Effectiveness of intradiscal platelet rich plasma for discogenic low back pain without Modic changes: A randomized controlled trial.

Objective: To determine if autologous platelet-rich plasma (PRP) injection into a degenerative intervertebral disc, without Modic changes on magnetic resonance imaging (MRI), improve pain and function. Design: Prospective, randomized controlled study. Setting: Outpatient spine practice (Stichting Rugpoli, Netherlands). Participants: Adults with chronic low back pain referred to Stichting Rugpoli, according to the Dutch General Practitioners Guidelines, unresponsive to conservative treatment, without Modic changes on MRI. Methods: Provocation discography was performed to confirm the suspected disc was the source of pain. Participants were randomized to receive 1.0 â€‹cc intradiscal PRP (intervention) or 1.0 â€‹cc Saline with 0.2g Kefzol (control). Data on pain (Numeric Rating Scale), physical function (Roland Morris Disabilty Questionnaire, RMDQ), and participants' general perceived health (SF-12) were collected at 1 week, 4 weeks, 2 months, 6 months, 9 months and 1 year. A repeated-measures analysis (mixed model) was used for comparing the outcomes of the groups. Results: Of the initial 98 (49 intervention, 49 control) patients randomized, 89 (91%) (44 intervention, 45 control) with complete outcome data were analyzed. Groups were balanced at baseline. After twelve months no differences between groups were found in the average pain (improved 21/44 in intervention vs 16/45 in control, p â€‹= â€‹0.244), the disability scores (RMDQ minimal 3 points improvement 22/44 in intervention vs 24/45 in control, p â€‹= â€‹0.753) and the SF-12 (mean difference physical health -1.19, 95% CI -5.39 to 2.99, p â€‹= â€‹0.721, and mental health -0.34, 95% CI -3.99 to 3.29, p â€‹= â€‹0.834). One serious adverse event occurred (spondylodiscitis) after intervention. Conclusion: Participants who received intradiscal PRP showed no significant improvement in pain or functionality compared to the control group at 1 year follow up.

Improved GMP-compliant multi-dose production and quality control of 6-[18F]fluoro-L-DOPA.

BACKGROUND: 6-[18F]Fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) is a frequently used radiopharmaceutical for detecting neuroendocrine and brain tumors and for the differential diagnosis of Parkinson's disease. To meet the demand for FDOPA, a high-yield GMP-compliant production method is required. Therefore, this study aimed to improve the FDOPA production and quality control procedures to enable distribution of the radiopharmaceutical over distances.FDOPA was prepared by electrophilic fluorination of the trimethylstannyl precursor with [18F]F2, produced from [18O]2 via the double-shoot approach, leading to FDOPA with higher specific activity as compared to FDOPA which was synthesized, using [18F]F2 produced from 20Ne, leading to FDOPA with a lower specific activity. The quality control of the product was performed using a validated UPLC system and compared with quality control with a conventional HPLC system. Impurities were identified using UPLC-MS. RESULTS: The [18O]2 double-shoot radionuclide production method yielded significantly more [18F]F2 with less carrier F2 than the conventional method starting from 20Ne. After adjustment of radiolabeling parameters substantially higher amounts of FDOPA with higher specific activity could be obtained. Quality control by UPLC was much faster and detected more side-products than HPLC. UPLC-MS showed that the most important side-product was FDOPA-quinone, rather than 6-hydroxydopa as suggested by the European Pharmacopoeia. CONCLUSION: The production and quality control of FDOPA were significantly improved by introducing the [18O]2 double-shoot radionuclide production method, and product analysis by UPLC, respectively. As a result, FDOPA is now routinely available for clinical practice and for distribution over distances.

Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas.

Oncogenic human papillomavirus (HPV) is a causative agent in a subgroup of head and neck carcinomas, particularly tonsillar squamous cell carcinomas (TSCC). This study was undertaken because controversial data exist on the physical status of HPV-DNA and the use of p16(INK4A) overexpression as surrogate HPV marker, and to examine the impact of HPV and tobacco consumption on the clinical course of TSCC. Tissue sections of 81 TSCC were analyzed by HPV 16-specific fluorescence in situ hybridization (FISH) and p16(INK4A)-specific immunohistochemistry. Results were correlated with clinical and demographic data. HPV 16 integration was detected by FISH as punctate signals in 33 out of 81 (41%) TSCC, 32 of which showed p16(INK4A) accumulation. Only 5 out of 48 HPV-negative tumors showed p16(INK4A) immunostaining (p < 0.0001). The presence of HPV furthermore correlates significantly with low tobacco (p = 0.002) and alcohol intake (p = 0.011), poor differentiation grade (p = 0.019), small tumor size (p = 0.024), presence of a local metastasis (p = 0.001) and a decreased (loco)regional recurrence rate (p = 0.039). Statistical analysis revealed that smoking significantly increases the risk of cancer death from TSCC and that non-smoking patients with HPV-containing TSCC show a remarkably better disease-specific survival rate. HPV 16 is integrated in 41% of TSCC and strongly correlates with p16(INK4A) overexpression, implicating the latter to be a reliable HPV biomarker. Patients with HPV-positive tumors show a favorable prognosis as compared to those with HPV-negative tumors, but tobacco use is the strongest prognostic indicator. These findings indicate that oncogenic processes in the tonsils of non-smokers differ from those occurring in smokers, the former being related to HPV 16 infection.

