How do forms and characteristics of Asian public housing neighbourhoods affect dementia risk among senior population? A cross-sectional study in Hong Kong.

BACKGROUND: Public housing estate is a key determinant of community health risk in American/European cities. However, how forms/characteristics of compact/hilly public housing's neighbourhoods affect dementia among Asian seniors was underestimated. DESIGN: This was a cross-sectional study. METHODS: A total of 2,077 seniors living in Hong Kong's public housing estates were included. Dementia was measured by a Cantonese version of Montreal - Cognitive Assessment. Built environment was measured based on three dimensions (greenery, walkability, accessibility), including 11 metrics. Circular buffers (without walking paths) and service areas (considering walking paths) with two-dimensional/three-dimensional (terrain) adjustment were applied to quantify forms/characteristics of neighbourhoods. Two spatial buffers were applied: immediate distance (200 m) and walkable distance (500 m). Exposure-by-exposure regressions were applied to evaluate the associations between form/characteristics of neighbourhood and dementia. RESULTS: Forms/characteristics without considering walking paths may overestimate health benefits from built environment. For circular buffers, higher percentage of building coverage, higher land use mix and more community/transportation/leisure facilities were negatively associated with dementia. All measures of greenery were positively associated with dementia. For service areas, measures of walkability and accessibility became insignificant except more community facilities at the immediate distance. Furthermore, terrain effect was insignificant when it was compared with the impacts of walking paths. CONCLUSION: Dementia among seniors in hilly public housing estates was negatively associated with neighbourhood's walkability and accessibility and was influenced by walking paths. For healthy ageing, improved forms/characteristics of public housing neighbourhoods should include more accessible spaces and community facilities along walking paths for physical activities and basic daily needs.

Complementary roles of MRI and endoscopic examination in the early detection of nasopharyngeal carcinoma.

BACKGROUND: Early-stage nasopharyngeal carcinoma (NPC) evades detection when the primary tumor is hidden from view on endoscopic examination. Therefore, in a prospective study of subjects being screened for NPC using plasma Epstein-Barr virus (EBV) DNA, we conducted a study to investigate whether magnetic resonance imaging (MRI) could detect endoscopically occult NPC. PATIENTS AND METHODS: Participants with persistently positive EBV DNA underwent endoscopic examination and biopsy when suspicious for NPC, followed by MRI blinded to the endoscopic findings. Participants with a negative endoscopic examination and positive MRI were recalled for biopsy or surveillance. Diagnostic performance was assessed by calculating sensitivity, specificity and accuracy, based on the histologic confirmation of NPC in the initial study or in a follow-up period of at least two years. RESULTS: Endoscopic examination and MRI were performed on 275 participants, 34 had NPC, 2 had other cancers and 239 without cancer were followed-up for a median of 36 months (24-60 months). Sensitivity, specificity and accuracy were 76.5%, 97.5% and 94.9%, respectively, for endoscopic examination and 91.2%, 97.5% and 96.7%, respectively, for MRI. NPC was detected only by endoscopic examination in 1/34 (2.9%) participants (a participant with stage I disease), and only by MRI in 6/34 (17.6%) participants (stage I = 4, II = 1, III = 1), two of whom had stage I disease and follow-up showing slow growth on MRI but no change on endoscopic examination for 36 months. CONCLUSION: MRI has a complementary role to play in NPC detection and can enable the earlier detection of endoscopically occult NPC.

Combined aspiration thrombectomy and continuous intrasinus thrombolysis for cerebral venous sinus thrombosis: technical note and case series.

Cerebral venous sinus thrombosis is an uncommon cause of stroke with high morbidity and mortality rates from venous infarction, intracranial hemorrhage, and extensive cerebral edema. Endovascular treatment with various devices has been proposed as a salvage treatment when standard medical treatment with systemic anticoagulation is ineffective, especially in long segment dural sinus thrombosis. We describe our technique of transvenous endovascular aspiration thrombectomy with large bore thrombectomy catheters, followed by placement of microcatheter for local thrombolytic infusion at the site of thrombosis. We report a retrospective study of angiographic and clinical outcome of six consecutive patients treated with this approach. Endovascular aspiration thrombectomy with large bore catheters followed by continuous local thrombolytic infusion appeared to be a safe and effective salvage treatment for selected patients with cerebral dural venous sinus thrombosis refractory to medical treatment.

Identification and analysis of murine pancreatic islet enhancers.

