Utilizing Fish Skin of Ikan Belida (Notopterus lopis) as a Source of Collagen: Production and Rheology Properties.

Collagen hydrogels have been extensively applied in biomedical applications. However, their mechanical properties are insufficient for such applications. Our previous study showed improved mechanical properties when collagen was blended with alginate. The current study aims to analyze the physico-chemical properties of collagen-alginate (CA) films such as swelling, porosity, denaturation temperature (Td), and rheology properties. Collagen was prepared from discarded fish skin of Ikan Belida (Notopterus lopis) that was derived from fish ball manufacturing industries and cross-linked with alginate from brown seaweed (Sargasum polycystum) of a local species as a means to benefit the downstream production of marine industries. CA hydrogels were fabricated with ratios (v/v) of 1:1, 1:4, 3:7, 4:1, and 7:3 respectively. FTIR spectrums of CA film showed an Amide I shift of 1636.12 cm-1 to 1634.64 cm-1, indicating collagen-alginate interactions. SEM images of CA films show a porous structure that varied from pure collagen. DSC analysis shows Td was improved from 61.26 °C (collagen) to 83.11 °C (CA 3:7). CA 4:1 swelled nearly 800% after 48 h, correlated with the of hydrogels porosity. Most CA demonstrated visco-elastic solid characteristics with greater storage modulus (G') than lost modulus (G″). Shear thinning and non-Newtonian behavior was observed in CA with 0.4% to 1.0% (w/v) CaCl2. CA hydrogels that were derived from discarded materials shows promising potential to serve as a wound dressing or ink for bio printing in the future.

Airway management in children with COVID-19.

The novel coronavirus disease (COVID-19) may result in acute respiratory distress syndrome and respiratory failure, necessitating mechanical respiratory support. Healthcare professionals are exposed to a particularly high risk of contracting the virus while providing resuscitation and respiratory support, which may in turn result in grave consequences and even death. Although COVID-19 has been shown to cause milder disease in children, paediatricians and intensivists who provide care for children must be prepared to provide optimal respiratory support without putting themselves or other medical, nursing, and paramedical staff at undue risk. We propose an airway management approach that is especially relevant in the current COVID-19 pandemic and provides instructions for: (1) Elective intubation for respiratory failure; and (2) Emergency intubation during cardiopulmonary resuscitation. To minimise risk, intubation methods must be kept as straightforward as possible and should include the provision of appropriate personal protection and equipment to healthcare workers. We identify two key considerations: that bag-mask ventilation should be avoided if possible and that bacterial and viral filters should be placed in the respiratory circuit. Our novel approach provides a framework for airway management that could benefit paediatric critical care practitioners who provide care for any children with a novel viral illness, with a focus on infection prevention during high-risk airway management procedures.

Burnout and well-being in young doctors in Hong Kong: a territory-wide cross-sectional survey.

INTRODUCTION: This territory-wide study evaluated the level of burnout and health status among young doctors in Hong Kong. METHODS: All young doctors in Hong Kong, defined as residents-in-training or doctors within 10 years of their specialist registration, were invited to participate in an online cross-sectional survey. This survey used standardised questionnaires including the Copenhagen Burnout Inventory (CBI) for burnout, Patient Health Questionnaire-9 for depression, and general health questionnaires. RESULTS: In total, 514 doctors completed the survey; 284 were doctors within 10 years of their specialist registration, while 230 were residents-in-training. There were 277 women (54%); among all respondents, the mean age was 33.7 ± 6.1 years. Using a CBI subscale cut-off score of ≥50 (moderate and higher), 72.6% (n=373) of respondents reported personal burnout; 70.6% (n=363) of respondents reported work-related burnout; and 55.4% (n=285) of respondents reported client-related burnout. Furthermore, 24% (n=125) of respondents were "somewhat dissatisfied" with their present job position; 4% (n=19) of respondents were "very dissatisfied" with their present job position. The prevalence of depression among respondents was 21% (n=110). CONCLUSIONS: In this territory-wide cross-sectional survey of young doctors in Hong Kong, a high prevalence of burnout was identified among young doctors; respondents exhibited a considerable level of depression and substantial dissatisfaction with their current positions. Strategies to address these problems must be formulated to ensure the future well-being of the medical and dental workforce in Hong Kong.

