CHANGES IN LEVELS OF CARTILAGE OLIGOMERIC PROTEINASE AND URINARY C-TERMINAL TELOPEPTIDE OF TYPE II COLLAGEN IN SUBJECTS WITH KNEE OSTEOARTHRITIS AFTER DEXTROSE PROLOTHERAPY: A RANDOMIZED CONTROLLED TRIAL

ObjectiveTo assess the effects of dextrose prolotherapy in patients with knee osteoarthritis on the levels of serum cartilage oligomeric proteinase and urinary C-terminal telopeptide of type II collagen, and on the Western Ontario McMaster Universities Index and numerical rating scale score for pain.MethodsA randomized controlled trial, in which participants were randomly allocated into 2 groups, receiving injections of either hyaluronic acid or dextrose prolotherapy. The hyaluronic acid group received 5 injections, 1 each on weeks 1, 2, 3, 4 and 5, and the dextrose prolotherapy group received 3 injections, 1 each on weeks 1, 5 and 9. Serum cartilage oligomeric proteinase, urinary C-terminal telopeptide of type II collagen, Western Ontario McMaster Universities Index score, and numerical rating scale score for pain were measured at baseline and 3 weeks after the last injection. Comparative analysis was conducted using Wilcoxon test within groups and analysis of covariance (ANCOVA) test between groups.ResultsA total of 47 participants (21 allocated to hyaluronic acid, 26 allocated to dextrose prolotherapy) completed the protocol. Both interventions resulted in significant improvements in numerical rating scale scores for pain, total Western Ontario McMaster Universities Index scores, and its subscales score. However, the dextrose prolotherapy outperformed hyaluronic acid in numerical rating scale score for pain and level of urinary C-terminal telopeptide of type II collagen, with score changes differences of 0.93 (p = 0.042) and 0.34 (p = 0.048), respectively. No significant changes in level of serum cartilage oligomeric proteinase were found in either group.ConclusionDextrose prolotherapy is an alternative injection therapy for knee osteoarthritis, which was found to be associated with a significant reduction in urinary C-terminal telopeptide of type II collagen compared with hyaluronic acid injection. Neither injection method resulted in reduced serum cartilage oligomeric proteinase.LAY ABSTRACTKnee osteoarthritis is a common musculoskeletal disorder, which is one of the most frequent causes of disability in elderly people. To improve patients’ quality of life, prolotherapy has been developed as a non-operative treatment option for osteoarthritis. This study compared the effectiveness of dextrose prolotherapy with that of standard therapy using hyaluronic acid injections. Both interventions were effective in terms of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score improvement and numerical rating scale score changes. Cartilage repair was assessed by measuring levels of specific biomarkers of cartilage breakdown: urinary C-terminal telopeptide of type II collagen (uCTX-II) and serum cartilage oligomeric matrix protein (sCOMP). Dextrose prolotherapy was more effective than hyaluronic acid in reducing these biomarkers and decreasing patients’ pain. Dextrose prolotherapy is therefore recommended for use in patients with knee osteoarthritis, since it gives better results, is cost beneficial, and is suitable for use in low-resource settings. Dextrose prolotherapy may help to repair cartilage in knee OA, as it reduces the uCTX-II level.Key words: knee osteoarthritis, prolotherapy, hyaluronic acid, COMP, uCTX-II, functional outcome