AIMS/HYPOTHESIS: The paucity of information on the epigenetic barriers that are blocking reprogramming protocols, and on what makes a beta cell unique, has hampered efforts to develop novel beta cell sources. Here, we aimed to identify enhancers in pancreatic islets, to understand their developmental ontologies, and to identify enhancers unique to islets to increase our understanding of islet-specific gene expression. METHODS: We combined H3K4me1-based nucleosome predictions with pancreatic and duodenal homeobox 1 (PDX1), neurogenic differentiation 1 (NEUROD1), v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA) and forkhead box A2 (FOXA2) occupancy data to identify enhancers in mouse islets. RESULTS: We identified 22,223 putative enhancer loci in in vivo mouse islets. Our validation experiments suggest that nearly half of these loci are active in regulating islet gene expression, with the remaining regions probably poised for activity. We showed that these loci have at least nine developmental ontologies, and that islet enhancers predominately acquire H3K4me1 during differentiation. We next discriminated 1,799 enhancers unique to islets and showed that these islet-specific enhancers have reduced association with annotated genes, and identified a subset that are instead associated with novel islet-specific long non-coding RNAs (lncRNAs). CONCLUSIONS/INTERPRETATIONS: Our results indicate that genes with islet-specific expression and function tend to have enhancers devoid of histone methylation marks or, less often, that are bivalent or repressed, in embryonic stem cells and liver. Further, we identify a subset of enhancers unique to islets that are associated with novel islet-specific genes and lncRNAs. We anticipate that these data will facilitate the development of novel sources of functional beta cell mass.

When to sweat: A history of chemotherapy in malignant sweat gland tumors. A unique case report and literature review.

Sarcomatoid sweat gland carcinomas are rare among cutaneous cancers, with less than 20 cases described. A 54-year-old woman with sarcomatoid sweat gland carcinoma of the right upper extremity suffered extensive recurrence at 15 months, unresponsive to chemotherapy. There is no standard treatment or chemotherapy regimens for metastatic sweat gland carcinoma.

Psychometric Properties of Chinese Version of Work and Social Adjustment Scale for Outpatients With Common Mental Disorders: Classical Test Theory and Rasch Analysis.

OBJECTIVES: To determine the psychometric properties of the Chinese version of the work and social adjustment scale (CWSAS) in outpatients with common mental disorders, and to evaluate the correlations of CWSAS with Physical Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 (GAD-7), World Health Organization Five Well-being Index (WHO-5), and Chinese version of the Perceived Stress Scale-10 (CPSS-10). METHODS: Forward and backward translations of the CWSAS was performed. Between October 2018 and March 2020, 252 outpatients with a common mental disorder who had a job or a job plan were recruited from two psychiatric centres in Hong Kong. Participants were asked to complete the CWSAS, PHQ-9, GAD-7, WHO-5, and CPSS-10. Classical test theory and Rasch analysis were undertaken to determine the psychometric properties of the CWSAS and its correlations with other tools. RESULTS: Principal component analysis revealed that the CWSAS was a one-factor structure and showed adequate convergent and discriminant validities, internal consistency, item-total correlation, and inter-item correlation. There was a significant group difference in terms of employment status. CPSS-10 and PHQ-9 were predictors for CWSAS score. The CWSAS was a distinct factor among other outcome measures. Rasch analysis indicated that the CWSAS was well-targeted and unidimensional. The CWSAS had an adequate person separation index, item separation index, person reliability, and item reliability. No categorical disordering was found, whereas inadequate adjacent threshold distance was reported. The item of ability to work indicated a noticeable differential item functioning in employment status and main source of finance. CONCLUSION: The CWSAS is psychometrically appropriate to measure functional outcomes in outpatients with common mental disorders.

Early Detection of Cancer: Evaluation of MR Imaging Grading Systems in Patients with Suspected Nasopharyngeal Carcinoma.

