A prospective study of screening for musculoskeletal pathology in the child with a limp or pseudoparalysis using erythrocyte sedimentation rate, C-reactive protein and MRI.

PURPOSE: To determine if the detection of musculoskeletal pathology in children with a limp or acute limb disuse can be optimized by screening with blood tests for raised inflammatory markers, followed by MRI. METHODS: This was a prospective observational study. Entry criteria were children (0 to 16 years of age) presenting to our emergency department with a non-traumatic limp or pseudoparalysis of a limb, and no abnormality on plain radiographs. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) blood tests were performed. Children with ESR > 10 mm/hr or CRP > 10 mg/L underwent a MRI scan. When the location of the pathology causing the limp was clinically unclear, screening images (Cor t1 and Short Tau Inversion Recovery) of both lower limbs from pelvis to ankles ('legogram') was undertaken. Data was gathered prospectively from 100 consecutive children meeting the study criteria. RESULTS: In all, 75% of children had a positive finding on their MRI. A total of 64% of cases had an infective cause for their symptoms (osteomyelitis, septic arthritis, pyomyositis, fasciitis, cellulitis or discitis). A further 11% had positive findings on MRI from non-infective causes (juvenile idiopathic arthritis, cancer or undisplaced fracture). The remaining 25% had either a normal scan or effusion due to transient synovitis. ESR was a more sensitive marker than CRP in infection, since ESR was raised in 97%, but CRP in only 70%. CONCLUSION: In our opinion MRI imaging of all children with a limp and either raised ESR or CRP is a sensitive method to minimize the chance of missing important pathology in this group, and is an effective use of MRI resources. We advocate the use of both blood tests in conjunction. LEVEL OF EVIDENCE: Level II.

Biomechanical evaluation of different osteosynthesis methods after mandibular sagittal split osteotomy in major advancements.

The aim of this study was to assess the biomechanical stability of six different osteosynthesis methods after sagittal split osteotomy. Sixty polyurethane hemimandibles were divided into two groups, with six subgroups in each. After 10-mm advancement of the distal segment (group 1) and 10-mm advancement combined with 20° counterclockwise rotation (group 2), the bone segments were fixed using 2.0-mm plates/screws as follows: subgroup A, one conventional straight plate; subgroup B, two conventional straight plates; subgroup C, one conventional sagittal plate; subgroup D, one locking straight plate; subgroup E, two locking straight plates; subgroup F, one locking sagittal plate. The hemimandibles were tested for compressive strength by three-point biomechanical test, until there was 3mm of displacement between the segments. The fixations showed better performance in group 1 than in group 2 in all cases, with statistical significance for subgroups A, C, and D. In both groups, the use of two straight miniplates showed the most resistance, followed by the sagittal miniplates. However, in counterclockwise rotations, no statistically significant difference was found between two conventional straight plates and the sagittal locking plate. This study shows that the use of two plates is the form of fixation with the minimum displacement. If the clinician opts to use one plate, a sagittal plate is the best alternative.

Can hip arthroscopy in the presence of arthritis delay the need for hip arthroplasty?

Hip arthroscopy for joint preservation surgery has grown immensely over the last two decades. There is now an increasing trend to try and expand the role of hip arthroscopy to include patients of an older age or perhaps even with signs of arthritis, instead of the established patient group of young adults with mechanical symptoms or serious athletes. But how much of this growth is really justified? Once arthritis is apparent, the arthroscopic procedures needed to try and limit progression of the disease are likely to be different to those needed in young adult non-arthritic hips. Similarly, the expectation of results following an arthroscopic procedure in an older adult with arthritis must also be different. With an almost 5-fold increase in conversion rate from arthroscopy to arthroplasty in the over 50s population, arthroscopy in arthritis is a different procedure, with a different outcome, to arthroscopy in young adults with no evidence of osteoarthritis. This article takes a closer inspection at outcomes following hip arthroscopy in the older population particularly in those with evidence of early arthritis. This paper does not attempt to make recommendations in other diagnoses such as inflammatory arthritis or other secondary arthritides. It must be considered that hip arthroscopy is not a benign intervention: as well as the surgical risks, the lengthy rehabilitation period should be factored into the equation. Although the nature of surgeons is to find new techniques and push boundaries, we highlight the need for caution in undertaking arthroscopic intervention when arthritis is already apparent at presentation.

The correlation between body mass index, limb circumferences and blood pressure cuff fit in bariatric surgical patients.