Osteoarthritis (OA) is a highly prevalent musculoskeletal disorder, which is one of the most common causes of disability in elderly people (1–3). Several studies have demonstrated the effectiveness of hyaluronic acid (HA) injections, and recent guidelines have recommended their use in knee OA (4, 5). Xin has shown that intra-articular injection of HA (Adant®, Meiji Seika Pharma Co., Ltd., Tokyo, Japan. Manufactured by microbial fermentation and Artz®, Dispo: Seikagaku Corporation, Tokyo, Japan. Manufactured by the extraction of cockscomb), can significantly reduce both the visual analogue scale (VAS) score for pain and the Lequesne index (6). In contrast to these findings, however, a meta-analysis concluded that treatment of knee OA with HA injection did not result in a significantly different outcome from intra-articular placebo, despite the higher costs compared with other common non-operative intra-articular modalities (7).Regenerative therapy is an alternative approach that has been considered for OA, due to its potential to aid tissue regeneration, improve clinical manifestations, and repair damaged tissue structure, which is the underlying pathological condition in OA (8). An example of a currently developing regenerative approach is prolotherapy, an injection-based modality for treating chronic musculoskeletal pain through the use of substances such as dextrose, phenol-glycerine-glucose (P2G), or sodium morrhuate (9). Previous reports have demonstrated the effectivity of prolotherapy in significantly reducing the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score relative to saline injections and at-home exercise over 18 weeks after injection (10–12). In line with these findings, other reports have shown the promising effects of prolotherapy for tissue regeneration through radiological and arthroscopy-based assessments of cartilage repair (13).Cartilage oligomeric matrix protein (COMP) and urinary C-terminal telopeptide of type II collagen (uCTX-II) are specific biomarkers used to evaluate cartilage break-down in OA. Increased levels of these biomarkers can indicate the severity and prognosis of OA(14). Meanwhile, decrease in levels of both biomarkers has been assumed which indicates the improvement in cartilage (15). COMP and uCTX-II are recommended as promising specific bio-markers in OAcases based on Burden of disease, Investigative, prognostic, efficacy of intervention, and diagnostic (BIPED) criteria, as stated in a systematic review (16).Although previous reports have demonstrated promising potential of HA-based therapy and dextrose prolotherapy (DPT) in improving functional outcome in knee OA, none have compared the efficacy of those modalities in cartilage repair by assessing specific biomarkers, such as serum COMP (sCOMP) and uCTX-II. Hence, the aim of this study was to compare the effects of intra-articular HAand DPT on cartilage repair in knee OA, by measuring the changes in sCOMP and uCTX-II biomarkers.     

Differential expression of hMLH1 in sporadic human colorectal cancer tumors and distant metastases

Somatic defects in the mismatch repair system constitute an important pathway in colorectal carcinogenesis. We have examined the expression of mismatch repair proteins in sporadic stage IV colorectal tumors and their derived metastases. Sporadic tumors were further examined for differences in expression between the tumor transition zone and the invasive front. Expression of hMSH2, hMLH1, and hPMS2 was screened immunohistochemically in 92 stage IV tumors and derived liver metastases. In cases with loss of mismatch repair protein expression, lymph node metastases were also examined. Clinicopathological parameters and Ki‐67 staining indexes were evaluated and compared. Four tumors displayed a complete loss of hMLH1/hPMS2 expression at the transition zone; however, three of these expressed both proteins at the invasive front and in liver and lymph node metastases. A further four were predominantly hMLH1/hPMS2 negative at the transition zone, but with distinct subclones of hMLH1/hPMS2‐expressing cells at the transition zone. All of these tumors expressed hMLH1/hPMS2 at the invasive front and in liver metastases, with three also expressing hMLH/hPMS2 in lymph node metastases. No significant difference in the proliferative index was observed for the hMLH1/hPMS2‐compromised group. In stage IV tumors re‐expression of hMLH1/hPMS2 occurred, leading to different patterns of expression within the primary tumor and between tumor and metastases. This may have functional importance for the chemosensitivity of metastases compared to the primary tumor.     