The PNKD gene is associated with Tourette Disorder or Tic disorder in a multiplex family.

Tourette Disorder (TD) is a childhood-onset neuropsychiatric and neurodevelopmental disorder characterized by the presence of both motor and vocal tics. The genetic architecture of TD is believed to be complex and heterogeneous. Nevertheless, DNA sequence variants co-segregating with TD phenotypes within multiplex families have been identified. This report examines whole exomes of affected and unaffected individuals in a multiplex TD family to discover genes involved in the TD etiology. We performed whole exome sequencing on six out of nine members in a three-generation TD multiplex family. Putative deleterious sequence variants co-segregating with TD patients were identified by our in-house bioinformatics pipeline. Induced pluripotent stem cells (iPSCs) were generated from one unaffected and two TD affected individuals. Neurons were derived from the iPSCs and biochemical assays were conducted to evaluate possible molecular differences between affected and unaffected. A rare heterozygous nonsense mutation in PNKD was co-segregated with TD in this multiplex family. Transcript and protein levels of the PNKD long isoform were reduced in neurons derived from the individuals with TD due to the nonsense mutation, indicating nonsense-mediated mRNA decay. We demonstrated that the PNKD long isoform monomer oligomerizes with itself as well as interacts with the synaptic active zone protein RIMS1α. We concluded that reduced PNKD long isoform levels are detected in all affected individuals and we provide evidence for a mechanism whereby this might contribute to the TD phenotype.

Ibuprofen versus indomethacin treatment of patent ductus arteriosus: comparative effectiveness and complications.

OBJECTIVES: To compare the effectiveness and complications of intravenous ibuprofen versus indomethacin treatment of patent ductus arteriosus in preterm infants. DESIGN: Retrospective case series. SETTING: A tertiary referral centre in Hong Kong. PATIENTS: A total of 95 infants who had received at least one course of indomethacin or ibuprofen for closure of patent ductus arteriosus from January 2008 to December 2011 were studied. MAIN OUTCOME MEASURES: Following the total switch from indomethacin to ibuprofen in clinical use in April 2010, outcomes of infants receiving indomethacin and ibuprofen were compared. The primary outcomes including rates of failed medical closure and recourse to surgical ligation were compared. The secondary outcomes including rates of all-cause mortality, bronchopulmonary dysplasia, intestinal complications (necrotising enterocolitis, spontaneous intestinal perforation), change in urine output and serum creatinine, and progression of any intraventricular haemorrhage were also evaluated. RESULTS: The failure rate of medical treatment was similar in the indomethacin and ibuprofen groups, with 16 (31%) such infants in the indomethacin group and 14 (33%) in the ibuprofen group; for ibuprofen this yielded a relative risk of 1.06 (95% confidence interval, 0.66-1.67; P=0.852). The proportion of infants having surgical ligation was also similar. A higher rate of intestinal complications (necrotising enterocolitis or spontaneous intestinal perforation) was encountered in our ibuprofen group (P=0.043). No significant difference was observed in other secondary outcomes determined. CONCLUSION: In our clinical practice, ibuprofen and indomethacin were shown to be equally effective for medical closure of patent ductus arteriosus in premature infants. With the higher rates of intestinal complications and similar effects on renal function in the ibuprofen group, we conclude that ibuprofen may not have fewer adverse effects than indomethacin.

A mathematical model on water redistribution mechanism of the seismonastic movement of Mimosa pudica.

A theoretical model based on the water redistribution mechanism is proposed to predict the volumetric strain of motor cells in Mimosa pudica during the seismonastic movement. The model describes the water and ion movements following the opening of ion channels triggered by stimulation. The cellular strain is related to the angular velocity of the plant movement, and both their predictions are in good agreement with experimental data, thus validating the water redistribution mechanism. The results reveal that an increase in ion diffusivity across the cell membrane of <15-fold is sufficient to produce the observed seismonastic movement.

The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population.