BACKGROUND AND PURPOSE: We evaluated modifications to our contrast-enhanced MR imaging grading system for symptomatic patients with suspected nasopharyngeal carcinoma, aimed at improving discrimination of early-stage cancer and benign hyperplasia. We evaluated a second non-contrast-enhanced MR imaging grading system for asymptomatic patients from nasopharyngeal carcinoma plasma screening programs. MATERIALS AND METHODS: Dedicated nasopharyngeal MR imaging before (plain scan system) and after intravenous contrast administration (current and modified systems) was reviewed in patients from a nasopharyngeal carcinoma-endemic region, comprising 383 patients with suspected disease without nasopharyngeal carcinoma and 383 patients with nasopharyngeal carcinoma. The modified and plain scan systems refined primary tumor criteria, added a nodal assessment, and expanded the system from 4 to 5 grades. The overall combined sensitivity and specificity of the 3 systems were compared using the extended McNemar test (a χ2 value [Formula: see text]> 5.99 indicates significance). RESULTS: The current, modified, and plain scan MR imaging systems yielded sensitivities of 99.74%, 97.91%, and 97.65%, respectively, and specificities of 63.45%, 89.56% and 86.42%, respectively. The modified system yielded significantly better performance than the current ([Formula: see text] = 122) and plain scan ([Formula: see text] = 6.1) systems. The percentages of patients with nasopharyngeal carcinoma in grades 1-2, grade 3, and grades 4-5 for the modified and plain scan MR imaging systems were 0.42% and 0.44%; 6.31% and 6.96%; and 90.36% and 87.79%, respectively. No additional cancers were detected after contrast administration in cases of a plain scan graded 1-2. CONCLUSIONS: We propose a modified MR imaging grading system that improves diagnostic performance for nasopharyngeal carcinoma detection. Contrast was not valuable for low MR imaging grades, and the plain scan shows potential for use in screening programs.

Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1.

Interleukin-1 (IL-1) is a major regulator of inflammation and immunity. IL-1 induces T lymphocyte growth by acting as a second signal (together with antigen) in enhancing the production of interleukin-2 (IL-2). An IL-1-responsive element in the promoter region of the human IL-2 gene was similar to the binding site for the transcription factor AP-1. IL-1 enhanced expression of c-jun messenger RNA, whereas the antigenic signal enhanced messenger RNA expression of c-fos. Thus, the two components of the AP-1 factor are independently regulated and the AP-1 factor may serve as a nuclear mediator for the many actions of IL-1 on cells.

The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator.

Studies have demonstrated that the retinoblastoma susceptibility gene product, RB, can either positively or negatively regulate expression of several genes through cis-acting elements in a cell-type-dependent manner. The nucleotide sequence of the retinoblastoma control element (RCE) motif, GCCACC or CCACCC, and the Sp1 consensus binding sequence, CCGCCC, can confer equal responsiveness to RB. Here, we report that RB activates transcription of the c-jun gene through the Sp1-binding site within the c-jun promoter. Preincubation of crude nuclear extracts with monoclonal antibodies to RB results in reduction of Sp1 complexes in a mobility shift assay, while addition of recombinant RB in mobility shift assay mixtures with CCL64 cell extracts leads to an enhancement of DNA-binding activity of SP1. These results suggest that RB is directly or indirectly involved in Sp1-DNA binding activity. A mechanism by which RB regulates transactivation is indicated by our detection of a heat-labile and protease-sensitive Sp1 negative regulator(s) (Sp1-I) that specifically inhibits Sp1 binding to a c-jun Sp1 site. This inhibition is reversed by addition of recombinant RB proteins, suggesting that RB stimulates Sp1-mediated transactivation by liberating Sp1 from Sp1-I. Additional evidence for Sp1-I involvement in Sp1-mediated transactivation was demonstrated by cotransfection of RB, GAL4-Sp1, and a GAL4-responsive template into CV-1 cells. Finally, we have identified Sp1-I, a approximately 20-kDa protein(s) that inhibits the Sp1 complexes from binding to DNA and that is also an RB-associated protein. These findings provide evidence for a functional link between two distinct classes of oncoproteins, RB and c-Jun, that are involved in the control of cell growth, and also define a novel mechanism for the regulation of c-jun expression.

Effects of a p38 MAP kinase inhibitor on bone ingrowth and tissue differentiation in rabbit chambers.