INTRODUCTION: The purpose of this study was to determine the correlation between body mass index (BMI) and upper and lower arm as well as lower leg circumferences and the frequency of correct blood pressure (BP) cuff fit. We explored recommendations for the most likely BP cuff size and location for the three BMI categories. MATERIALS AND METHODS: Following IRB approval we retrospectively analyzed a research database of bariatric surgical patients with a BMI of ≥40 kg/m(2). Data included patients' characteristics, upper and lower arm as well as lower leg circumferences. Patients were divided into three groups based on BMI (kg/m(2), Group I: <45, Group II: 45-55, and Group III: >55). Appropriate cuff fit using a standard or large adult BP cuff (CRITIKON(®), GE Healthcare, Waukesha, Wisconsin, USA) on the upper and lower arm, and lower leg was determined. We analyzed the percent proportion of proper cuff fit for cuff sizes and locations between groups using appropriate nonparametric testing. RESULTS: Limb circumference correlated significantly with BMI (P = 0.01), and the upper arm correlated most closely (r = 0.76). A standard adult BP cuff on the lower arm fit properly in >90% and >80% and in Groups I and II, respectively. A large cuff on the lower arm was appropriate in 87% of Group III. In two participants, a large cuff fit properly on the lower leg. DISCUSSION: Limb circumference significantly correlated with BMI. Recommendations for proper cuff fit in different BMI categories can be made.

Obstructive sleep apnea: awakening the hidden truth.

Obstructive sleep apnea (OSA) is a common type of sleep apnea and is caused by obstruction of upper airway. Sleep apnea is clinically defined as frequent episodes of apnea, hypopnea and symptoms of functional impairment, which could be life-threatening and associated with extreme daytime hyper somnolence, dysfunction, discrements in health-related quality of life, automobile accidents, and cardiovascular morbidity and mortality. Etiopathogenic factors that contribute to OSA include reduced upper-airway dilator muscle activity during sleep, upper-airway anatomical features, ventilatory control insufficiency, lung volume, and rostral fluid shifts. The presence of risk factors such as age, gender and obesity increases the incidence of OSA. The repetitive nocturnal hypoxemia experienced by patients with OSA is associated with activation of a number of neural, humoral, thrombotic, metabolic, and inflammatory disease mechanisms, all of which have also been implicated in the pathophysiology of various systemic diseases. This article summarizes the etiopathogenesis, epidemiology, associated systemic diseases such as cardiovascular diseases, diabetes, and dental diseases with OSA and the influence of tongue on oropharyngeal airway in OSA patients.

Magnetically retained silicone facial prosthesis.

Patients with orocutaneous fistulas suffer from discomfort in terms of facial esthetics, food spill over and lack of psychological confidence to present them socially. Prosthetic camouflaging of facial defects and use of silicone maxillofacial material are the alternatives to the surgical retreatment. Silicone elastomers provide more options to clinician for customization of the facial prosthesis which is simple, esthetically good when coupled with bio magnets for retention.

Synthesis and biological evaluation of diaryl ether linked DC-81 conjugates as potential antitumor agents.

A series of new diaryl ether linked pyrrolobenzodiazepine (PBD) conjugates (4a-i, 5a-i and 6a-f) was synthesized and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. These conjugates exhibited significant anticancer activity with GI50 values in the range of 0.1-3.88 µM. Some of the potent conjugates (4b, 4h, 5h, 6b, 6c and 6e) were further investigated on cell cycle distribution. FACS analysis showed the accumulation of cells in G0 phase indicating the apoptosis inducing nature of these conjugates. Moreover, compound 6b caused a decrease in the mitochondrial membrane potential, which indicates the apoptotic nature of the compound through mitochondrial mediated pathway. Further conjugates 4b, 4h and 6b induce the activation of caspase and PARP proteins, followed by apoptotic cell death in MCF7 cell line.

Anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates as p53 activators in cervical cancer cells.

A library of new anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates were designed, synthesized, and evaluated for their anticancer activity in cervical cancer cells such as HeLa and SiHa that possess low levels of p53. All 24 conjugates showed antiproliferative activity, while some of them exhibit significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G(2) /M arrest in HeLa cells and G(1) cell-cycle arrest in SiHa cells. Immunocytochemistry assays revealed that these compounds cause nuclear translocation of p53, thereby indicating the activation of p53. In cervical cancer cells, the p53 protein is degraded by E6 oncoprotein. Immunoblot and RT-PCR analyses proved the presence of mitochondria-mediated apoptosis with involvement p53 target genes such as BAX, Bcl2, and p21 (CDKI). Moreover, these compounds increased the phosphorylated forms of p53 and provide signals for apoptosis induction. Interestingly, one of the conjugates, (2-phenyl-7-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-(2-(thiophen-2-ylmethylamino)benzoyl)piperazin-1-yl)methanone, is the most promising candidate in this series and has the potential to be taken up for further detailed studies.

Synthesis, biological evaluation of 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone, 5-carboethoxymethyl-4',7-dihydroxyflavone and their analogues.