BACKGROUND: Sexually transmitted infection with the human papillomavirus (hpv) is responsible for a significant burden of human cancers involving the cervix, anogenital tract, and oropharynx. Studies in the United States and Europe have demonstrated an alarming increase in the frequency of hpv-positive oropharyngeal cancer, but the same direct evidence does not exist in Canada. METHODS: Using the London Health Sciences Centre pathology database, we identified tonsillar cancers diagnosed between 1993 and 2011. Real-time polymerase chain reaction was then used on pre-treatment primary-site biopsy samples to test for dna from the high-risk hpv types 16 and 18. The study cohort was divided into three time periods: 1993-1999, 2000-2005, and 2006-2011. RESULTS: Of 160 tumour samples identified, 91 (57%) were positive for hpv 16. The total number of tonsillar cancers significantly increased from 1993-1999 to 2006-2011 (32 vs. 68), and the proportion of cases that were hpv-positive substantially increased (25% vs. 62%, p < 0.002). Those changes were associated with a marked improvement in 5-year overall survival (39% in 1993-1999 vs. 84% in 2006-2011, p < 0.001). When all factors were included in a multivariable model, only hpv status predicted treatment outcome. INTERPRETATION: The present study is the first to provide direct evidence that hpv-related oropharyngeal cancer is increasing in incidence in a Canadian population. Given the long lag time between hpv infection and clinically apparent malignancy, oropharyngeal cancer will be a significant clinical problem for the foreseeable future despite vaccination efforts.

Computational analysis of tibial slope adjustment with fixed-bearing medial unicompartmental knee arthroplasty in ACL- and PCL-deficient models.

AIMS: A functional anterior cruciate ligament (ACL) or posterior cruciate ligament (PCL) has been assumed to be required for patients undergoing unicompartmental knee arthroplasty (UKA). However, this assumption has not been thoroughly tested. Therefore, this study aimed to assess the biomechanical effects exerted by cruciate ligament-deficient knees with medial UKAs regarding different posterior tibial slopes. METHODS: ACL- or PCL-deficient models with posterior tibial slopes of 1°, 3°, 5°, 7°, and 9° were developed and compared to intact models. The kinematics and contact stresses on the tibiofemoral joint were evaluated under gait cycle loading conditions. RESULTS: Anterior translation increased in ACL-deficient UKA cases compared with intact models. In contrast, posterior translation increased in PCL-deficient UKA cases compared with intact models. As the posterior tibial slope increased, anterior translation of ACL-deficient UKA increased significantly in the stance phase, and posterior translation of PCL-deficient UKA increased significantly in the swing phase. Furthermore, as the posterior tibial slope increased, contact stress on the other compartment increased in cruciate ligament-deficient UKAs compared with intact UKAs. CONCLUSION: Fixed-bearing medial UKA is a viable treatment option for patients with cruciate ligament deficiency, providing a less invasive procedure and allowing patient-specific kinematics to adjust posterior tibial slope. Patient selection is important, and while AP kinematics can be compensated for by posterior tibial slope adjustment, rotational stability is a prerequisite for this approach. ACL- or PCL-deficient UKA that adjusts the posterior tibial slope might be an alternative treatment option for a skilled surgeon. Cite this article: Bone Joint Res 2022;11(7):494-502.

Biomechanical effect of anatomical tibial component design on load distribution of medial proximal tibial bone in total knee arthroplasty : finite element analysis indicating anatomical design prevents stress-shielding.

AIMS: This study aimed to identify the effect of anatomical tibial component (ATC) design on load distribution in the periprosthetic tibial bone of Koreans using finite element analysis (FEA). METHODS: 3D finite element models of 30 tibiae in Korean women were created. A symmetric tibial component (STC, NexGen LPS-Flex) and an ATC (Persona) were used in surgical simulation. We compared the FEA measurements (von Mises stress and principal strains) around the stem tip and in the medial half of the proximal tibial bone, as well as the distance from the distal stem tip to the shortest anteromedial cortical bone. Correlations between this distance and FEA measurements were then analyzed. RESULTS: The distance from the distal stem tip to the shortest cortical bone showed no statistically significant difference between implants. However, the peak von Mises stress around the distal stem tip was higher with STC than with ATC. In the medial half of the proximal tibial bone: 1) the mean von Mises stress, maximum principal strain, and minimum principal strain were higher with ATC; 2) ATC showed a positive correlation between the distance and mean von Mises stress; 3) ATC showed a negative correlation between the distance and mean minimum principal strain; and 4) STC showed no correlation between the distance and mean measurements. CONCLUSION: Implant design affects the load distribution on the periprosthetic tibial bone, and ATC can be more advantageous in preventing stress-shielding than STC. However, under certain circumstances with short distances, the advantage of ATC may be offset. Cite this article: Bone Joint Res 2022;11(5):252-259.