The effects of an oral p38 mitogen-activated protein kinase (MAPK) inhibitor and polyethylene particles separately and together on tissue differentiation in the bone harvest chamber (BHC) in rabbits over a 3-week treatment period were investigated. The harvested tissue was analyzed histomorphometrically for markers of bone formation (percentage of bone area), osteoblasts (alkaline phosphatase staining), and osteoclasts (CD51, the alpha chain of the vitronectin receptor). Polyethylene particles decreased the percentage of bone ingrowth and staining for alkaline phosphatase. The p38 MAPK inhibitor alone decreased alkaline phosphatase staining. When the oral p38 MAPK inhibitor was given and the chamber contained polyethylene particles, there was a suppression of bone ingrowth and alkaline phosphatase staining. In contrast to oral non-steroidal anti-inflammatory drugs (NSAIDs) and local Interleukin-1 receptor antagonist (IL-1ra) administration, the oral p38 MAPK inhibitor alone did not suppress bone formation when given during the initial phase of tissue differentiation. Particle-induced inflammation and the foreign body reaction were not curtailed when the p38 MAPK inhibitor was given simultaneously with particles. Additional experiments are needed to establish the efficacy of p38 MAPK inhibitor administration on mitigating an established inflammatory and foreign body reaction that parallels the clinical situation more closely.

Mitochondrial dysfunction after aerobic exposure to the hypoxic cytotoxin tirapazamine.

Tirapazamine (TPZ) is a bioreductive drug that exhibits a high degree of selective toxicity toward hypoxic cells, and at doses that are used clinically, little or no cell killing is observed in aerobic cells. Nonetheless, the effects of TPZ on aerobic tissues are still responsible for the dose limitations on the clinical administration of this drug. Clinical side effects include fatigue, muscle cramping, and reversible ototoxicity. We have investigated TPZ-induced changes in the mitochondria in aerobically exposed cells as a potential mediator of these side effects. Our data show that aerobic administration of TPZ at clinically relevant doses results in a profound loss in the mitochondrial membrane potential (MMP). We show that loss in the MMP occurs in a variety of cell lines in vitro and also occurs in muscle tissues in vivo. The loss in MMP is temporary because recovery occurs within 2 h. TPZ is directly metabolized within mitochondria to a DNA-damaging form, and this metabolism leads to both the cell-killing effects of TPZ on aerobic cells at high doses and to the loss in MMP at clinically relevant doses. Using cell lines derived from genetically modified mice with a targeted deletion in manganese superoxide dismutase, we have further distinguished the phenotypic effects of TPZ in mitochondria at high toxic doses versus those at clinically relevant doses. We have investigated several potential mechanisms for this TPZ-induced loss in MMP. Our results indicate no change in the rate of cellular respiration in TPZ-treated cells. This implies that the loss in MMP results from an inability of the inner mitochondrial membrane to sustain a potential across the membrane after TPZ treatment. Incubation of cells with an inhibitor of the mitochondrial permeability transition suggests that the loss of MMP may result from the regulated opening of a large mitochondria channel.

The Fos and Jun/AP-1 proteins are involved in the downregulation of Fos transcription.

The low basal expression of Fos and the rapid and effective turn-off of serum induced Fos transcription is due to autoregulation. Fos and Jun/AP-1 protein cooperate in the repression mechanism. Overexpressions of Fos and Jun decrease basal and induced transcription from Fos-CAT constructs and from the endogenous gene in NIH3T3 cells. The introduction into cells of either antisense Fos or antisense Jun sequences leads to elevated basal Fos promoter activity. Gel retardation experiments with synthetic oligonucleotides define two target sequences in the Fos promoter which bind Fos-Jun/AP-1 (centering at about -296 and -60). In vivo competition with these oligonucleotides relieves repression.

A unique cathepsin-like protease isolated from CV-1 cells is involved in rapid degradation of retinoblastoma susceptibility gene product, RB, and transcription factor SP1.

The regulation of transcription factors by kinase or phosphatase has been well-described. However, little is known about the inactivation of transcription factors or the nuclear regulators by proteolytic degradation. In this report, we purified a specific protease, SPase, from nuclear extracts of the green monkey kidney cell line, CV-1. Studies of biochemical characteristics and substrate specificity indicated that SPase is a cathepsin B-like cysteinyl protease. However, the two tryptic peptide sequences derived from the purified SPase are either identical or highly homologous to those of human cathepsin L, and furthermore, SPase shares immunoreactivity with both anti-human cathepsin L and anti-mouse cathepsin L antibody. The SPase was shown to be localized in both cytoplasm and nucleus when subcellular compartments of CV-1 cells were fractionated. Transcription factor, SP1, and retinoblastoma susceptible gene product, RB, are substrates of SPase while other nuclear factors such as c-Jun and c-Fos are not. These results implied that SPase plays an integral role in regulating a set of proteins in the nuclei. In vivo treatment of CV-1 cells with cysteinyl protease inhibitor, E-64d, protected RB from degradation. SPase failed to degrade underphosphorylated RB present in TPA induced terminally differentiated HL-60 or U937 cells. Phosphorylation of RB may cause conformational changes, thus facilitating proteolytic digestion. These observations suggest that an alternative pathway inactivates the function of RB in controlling cell growth. Therefore, a possible role of SPase may be to affect the stability of important regulators involved in controlling cellular proliferation and differentiation.