Effects of luminal oxalate or calcium oxalate on renal tubular cells in culture.

Oxalate or calcium oxalate crystal-induced tissue damage could be conducive to renal stone disease. We studied the response of renal proximal (LLC-PK1 and MDCK-II) and collecting (RCCD1 and MDCK-I) tubule cell lines to oxalate ions as well as to calcium oxalate monohydrate (COM) crystals. Cells grown on tissue culture plastic or permeable growth substrates were exposed to high (1 mM) and extremely high (5 and 10 mM) oxalate concentrations, or to a relatively large quantity of crystals (146 microg), after which cell morphology, prostaglandin E(2) (PGE(2)) secretion, [(3)H]thymidine incorporation, total cell numbers and various forms of cell death were studied. Morphological alterations, increased PGE(2) secretion, elevated levels of DNA synthesis and necrotic cell death were induced by extremely high, but not by high oxalate. Crystals were rapidly internalized by proximal tubular cells, which stimulated PGE(2) secretion and DNA synthesis and the release of crystal-containing necrotic cells from the monolayer. Crystals did not bind to, were not taken up by, and did not cause marked responses in collecting tubule cells. These results show that free oxalate is toxic only at supraphysiological concentrations and that calcium oxalate is toxic only to renal tubular cells that usually do not encounter crystals. Based on these results, it is unlikely that oxalate anions or calcium oxalate crystals are responsible for the tissue damage that may precede renal stone formation.

Long-term follow-up of manipulative treatment in a horse with back problems.

In order to objectively quantify the effect of manipulation on back-related locomotion anomalies in the horse, a recently developed kinematic measuring technique for the objective quantification of thoracolumbar motion in the horse was applied in a dressage horse that was suffering from a back problem. In this horse, clinically, a right-convex bending (scoliosis) from the 10th thoracic vertebra to the second lumbar vertebra was diagnosed. As a result, there was a marked asymmetric movement of the thoracolumbar spine. Functionally, there was severe loss of performance. Thoracolumbar motion was measured in terms of ventrodorsal flexion, lateral flexion, and axial rotation using an automated gait analysis system. Measurements were repeated before and 2 days after treatment, before the second treatment 3 weeks later, and at 4 weeks and 8 months after the second treatment to assess long-term effect. At the same time, performance of the horse was assessed subjectively by the trainer as well. Symmetry of movement improved dramatically after the first treatment. After this, there was a slight decrease in symmetry, but 8 months after the last treatment the symmetry indexes for the various joints were still considerably better than during the first (pre-treatment) measuring session. Subjectively, the trainer did not notice improvement until after measurement session 4. Between sessions 4 and 5 (at 4 weeks and 8 months after the second treatment) there was a change of trainer. The new trainer did not report any back problem, and succeeded in bringing the horse back to its former level in competition. It is concluded that manipulation had a measurable influence on the kinematics of the thoracolumbar spine. However, it is recognized that an improvement in symmetry of motion is not equivalent to clinical improvement and that other measures, such as changes in management, may be more decisive.

Changing concepts in the aetiology of renal stones.

In the past two decades an increasing number of nephrolithiasis-related urinary proteins have been identified. This paper focuses on two of them, namely prothrombin fragment 1 and bikunin, members of the prothrombin and inter-alpha-trypsin inhibitor families of proteins, respectively. Besides their role as inhibitors of crystallization, these proteins are also involved in inflammation-mediated tissue repair. This is the basis for the concept that the response of renal tissue to injury might play an important role in the aetiology of kidney stones.

The effect of a patient charge and a prescription regulation on the use of antihypertension drugs in Limburg, The Netherlands.

On 1 February 1983 a patient charge was introduced for prescription drugs for persons insured under the Dutch Sickness Funds Insurance Act. The charge consisted of a co-payment of NLG 2.50 per prescription item up to a maximum of NLG 125 for each family per calendar year. In the period before the introduction of the charge a prescription regulation was in force. For the majority of drugs this rule directed that each prescription item should be for a dosage of not more than 30 days. The prescription regulation was officially introduced on 1 January 1981 and ceased with the introduction of the charge. The effect of both measures on the use of antihypertension drugs in Limburg was investigated in an interrupted time-series analysis. Both the prescription regulation and the charge appeared to have an effect on the number of prescription items per insurant and the number of units delivered per prescription item. However, neither measure resulted in a reduction in the number of units delivered per insurant or the number of 'defined daily doses' (DDDs) per insurant. These findings suggest that neither measure resulted in a decrease in the inappropriate or appropriate use of antihypertension drugs.

Enantioselective structure-pharmacokinetic relationships of ring substituted warfarin analogues in the rat.

The enantiomer specific pharmacokinetics of ring substituted warfarin analogues have been studied in the rat after the administration of 2 mg kg-1 of the racemates. The stereoselective differences observed were due to stereoselective plasma protein binding and stereoselective intrinsic hepatic clearance. Greater binding was observed for the S-enantiomers except for 2'-substituted analogues where the R-enantiomers were more tightly bound. The stereoselectivity in the binding ranged up to a factor of about 4. All substituted warfarins showed a higher intrinsic clearance than warfarin. Enantiomer selectivity depended on the position of the substituent; warfarin and 3'-substituted analogues showed R greater than S; 4'- and 2' substituted warfarins showed S greater than R stereoselectivity. Exceptions to this generality were seen for 4'- methoxy- and 4'-methylwarfarin which did not show stereoselective hepatic clearance.