Evaluation of procedures for the collection, processing, and analysis of biomolecules from low-biomass surfaces.

To comprehensively assess microbial diversity and abundance via molecular-analysis-based methods, procedures for sample collection, processing, and analysis were evaluated in depth. A model microbial community (MMC) of known composition, representative of a typical low-biomass surface sample, was used to examine the effects of variables in sampling matrices, target cell density/molecule concentration, and cryogenic storage on the overall efficacy of the sampling regimen. The MMC used in this study comprised 11 distinct species of bacterial, archaeal, and fungal lineages associated with either spacecraft or clean-room surfaces. A known cellular density of MMC was deposited onto stainless steel coupons, and after drying, a variety of sampling devices were used to recover cells and biomolecules. The biomolecules and cells/spores recovered from each collection device were assessed by cultivable and microscopic enumeration, and quantitative and species-specific PCR assays. rRNA gene-based quantitative PCR analysis showed that cotton swabs were superior to nylon-flocked swabs for sampling of small surface areas, and for larger surfaces, biological sampling kits significantly outperformed polyester wipes. Species-specific PCR revealed differential recovery of certain species dependent upon the sampling device employed. The results of this study empower current and future molecular-analysis-based microbial sampling and processing methodologies.

Secondary attack rate of pandemic influenza A(H1N1) 2009 in Western Australian households, 29 May-7 August 2009.

Understanding household transmission of the pandemic influenza A(H1N1)2009 virus, including risk factors for transmission, is important for refining public health strategies to reduce the burden of the disease. During the influenza season of 2009 we investigated transmission of the emerging virus in 595 households in which the index case was the first symptomatic case of influenza A(H1N1)2009. Secondary cases were defined as household contacts with influenza-like illness (ILI) or laboratory-confirmed influenza A(H1N1)2009, occurring at least one day after but within seven days following symptom onset in the index case. ILI developed in 231 of the 1,589 household contacts, a secondary attack rate of 14.5% (95% confidence interval (CI): 12.9­16.4). At least one secondary case occurred in 166 of the 595 households (a household transmission rate of 27.9%; 95% CI: 24.5­31.6).Of these, 127 (76.5%) households reported one secondary case and 39 (23.5%) households reported two or more secondary cases. Secondary attack rates were highest in children younger than five years (p=0.001), and young children were also more efficient transmitters (p=0.01). Individual risk was not associated with household size. Prophylactic antiviral therapy was associated with reduced transmission (p=0.03). The secondary attack rate of ILI in households with a confirmed pandemic influenza A(H1N1)2009 index case was comparable to that described previously for seasonal influenza.

Does timing of surgery matter in fragility hip fractures?

The effect of delay of surgery on the geriatric hip fractures has been a subject of interest in the past two decades. While the elderly patients will not tolerate long periods of immobilization, it is still unclear how soon these surgeries need to be performed. A review of existing literature was performed to examine the effect of timing of surgery on the different outcome parameters of these patients. Although there is conflicting evidence that early surgery would improve mortality, there is widespread evidence in the literature that other outcomes including morbidity, the incidence of pressure sores, and the length of hospital stay could be improved by shortening the waiting time of hip fracture surgery. We concluded that it is beneficial to the elderly patients to receive surgical treatment as an urgent procedure as soon as the body meets the basic anesthetic requirements.

Association between 2009 seasonal influenza vaccine and influenza-like illness during the 2009 pandemic: preliminary results of a large household transmission study in Western Australia.

We conducted a prospective household transmission study to examine whether receipt of 2009 trivalent influenza vaccine (TIV) was associated with increased risk of influenza-like illness (ILI) among contacts of confirmed pandemic influenza A(H1N1) 2009 patients. In the week following onset of pandemic illness in a household member, 46 (15%) of 304 TIV-vaccinated contacts, and 174 (15%) of 1,162 unvaccinated contacts developed ILI (p=0.95). Receipt of 2009 TIV had no effect on one's risk of pandemic illness.