Induction by adenovirus-5 E1A of the differentiation phenotype of F9 teratocarcinoma cells involves a conserved region (CR1) of E1A.

The effects of the E1A protein of adenovirus-5 on the differentiation program of F9 teratocarcinoma cells were examined by the stable introduction of plasmids that expressed wild-type or mutated forms of E1A. Constitutive expression of plasmids for most of the mutant E1As induced loss of expression of the cell-surface antigen SSEA-1 and the enhanced expression of genes specific for the differentiated phenotype of F9 cells, such as genes for laminin B1, tissue-type plasminogen activator (tPA) and type IV collagen, as well as the altered cell morphology that is associated with the differentiated state. However, such changes were not observed in the case of genes for mutant proteins from which a conserved region (CR1) of E1A had been deleted. Furthermore, no significant induction of expression of the c-jun gene or transactivation of the c-jun-CAT reporter gene were observed when the sequence that encodes CR1 of E1A had been deleted. A palindromic sequence element (DRE) of the c-jun promoter was essential for the E1A-mediated up-regulation of the c-jun gene. These results imply that CR1 is required for activation of the c-jun gene and that it is implicated in the growth arrest, expression of parietal endoderm-specific functions and the orderly differentiation of F9 cells.

Genomic characterisation of the severe acute respiratory syndrome coronavirus of Amoy Gardens outbreak in Hong Kong.

Severe acute respiratory syndrome (SARS) is a global health concern. In Hong Kong, two major outbreaks, one hospital based and the other in the Amoy Gardens apartments, were identified. The frequency of diarrhoea, admission to intensive care, and mortality differed significantly between the two outbreaks. We did genomic sequencing for viral isolates from five Amoy Gardens patients. The virus sequence was identical in four of these five patients. The sequence data from one hospital case and the four identical community cases had only three nucleotide differences. Alterations in the SARS coronavirus genome are unlikely to have caused the distinctive clinical features of the Amoy Gardens patients, and these results highlight the importance of non-viral genomic factors in this outbreak.

Circulating nucleic acid analysis: diagnostic applications for acute pathologies.

Much research interest has been shown in recent years for the development of molecular diagnostic strategies based on the analysis of DNA/RNA molecules that are present in the plasma/serum of human subjects. Reported applications include the diagnosis, prognostication or monitoring of malignancies and pregnancy-associated complications. While researchers have speculated that cell death is a potential mechanism that leads to the release of DNA/RNA into the circulation, studies have demonstrated that indeed increased amounts of plasma DNA and RNA could be detected in patients sustaining acute traumatic injuries. The degree of plasma DNA elevation correlated with the severity of injury. Similarly, plasma DNA concentrations have been shown to correlate with indices of prognostic significance in patients with acute stroke. It is expected that new diagnostic markers based on plasma RNA detection could be developed for the evaluation of acute pathologies.

Rad18 and Rnf8 facilitate homologous recombination by two distinct mechanisms, promoting Rad51 focus formation and suppressing the toxic effect of nonhomologous end joining.