In this letter, we describe the first synthesis of two recently isolated flavones 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone (3a), 5-carboethoxymethyl-4',7-dihydroxyflavone (3b) and their derivatives (3c-t), evaluated for their antimicrobial, antioxidant and anticancer activities. Most of the synthesized compounds exhibited antimicrobial activity against the tested microbial strains and some of these compounds were found to be more potent as compared to the standard drugs like neomycin and luteolin. Interestingly, some of these synthesized compounds also showed moderate antioxidant property.

3-substituted 2-phenylimidazo[2,1-b]benzothiazoles: synthesis, anticancer activity, and inhibition of tubulin polymerization.

A new series of 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles (3 a-h) were synthesized by C-arylation of 2-arylimidazo[2,1-b]benzothiazoles using palladium acetate as catalyst, and the resulting compounds were evaluated for their anticancer activity. Compounds 3 a, 3 e, and 3 h exhibited good antiproliferative activity, with GI50 values in the range of 0.19-83.1 µM. Compound 3 h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI50 value of 0.88 µM. This compound also induced cell-cycle arrest in the G2/M phase and inhibited tubulin polymerization followed by activation of caspase-3 and apoptosis. A high-throughput tubulin polymerization assay showed that the level of inhibition for compound 3 h is similar to that of combretastatin A-4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3 a, 3 e, and 3 h to the colchicine binding pocket of tubulin.

Design and synthesis of benzo[c,d]indolone-pyrrolobenzodiazepine conjugates as potential anticancer agents.

A series of benzo[c,d]indol-2(1H)one-PBD conjugates (11a-l) have been designed and synthesized as potential anticancer agents. These compounds were prepared by linking the C8-position of DC-81 with a benzo[c,d]indol-2(1H)one moiety through different alkane spacers in good yields and confirmed by (1)H NMR, mass and HRMS data. The DNA binding ability of these conjugates was evaluated by thermal denaturation studies and interestingly, compound 11l showed enhanced DNA binding ability. These compounds were also evaluated for their anticancer activity in selected human cancer cell lines of lung, skin, colon and prostate by using MTT assay method. These new conjugates showed promising anticancer activity with IC(50) values ranging from 1.05 to 36.49 µM. Moreover, cell cycle arrest in SubG1 phase was observed upon treatment of A549 cells with 1 and 2 µM (IC(50)) concentrations of compound 11l and it induced apoptosis. This is confirmed by Annexin V-FITC, Hoechst staining, caspase-3 activity as well as DNA fragmentation analysis.

Synthesis and anticancer activity of oxindole derived imidazo[1,5-a]pyrazines.

A series of oxindole derivatives of imidazo[1,5-a]pyrazines were prepared and confirmed by 1H NMR, mass and HRMS data. These compounds were evaluated for their anticancer activity against a panel of 52 human tumor cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Among them compound 7l showed significant anticancer activity with GI50 values ranging from 1.54 to 13.0 µM. Cell cycle arrest was observed in G0/G1 phase upon treatment of A549 cells with 6.5 µM (IC50) concentration of compound 7l and induced apoptosis. This was confirmed by Annexin V-FITC as well as DNA fragmentation analysis and interestingly this compound (7l) did not affect the normal cells.

Synthesis and biological evaluation of 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydroquinazolinone hybrids as anticancer agents.

A series of new 3,5-diaryl isoxazoline/isoxazole linked 2,3-dihydro quinazolinone hybrids with different linker architectures have been designed and synthesized. These compounds have been evaluated for their anticancer activity. One of the compounds 4c amongst this series has shown promising anticancer activity. Further some detailed biological assays relating to the cell cycle aspects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of this conjugate.

Synthesis and anti-cancer activity of chalcone linked imidazolones.

A series of novel chalcone linked imidazolones were prepared and evaluated for their anti-cancer activity against a panel of 53 human tumour cell lines derived from nine different cancer types: leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast. Some of these hybrids (6, 7 and 8) showed good anti-cancer activity with GI(50) values ranging from 1.26 to 13.9 microM. When breast carcinoma cells (MCF-7) were treated with 10 microM concentration of compounds TMAC, CA-4, 6 and 8 cell cycle arrest was observed in G2/M phase. Surprisingly, the increased concentration of the same compound to 30 microM caused accumulation of cells in G0/G1 phase of the cell cycle.

Synthesis, anticancer activity and apoptosis inducing ability of anthranilamide-PBD conjugates.

A series of novel anthranilamide linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates were prepared and evaluated for their anticancer activity. The effects of three promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These promising compounds showed the characteristic features of apoptosis like enhancement in the levels of p53 and activation of caspase-3.

Quinazolinone linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates: Design, synthesis and biological evaluation as potential anticancer agents.

