Nitric oxide-induced cytostasis and cell cycle arrest of a human breast cancer cell line (MDA-MB-231): potential role of cyclin D1

DETA-NONOate, a nitric oxide (NO) donor, induced cytostasis in the human breast cancer cells MDA-MB-231, and the cells were arrested in the G(1) phase of the cell cycle. This cytostatic effect of the NO donor was associated with the down-regulation of cyclin D1 and hypophosphorylation of the retinoblastoma protein. No changes in the levels of cyclin E or the catalytic partners of these cyclins, CDK2, CDK4, or CDK6, were observed. This NO-induced cytostasis and decrease in cyclin D1 was reversible for up to 48 h of DETA-NONOate (1 mM) treatment. DETA-NONOate (1 mM) produced a steady-state concentration of 0.5 microM of NO over a 24-h period. Synchronized population of the cells exposed to DETA-NONOate remained arrested at the G(1) phase of the cell cycle whereas untreated control cells progressed through the cell cycle after serum stimulation. The cells arrested at the G(1) phase after exposure to the NO donor had low cyclin D1 levels compared with the control cells. The levels of cyclin E and CDK4, however, were similar to the control cells. The decline in cyclin D1 protein preceded the decrease of its mRNA. This decline of cyclin D1 was due to a decrease in its synthesis induced by the NO donor and not due to an increase in its degradation. We conclude that down-regulation of cyclin D1 protein by DETA-NONOate played an important role in the cytostasis and arrest of these tumor cells in the G(1) phase of the cell cycle.     

Medial patellofemoral ligament reconstruction in patellar instability

Background:

Medial patellofemoral ligament (MPFL) is one of the major static medial stabilising structures of the patella. MPFL is most often damaged in patients with patellar instability. Reconstruction of MPFL is becoming a common surgical procedure in treating patellar instability. We hypothesised that MPFL reconstruction was adequate to treat patients with patellar instability if the tibial tubercle and the centre of the trochlear groove (TT-TG) value was less than 20 mm and without a dysplastic trochlea.

Materials and Methods:

30 patients matching our inclusion criteria and operated between April 2009 and May 2011 were included in the study. MPFL reconstruction was performed using gracilis tendon fixed with endobutton on the patellar side and bio absorbable interference screw or staple on the femoral side. Patients were followed up with subjective criteria, Kujala score and Lysholm score.

Results:

The mean duration of followup was 25 months (range 14-38 months). The mean preoperative Kujala score was 47.5 and Lysholm score was 44.7. The mean postoperative Kujala score was 87 and Lysholm score was 88.06. None of the patients had redislocation.

Conclusion:

MPFL reconstruction using gracilis tendon gives excellent results in patients with patellar instability with no redislocations. Some patients may have persistence of apprehension.     

Successful Aortic Valve Replacement Surgery in a Patient with Severe Haemophilia a with Low Titre Inhibitor

Acute leukemia, secondary myelodysplasia and paroxysmal nocturnal hemoglobinuria evolving from severe aplastic anemia (AA) following immunosuppressive therapy are well recognized. However, severe AA occurring after complete remission of acute promyelocytic leukemia (APL) has been documented only once in 2009. We report a case of 30-year-old male diagnosed with APL who achieved complete cytogenetic remission with all-trans retinoic acid based induction regimen and developed severe AA few months later during maintenance therapy.     

The cost-effectiveness of deep brain stimulation in combination with best medical therapy, versus best medical therapy alone, in advanced Parkinson’s disease

Parkinson’s disease (PD) is a complex progressive movement disorder leading to motor and non-motor symptoms that become increasingly debilitating as the disease advances, considerably reducing quality of life. Advanced treatment options include deep brain stimulation (DBS). While clinical effectiveness of DBS has been demonstrated in a number of randomised controlled trials (RCT), evidence on cost-effectiveness is limited. The cost-effectiveness of DBS combined with BMT, versus BMT alone, was evaluated from a UK payer perspective. Individual patient-level data on the effect of DBS on PD symptom progression from a large 6-month RCT were used to develop a Markov model representing clinical progression and capture treatment effect and costs. A 5-year time horizon was used, and an incremental cost-effectiveness ratio (ICER) was calculated in terms of cost per quality-adjusted life-years (QALY) and uncertainty assessed in deterministic sensitivity analyses. Total discounted costs in the DBS and BMT groups over 5 years were £68,970 and £48,243, respectively, with QALYs of 2.21 and 1.21, giving an incremental cost-effectiveness ratio of £20,678 per QALY gained. Utility weights in each health state and costs of on-going medication appear to be the key drivers of uncertainty in the model. The results suggest that DBS is a cost-effective intervention in patients with advanced PD who are eligible for surgery, providing good value for money to health care payers.