphine‐injected subjects drank a significantly lower percentage of saccharin than vehicle‐injected controls with adults exhibiting stronger aversions than adolescents. These age‐dependent differences in morphine‐induced CTAs extend the findings with other drugs of abuse for which adolescents exhibit weaker aversions. The possible basis for and implications of these differences were discussed. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 415–428, 2013     

Localization of CD4+ T cell epitope hotspots to exposed strands of HIV envelope glycoprotein suggests structural influences on antigen processing

The spectrum of immunogenic epitopes presented by the H2-IA(b) MHC class II molecule to CD4(+) T cells has been defined for two different (clade B and clade D) HIV envelope (gp140) glycoproteins. Hybridoma T cell lines were generated from mice immunized by a sequential prime and boost regime with DNA, recombinant vaccinia viruses, and protein. The epitopes recognized by reactive T cell hybridomas then were characterized with overlapping peptides synthesized to span the entire gp140 sequence. Evidence of clonality also was assessed with antibodies to T cell receptor Valpha and Vbeta chains. A total of 80 unique clonotypes were characterized from six individual mice. Immunogenic peptides were identified within only four regions of the HIV envelope. These epitope hotspots comprised relatively short sequences ( approximately 20-80 aa in length) that were generally bordered by regions of heavy glycosylation. Analysis in the context of the gp120 crystal structure showed a pattern of uniform distribution to exposed, nonhelical strands of the protein. A likely explanation is that the physical location of the peptide within the native protein leads to differential antigen processing and consequent epitope selection.     

The subunits of activator 1 (replication factor C) carry out multiple functions essential for proliferating-cell nuclear antigen-dependent DNA synthesis.

p37 and p40 are two cloned gene products of the five-subunit human cellular DNA replication factor activator 1 (A1) protein complex (also called replication factor C). Here, we describe the solubilization, purification, and characterization of these two proteins that were overproduced in Escherichia coli. Using a nitrocellulose filter binding assay, we demonstrated that the purified A1 p37 protein associated with DNA preferentially at the primer terminus, a property resembling that of the A1 complex. We also show that in the presence of relatively high levels of salt, the recombinant p37 protein alone activated DNA polymerase epsilon but not polymerase delta in catalyzing the elongation of DNA chains. The p40 protein specifically associated with cellular p37 and proliferating-cell nuclear antigen (PCNA) present in HeLa cell cytosolic extract. The addition of purified p40 protein abolished the in vitro polymerase delta-catalyzed DNA elongation reaction dependent on both PCNA and A1. However, this inhibition was reversed by excess polymerase delta, suggesting a specific interaction between the polymerase and the p40 protein. Thus, while p37 binds DNA at the primer end and has a specific affinity for pol epsilon, p40, which binds ATP, interacts with PCNA and pol delta. These activities are essential for the DNA elongation reactions that lead to the synthesis of leading-strand DNA and the maturation of Okazaki fragments.     

Replication of simian virus 40 origin-containing DNA in vitro with purified proteins.

Simian virus 40 (SV40) DNA replication dependent on the SV40 origin of replication and the SV40 large tumor (T) antigen has been reconstituted in vitro with purified protein components isolated from HeLa cells. In addition to SV40 T antigen, these components included the DNA polymerase alpha-primase complex, topoisomerase I, and a fraction that contained a single-stranded DNA binding protein. The latter protein, which sediments at 5.1 S on glycerol gradients and copurifies with two major protein species of 72 and 76 kDa, was isolated solely by its ability to support SV40 DNA replication. The purified system retained the species-specific DNA polymerase alpha-primase requirement previously observed with crude fractions; the complex from HeLa cells supported SV40 replication, whereas that from calf thymus and mouse cells did not. DNA containing the polyomavirus origin of replication was replicated in a system containing polyomavirus T antigen, the HeLa single-stranded DNA binding protein-containing fraction, and DNA polymerase alpha-primase complex from mouse, but not HeLa, cells. While crude fractions yielded closed circular duplex DNA, none was detected with the purified system. Nevertheless, the addition of a crude fraction to the purified system yielded closed circular monomer products.