A series of novel quinazolinone linked pyrrolobenzodiazepine (PBD) conjugates were synthesized. These compounds 4a-f and 5a-f were prepared in good yields by linking C-8 of DC-81 with quinazolinone moiety through different alkane spacers. These conjugates were tested for anticancer activity against 11 human cancer cell lines and found to be very potent anticancer agents with GI(50) values in the range of <0.1-26.2microM. Among all the PBD conjugates, one of the conjugate 5c was tested against a panel of 60 human cancer cells. This compound showed activity for individual cancer cell lines with GI(50) values of <0.1microM. The thermal denaturation studies exhibited effective DNA binding ability compared to DC-81 and these results are further supported by molecular modeling studies. The detailed biological aspects of these conjugates on A375 cell line were studied. It was observed that compounds 4b and 5c induced the release of cytochrome c, activation of caspase-3, cleavage of PARP and subsequent cell death. Further, these compounds when treated with A375 cells showed the characteristic features of apoptosis like enhancement in the levels of p53, p21 and p27 inhibition of cyclin dependent kinase-2 (CDK2) and suppression of NF-kappaB. Moreover, these two compounds 4b and 5c control the cell proliferation by regulating anti-apoptotic genes like (B-cell lymphoma 2) Bcl-2. Therefore, the data generated suggests that these PBD conjugates activate p53 and inhibit NF-kappaB and thereby these compounds could be promising anticancer agents with better therapeutic potential for the suppression of tumours.

Glycaemic control and body mass index in late-adolescents and young adults with Type 1 diabetes mellitus: a population-based study.

AIMS: Studies of children with diabetes up to the age of 15 years report deteriorating glycaemic control in the early teenage years. The aim was to investigate glycaemia and body mass index in older teenagers and young adults. METHOD: A Scottish, regional, population-based, cross-sectional study of 255 young people (117 female, 138 male) with Type 1 diabetes, aged 15-25 years (mean +/-sd 19.8 +/- 2.8 years, diabetes duration: 8.8 +/- 5.4 years) registered on a diabetes database. Glycaemic control, body mass index (BMI) and insulin regimens were assessed in three age groups [group 1 (n = 96) 15-18 years; group 2 (n = 74) 18.1-22 years; and group 3 (n = 85) 22.1-25 years]. RESULTS: Subjects in the oldest age group had a significantly lower mean HbA(1c) than those in the youngest age group (8.8 +/- 1.7 vs. 9.9 +/- 1.9%; P < 0.001). Mean BMI was higher in group 3 (25.2 +/- 3.4 kg/m(2)) compared with group 1 (23.9 +/- 3.1 kg/m(2); P < 0.001). HbA(1c )levels were higher in the younger subjects and women. Lower HbA(1c) levels were associated with a higher BMI (r = -0.324, P < 0.001) in men only. Overall, 74% took three or more injections a day, of whom 60% were on basal/bolus therapy. The proportion on basal/bolus insulin therapy increased with age and duration of diabetes. CONCLUSION: Compared with adolescents, young adults with Type 1 diabetes have better glycaemic control and higher BMI. This was associated with lower insulin requirements.

Home administration of lanreotide Autogel by patients with acromegaly, or their partners, is safe and effective.

OBJECTIVE: The introduction of ready-to-use lanreotide Autogel has presented the possibility of patients receiving their acromegaly treatment at home. The objective of this study was to assess the ability of patients (or their partners) to administer repeat, unsupervised, injections of lanreotide Autogel without compromising efficacy or safety. DESIGN: Multicentre (10 UK regional endocrine centres), open-label, nonrandomised, controlled study. Patients elected either to receive/administer unsupervised home injections after injection technique training (Test group) or continued to receive injections from a healthcare professional (Control group). Patients received monthly injections of lanreotide Autogel at their established dose. Effects were monitored for up to 40 weeks. PATIENTS: Thirty patients (15 per treatment group) with acromegaly treated with a stable dose of lanreotide Autogel (60, 90 or 120 mg) for > or = 4 months before screening. Measurements The main outcome measure was the proportion of patients/partners who successfully administered injections throughout the study. RESULTS: All Test group patients/partners qualified to administer injections. Fourteen of 15 patients fulfilled all criteria for successful administration of unsupervised injections (95% confidence interval, 70%-99%). Fourteen of 15 Test and 14/15 Control patients maintained growth hormone and IGF-1 control. Local injection tolerability was good for both treatment groups, and safety profiles were similar. All Test group patients continued with unsupervised injections after the study. CONCLUSIONS: Patients with acromegaly or their partners were able to administer lanreotide Autogel injections with no detrimental effect on efficacy and safety; therefore, unsupervised home injections are a viable alternative to healthcare professional injections for suitably motivated patients.