Abnormal compartmentalization of cartilage matrix components in mice lacking collagen X: implications for function.

There are conflicting views on whether collagen X is a purely structural molecule, or regulates bone mineralization during endochondral ossification. Mutations in the human collagen alpha1 (X) gene (COL10A1) in Schmid metaphyseal chondrodysplasia (SMCD) suggest a supportive role. But mouse collagen alpha1 (X) gene (Col10a1) null mutants were previously reported to show no obvious phenotypic change. We have generated collagen X deficient mice, which shows that deficiency does have phenotypic consequences which partly resemble SMCD, such as abnormal trabecular bone architecture. In particular, the mutant mice develop coxa vara, a phenotypic change common in human SMCD. Other consequences of the mutation are reduction in thickness of growth plate resting zone and articular cartilage, altered bone content, and atypical distribution of matrix components within growth plate cartilage. We propose that collagen X plays a role in the normal distribution of matrix vesicles and proteoglycans within the growth plate matrix. Collagen X deficiency impacts on the supporting properties of the growth plate and the mineralization process, resulting in abnormal trabecular bone. This hypothesis would accommodate the previously conflicting views of the function of collagen X and of the molecular pathogenesis of SMCD.

An electro-osmotic microfluidic system to characterize cancer cell migration under confinement.

We have developed a novel electro-osmotic microfluidic system to apply precisely controlled osmolarity gradients to cancer cells in micro-channels. We observed that albeit adhesion is not required for cells to migrate in such a confined microenvironment, the migrating velocity of cells is strongly influenced by the interactions between the cells and the channel wall, with a stronger adhesion leading to diminished cell motility. Furthermore, through examining more than 20 different types of cancer cells, we found a linear positive correlation between the protein concentration of the aquaporin-4 (AQP4) and the cell migrating speed. Knockdown of AQP4 in invasive re-populated cancer stem cells reduced their migration capability down to the level that is comparable to their parental cancer cells. Interestingly, these observations can all be quantitatively explained by the osmotic engine model where the cell movement is assumed to be driven by cross-membrane ion/water transport, while adhesion acts as a frictional resistance against the cell motility. By providing versatile and controllable features in regulating and characterizing the migration capability of cells, our system may serve as a useful tool in quantifying how cell motility is influenced by different physical and biochemical factors, as well as elucidating the mechanisms behind, in the future.

A randomized cross-over study of auto-continuous positive airway pressure versus fixed-continuous positive airway pressure in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVES: To compare the efficacy of auto-CPAP (AutoSet Spirit, ResMed) versus fixed-CPAP (S6 Elite, ResMed) in improving daytime sleepiness, health status, objective compliance and the ultimate treatment preference in patients with severe OSA. METHODS: The study recruited 43 subjects aged 18-65 years with newly diagnosed severe OSA (AHI >30/h). Patients were initially treated with either auto-CPAP or fixed-CPAP for 2 months and then crossed over after a washout period of 1 week for another 2 months. RESULTS: The study was completed by 41 patients. Results are presented as mean (SE). Use of auto-CPAP in the first and the second month was significantly higher than that of fixed-CPAP [129.7 (9.9) and 130.5 (10.7) h vs 115.2 (9.5) and 113.2 (9.4) h, P = 0.04 and 0.01], whereas mean hourly use per night was 4.3 and 4.4 h versus 3.8 and 3.7 h, respectively. The Epworth sleepiness scores improved after 1 month in both treatments (13.4 to 8.5 and 8.2, P < 0.01 for both). The Sleep apnoea quality of life index improved in the first month in both compared with baseline [4.6 (0.2) to 5.0 (0.2) for auto-CPAP and 4.9 (0.2) for fixed-CPAP, P = 0.01 and 0.04, respectively], with no difference between the two treatments. Nine and 30 patients preferred auto-CPAP and fixed-CPAP, respectively, at the end of the trial, whereas 14 and 25 patients would have chosen the same treatments if cost had not been a consideration. CONCLUSIONS: Auto-CPAP and fixed-CPAP were equally effective in improving symptoms and health status in patients with severe OSA. Usage was higher with auto-CPAP, but more patients ultimately chose fixed-CPAP.