INTRAVENOUS GLUCOSE TOLERANCE, PLASMA INSULIN, FREE FATTY ACIDS AND β-HYDROXYBUTYRATE IN UNDERWEIGHT NEWBORN INFANTS

Blood glucose, plasma insulin, FFA and β-hydroxybutyrate values during intravenous glucose tolerance were reported in 20 small for gestational age (SGA) and 15 appropriate for gestational age (AGA) low birthweight infants. The babies were divided into three groups according to their age when tested; <24 hours, 24–48 hours and >48 hours. Both the SGA and AGA infants cleared glucose more rapidly with increasing age. The change was more marked in the SGA babies. The clearance rates were similar to those reported in normal full-sized infants. The insulin values before the glucose load were similar in all groups and comparable to those reported in normal newborn infants. The insulin response to glucose was variable. There were no significant differences with increasing age or between the two groups of infants. The insulin curve of the individual infant followed one of three patterns. Most commonly seen was a double-peak curve. The infants who showed a single-peak insulin response had a better but not significantly different glucose tolerance than that of the other babies. Infants with no appreciable insulin response still removed glucose from plasma at a rate similar to those with a double-peak insulin curve. It is concluded that insulin as measured in peripheral plasma could not explain the rate of removal of glucose from the plasma of the newborn low birthweight infant. Infants of low birthweight had higher plasma FFA values as compared to that reported in normal full term infants. The FFA values in SGA infants were higher than those in AGA babies. In both groups of infants, the jS-hydroxybutyrate values were comparable to those reported in normal full-term babies. Thus there was an unexpected discrepancy between the high FFA and relatively low β-hydroxybutyrate levels in plasma. The fall in plasma FFA and β-hydroxybutyrate after glucose was minimal but similar in both groups of infants. The findings are compatible with a decreased sensitivity to insulin in the infants studied.     

THERAPEUTIC STUDIES IN OSTEOPETROSIS

Four cases of osteopetrosis, with manifestations within the first months of life, are presented. The first two cases were siblings. One of them received no therapy, the other 12 blood transfusions and antibiotics. Therapy had no influence on the thrombocytopenia and haemolytic process in Case 2, and he developed rachitic-like changes and a decrease in serum calcium during hospitalization. Both these two siblings died at the age of 5 months. The last two cases have been on prednisone therapy for 21 and 14 months, respectively. Case 3 is now doing well on prednisone, 7.5–10 mg every other day. Her mental and stato-motoric development has so far been normal. Optic nerve decompression was performed in March 1968, and the eye on which the operation was performed still retains some vision. Case 4 was started on steroids when he was about 3 months older than Case 3. Splenectomy had to be performed due to high prednisone requirements, and he still needs prednisone, 15 mg every other day. He seems, unfortunately, to be blind and slightly retarded. Heparin seems to be of no practical value in this disorder. Cellulose phosphate therapy resulted in impaired calcium absorption. The resulting hypocalcemia seems, however, to have very little, if any, effect on the underlying disease.     

Tuberculosis of the Colon in a Kidney Transplant Patient

ABSTRACT A 58-year-old woman experienced recurrent fever episodes after kidney transplantation. She was treated with antibiotics because of suspicion of staphylococcus infection. Abdominal pain combined with haemorrhagic diarrhoea occurred eight months after transplantation. A barium enema revealed a stenotic process in the middle part of the ascending colon mimicking carcinoma, and hemicolectomy was consequently performed. Histological examination revealed tuberculosis with little granuloma formation and abundant acid-fast tubercle bacilli in the mucosa and submucosa, and only slight perigranulomatous reactions. The patient was successfully treated with triple antituberculous chemotherapy without deterioration of allograft function. Tuberculosis should be suspected in immuno-suppressed patients suffering from pyrexia of unknown origin, even when chest X-ray is normal.     

SERUM LYSOZYME ACTIVITY IN CHILDREN WITH HEMATOLOGICAL AND MALIGNANT DISORDERS

ABSTRACT: Moe, P. J., Haneberg, B. and Finne, P. H. (Department of Paediatrics, University of Tromsø, Tromsø and Department of Paediatrics, University of Bergen, Bergen, Norway). Serum lysozyme activity in children with hematological and malignant disorders. Acta Paediatr Scand, 64: 830, 1975.–Pretreatment serum lysozyme activity was high in 2 children with myelomonocytic leukemia, 800 and 1000'/ig/ml, normal in all 10 cases of acute myelocytic leukemia and subnormal in 21 of 34 cases of acute lymphocytic leukemia. Normal values were found in all but one case of acute lymphocytic leukemia during complete remission including 8 cases after all therapy had been discontinued. All 8 are still in complete remission. Low serum lysozyme activity was found in 5 patients with acute lymphocytic leukemia in complete relapse, this could possibly be helpful in the diagnosis of early relapse. Activity was subnormal in 5 of 17 children with malignant tumours, and in 3 of 65 cases of various benign hematological disorders.