The E2 ubiquitin conjugating enzyme Ubc13 and the E3 ubiquitin ligases Rad18 and Rnf8 promote homologous recombination (HR)-mediated double-strand break (DSB) repair by enhancing polymerization of the Rad51 recombinase at γ-ray-induced DSB sites. To analyze functional interactions between the three enzymes, we created RAD18(-/-), RNF8(-/-), RAD18(-/-)/RNF8(-/-) and UBC13(-/-)clones in chicken DT40 cells. To assess the capability of HR, we measured the cellular sensitivity to camptothecin (topoisomerase I poison) and olaparib (poly(ADP ribose)polymerase inhibitor) because these chemotherapeutic agents induce DSBs during DNA replication, which are repaired exclusively by HR. RAD18(-/-), RNF8(-/-) and RAD18(-/-)/RNF8(-/-) clones showed very similar levels of hypersensitivity, indicating that Rad18 and Rnf8 operate in the same pathway in the promotion of HR. Although these three mutants show less prominent defects in the formation of Rad51 foci than UBC13(-/-)cells, they are more sensitive to camptothecin and olaparib than UBC13(-/-)cells. Thus, Rad18 and Rnf8 promote HR-dependent repair in a manner distinct from Ubc13. Remarkably, deletion of Ku70, a protein essential for nonhomologous end joining (NHEJ) significantly restored tolerance of RAD18(-/-) and RNF8(-/-) cells to camptothecin and olaparib without affecting Rad51 focus formation. Thus, in cellular tolerance to the chemotherapeutic agents, the two enzymes collaboratively promote DSB repair by HR by suppressing the toxic effect of NHEJ on HR rather than enhancing Rad51 focus formation. In contrast, following exposure to γ-rays, RAD18(-/-), RNF8(-/-), RAD18(-/-)/RNF8(-/-) and UBC13(-/-)cells showed close correlation between cellular survival and Rad51 focus formation at DSB sites. In summary, the current study reveals that Rad18 and Rnf8 facilitate HR by two distinct mechanisms: suppression of the toxic effect of NHEJ on HR during DNA replication and the promotion of Rad51 focus formation at radiotherapy-induced DSB sites.

Identification and characterization of CD44RC, a novel alternatively spliced soluble CD44 isoform that can potentiate the hyaluronan binding activity of cell surface CD44.

Soluble CD44 proteins generated by proteolytic cleavage or aberrant intron retention have been shown to antagonize the ligand binding activity of the corresponding cell surface receptor, inducing apoptosis and inhibiting tumor growth. Interestingly, such findings appear to contradict recent studies demonstrating a correlation between the presence of high levels of soluble CD44 in the serum of cancer patients and poor prognosis. In the present study, we report the cloning of a novel, naturally occurring, differentially expressed, soluble CD44 isoform, designated CD44RC, which, in contrast to previously described soluble CD44 proteins, can dramatically enhance the hyaluronan binding activity of cell surface CD44. Sequence analysis suggests that CD44RC is generated by an alternative splicing event in which the 3' end of CD44 exon 2 is spliced into an internal splice acceptor site present within exon 18, altering reading frame and giving rise to a soluble protein with a unique COOH terminus. Functional studies suggest that CD44RC enhances hyaluronan binding by adhering to chondroitin sulfate side-chains attached to cell surface CD44, generating a multivalent complex with increased avidity for hyaluronan.

Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia.

Animal studies, experimental models on cell lines, and epidemiological case-control studies have all suggested the possibility that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors have a beneficial effect on bone metabolism. However, all epidemiological studies are not prospective in nature and based on either measurement of bone mineral density or fracture risk. They also differ in recruitment criteria, definition of statin exposure, and outcome assessment. We performed a first prospective study using specific biochemical bone markers on 17 hypercholesterolaemic non-osteoporotic subjects treated with a therapeutic dose of simvastatin 20 mg daily for 4 weeks. Our results show that serum osteocalcin concentration increased significantly (p-value < 0.05) 4 weeks after therapy, whereas other bone markers including serum bone-specific alkaline phosphatase activity, urine deoxypyridinoline, and urine cross-linked N-telopeptides of type I collagen did not show any significant changes. Our data support that simvastatin causes a beneficial effect on bone metabolism as reflected by an increase in serum osteocalcin concentration. This added beneficial effect of statins on bone metabolism could potentially allow statins to become the first effective anabolic agent for the treatment of osteoporosis. We urge that priority should be given to a randomised controlled study to re-evaluate this group of drugs.

A retinoblastoma susceptibility gene product, RB, targeting protease is regulated through the cell cycle.

Degradation of cyclin B and cyclin-dependent kinase inhibitor, p27, at a specific time has been shown to play a critical role in regulating the cell cycle. SPase, a nuclear and cytosol protease with cathepsin B- and L-like proteolytic activity, has been identified in several cell lines. This proteolytic enzyme selectively degraded nuclear proteins such as retinoblastoma susceptibility gene product, RB, and transcription factor, SP-1. High levels of SPase activity were detected at the G1/S, moderate levels at the G1 and S phases, and undetectable activity at the M phase of synchronized CV-1 cells, suggesting that SPase activity is regulated through the cell cycle. Degradation of RB correlated with SPase activity throughout the cell cycle, suggesting that SPase regulates RB, which has a functional role in regulating cell cycle. These results demonstrated that SPase plays an integral role in regulating the nuclear regulator, RB, in controlling cell cycle progression.