Light-stimulated actuators based on nickel hydroxide-oxyhydroxide.

Light-induced actuators that are self-contained and compact can be used as artificial muscles for microrobotics because their actuation can be induced wirelessly, which reduces the complexity of the device or system. Here, we report a material system, nickel hydroxide-oxyhydroxide, that could actuate because of a volume change stimulated by illumination of visible light of low intensities. The actuating material here exhibited a turbostratic crystal structure capable of intercalating water, and we show that the intercalated water can be rapidly and reversibly desorbed into the environment under visible light of low intensities, resulting in fast actuation driven wirelessly by light. By electroplating the actuating material on passive substrates, we have fabricated film actuators capable of undergoing reversible bending and curling with an intrinsic actuating stress of 5 to 65 megapascals at response rates in the order of tens to hundreds of degrees per second depending on the light intensity, which are comparable to mammalian skeletal muscles. By intentionally electroplating the nickel hydroxide-oxyhydroxide on selected areas of the substrate, a hinged actuator that can lift objects ~100 times the weight of the actuating material is achieved. Other demonstrations show the potential uses in robotic devices, including sunlight-induced actuation, a biomimicked "sensitive plant" with rapid leaf movement, and a light-powered walking bot.

Molecular cloning and characterization of NF-IL3A, a transcriptional activator of the human interleukin-3 promoter.

To isolate transcription factors important in the regulation of the human interleukin-3 (IL-3) gene, we screened a lambda gt11 cDNA library, constructed from phytohemagglutinin-stimulated human T-cell RNA, with a probe containing regulatory sequences in the upstream region of the IL-3 gene (located from bp -165 to -128 and referred to as the DNase I footprint A region). We isolated a 0.96-kb cDNA that encoded a basic amino acid domain and a leucine zipper domain and used the "rapid amplification and cloning of 3' ends" technique to isolate the 3' half of the cDNA clone, generating a 1.9-kb full-length cDNA clone. Using in vitro-translated protein, which we call NF-IL3A, we defined the IL-3 promoter sequences bound by NF-IL3A in DNase I footprinting assays as TAATTACGTCTG and, using gel shift assays, defined ATTACG as the minimal sequence required for binding of NF-IL3A in vitro. Proteins that bind to the NF-IL3A binding site are found in both unstimulated and stimulated T-cell lines in similar amounts, although the level of NF-IL3A mRNA increases after T-cell activation in several mature T-cell lines. The NF-IL3A protein is nearly identical to a recently identified transcriptional repressor protein, E4BP4, and NF-IL3A binds specifically to regulatory sequences in both the adenovirus E4 promoter and the human gamma interferon promoter. Cotransfection experiments demonstrate that introduction of an expression vector containing the NF-IL3A cDNA into resting T cells transactivates IL-3 promoter-chloramphenicol acetyltransferase gene plasmids that contain the A region; this effect requires the presence of an intact NF-IL3A binding site. One or more copies of the A region also confer NF-IL3A responsiveness on a heterologous promoter in T cells. NF-IL3A appears to play an important role in the expression of IL-3 by T 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.

New steroidal anti-inflammatory antedrugs: 21-thioalkylether derivatives of methyl 16-prednisolone carboxylates.

Antedrug approach of the corticosteroids has been described as a fundamentally sound approach for the development of safer anti-inflammatory steroids devoid of systemic side effects. In our continued efforts under the antedrug paradigm, we have recently extended this effort to synthesize the 21-thioalkylether derivatives of methyl 16-prednisolonecarboxylates. The 21-mesylate of the methyl-16-perdnisolonecarboxylates and 9-fluoro-17-dehydro methyl 16-prednisolonecarboxylate were reacted with Na-thioalkoxides to furnish the desired thioalkylethers in 60-75% yields. These newly synthesized thioalkylether steroid series were tested for their in vitro metabolism and corticosteroid receptor binding affinity. They were metabolized in predictable manner to inactive 16-carboxylic acids. All the newly synthesized antedrugs showed lowered glucocorticoid receptor binding affinity than prednisolone indicating that the replacement of the 21-OH function with thioalkylether of the 16-prednisolone carboxylate esters decreases their receptor binding affinity.