The chondrocyte channelome: A narrative review

Chondrocytes are the main cells in the extracellular matrix (ECM) of articular cartilage and possess a highly differentiated phenotype that is the hallmark of the unique physiological functions of this specialised load-bearing connective tissue. The plasma membrane of articular chondrocytes contains a rich and diverse complement of membrane proteins, known as the membranome, which defines the cell surface phenotype of the cells. The membranome is a key target of pharmacological agents and is important for chondrocyte function. It includes channels, transporters, enzymes, receptors, and anchors for intracellular, cytoskeletal and ECM proteins and other macromolecular complexes. The chondrocyte channelome is a sub-compartment of the membranome and includes a complete set of ion channels and porins expressed in these cells. Many of these are multi-functional proteins with “moonlighting” roles, serving as channels, receptors and signalling components of larger molecular assemblies. The aim of this review is to summarise our current knowledge of the fundamental aspects of the chondrocyte channelome, discuss its relevance to cartilage biology and highlight its possible role in the pathogenesis of osteoarthritis (OA). Excessive and inappropriate mechanical loads, an inflammatory micro-environment, alternative splicing of channel components or accumulation of basic calcium phosphate crystals can result in an altered chondrocyte channelome impairing its function. Alterations in Ca²⁺ signalling may lead to defective synthesis of ECM macromolecules and aggravated catabolic responses in chondrocytes, which is an important and relatively unexplored aspect of the complex and poorly understood mechanism of OA development.     

A new method for the termination of cervical pregnancy]

The authors described a 7 weeks old cervical pregnant case, whome was administered 250 mg methotrexate in infusion to eliminate the throphoblastic tissue. 3 days later the HCG was negative in the urine. After the dilatation of cervix by laminaria, the collapsed amniotic sac came from the cervix with minimal hemorrhage. They suggest the method is suitable to prevent the serious complications of cervical pregnancy.     

Displaced acetabular fractures

Displaced acetabular fractures occur primarily in young adults involved in high energy trauma and can lead to disabling posttraumatic arthritis. An initial roentgenographic evaluation with accurate delineation of all fracture lines provides the key to decisions about whether to give closed or open treatment. When open treatment is indicated, a surgical approach can be chosen that will almost always lead to reduction without the necessity of a second approach. The authors have found that the Kocher-Langenbeck, ilioinguinal, and extended iliofemoral approaches are the most useful. A fracture table and specialized reduction instruments aid fracture reduction and fixation. Satisfactory operative reduction of the fracture is the factor that correlates best with a satisfactory clinical result. The rate of satisfactory operative reductions improved gradually over the first 50 operations of a prospective study of 121 displaced acetabular fractures. Overall, there were 80% satisfactory clinical results in this series. Complications included a 3% infection rate and a 5% incidence of nerve palsy. Open reduction and internal fixation are indicated for the majority of displaced fractures. However, closed treatment can produce satisfactory results in selected patients.     

Buserelin in premenstrual syndrome.

Buserelin, a luteinizing hormone releasing hormone agonist was administered nasally in doses of 900 micrograms daily to inhibit the ovarian cycle. Of 16 patients recruited, ten completed the treatment. Daily symptoms were measured on the Visual Analogue Scale and Trigg's trend analysis utilized for the analysis. The peak severity of symptoms (ESAmax) and the maximum global scores (Gmax) reduced on buserelin treatment. The minimum global scores (Gmin) and the minimum score for each symptom (ESAmin) increased, suggesting worsening of underlying symptoms. The difference between ESAmax and ESAmin (ESAdelta) and Gmax and Gmin (Gdelta) were calculated to determine the degree of symptom change. The delta scores for symptoms of depression, bloatedness and breast symptoms, and Gdelta were significantly reduced (p less than 0.05) on buserelin, whilst the latter significantly worsened in the follow-up months. Side-effects may limit the place of buserelin in the long-term treatment of premenstrual syndrome, although combination of additional hormonal treatment may facilitate long-term treatment.     

Antigenic studies on an enzymatically sialylated carbohydrate: NeuAc(alpha 2-3)Gal(beta 1-3)GalNAc

Sialic acid residues are often the end moiety of the carbohydrate chain of biologically important glycoconjugates. It is difficult to study sialylated glycoconjugates because the purification of these compounds is often laborious yielding only very small amounts of oligosaccharides for study. Chemical synthesis of sialylated compounds is complicated by the labile nature of the sialic acid bond. In both of these cases the sialylated compounds would need to be conjugated to a polypeptide to be an effective immunogen, and again, such conjugation is fraught with problems due to the instability of the sialic acid linkage. We have developed a combined enzymatic and synthetic route for obtaining quantities of sialylated carbohydrates conjugated to a protein carrier in amounts sufficient for antigenic studies. The notable novelty of this protocol is the addition of sialic acid after the carbohydrate-protein conjugation step. Antiserum to the compounds was developed and after absorption, antibodies that demonstrate a requirement for sialic acid for their binding were produced and studied. CA 125 has been shown to be a prognostically significant marker for ovarian adenocarcinoma. The nature of the epitope involved has been analyzed with conflicting results. To attempt to resolve this conflict, we initiated studies on sialylated antigens with NeuAc alpha 2-3Gal beta 1-3GalNAc. This trisaccharide occupies the terminal region in a series of complex carbohydrates which have been suggested to be involved as the epitope. Hanisch et al. reported that the neuraminic acid was important for the reaction.     

Primary Radiotherapy of Stage IIA/B–IIIB Cervical Carcinoma

BACKGROUND: Comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. PATIENTS AND METHODS: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i. e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. RESULTS: Progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). CONCLUSION: For the patients included in this study, no advantage has been found so far in using CRT, i. e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per fraction of HDR-BT in the SRT regimen was obviously too high. To achieve a significant improvement in local control and disease-free survival (DFS) as well as overall survival (OS), the combination with modern chemotherapy regimens and regional deep hyperthermia may rather be the treatment option.