An optimal control model for cloud seeding in a deterministic and stochastic environment

To promote artificial rain in India and other such developing countries, in this article, we have proposed and analyzed a nonlinear mathematical model for cloud seeding by considering that aerosols are introduced proportional to the density of water vapors present in the atmosphere. The model is analyzed using Lyapunov's stability theory of differential equations. To reduce the cost of cloud seeding, an optimal control strategy is designed by incorporating four control parameters. We have shown the existence and uniqueness of solution of this optimal control problem, using Pontryagins Maximum Principle. To minimize the cost in making artificial rain, the optimal control problem provides the strategy for the rate of introduction of aerosols in the atmosphere. To capture the effects of environmental noise on control strategies, the model in deterministic framework is converted into stochastic framework. In this regard, the Hamilton-Jacobi-Bellman equation for stochastic control cost function has been formed. The stochastic analysis implies that the control strategy is effective in reducing the cost and increasing rainfall.     

Is Use of BMP-2 Associated with Tumor Growth and Osteoblastic Differentiation in Murine Models of Osteosarcoma?

BackgroundThe putative benefit of rhBMP-2 is in the setting of limb reconstruction using structural allografts, whether it be allograft-prosthetic composites, osteoarticular allografts, or intercalary segmental grafts. There are also potential advantages in augmenting osseointegration of uncemented endoprosthetics and in reducing infection. Recombinant human BMP-2 might mitigate nonunion in structural allograft augmented osteosarcoma limb salvage surgery; however, its use is limited because of concerns about the prooncogenic effects of the agent.Questions/purposes(1) To assess if BMP-2 signaling influences osteosarcoma cell line growth. (2) To characterize degree of osteosarcoma cell line osteoblastic differentiation in response to BMP-2. (3) To assess if BMP-2 signaling has a consistent effect on local or systemic tumor burden in various orthotopic murine models of osteosarcoma.MethodsIn this study, 143b, SaOS-2 and DLM8-M1 osteosarcoma cell lines were transfected with BMP-2 cDNA controlled by a constitutive promoter (experimental) or an empty vector (control) using a PiggyBac transposon system. Cellular proliferation was assessed using a quantitative MTT colorimetric assay. Osteoblastic differentiation was compared between control and experimental cell lines using quantitative real-time polymerase chain reaction of the osteoblastic markers connective tissue growth factor, Runx-2, Osterix, alkaline phosphatase and osteocalcin. Experimental and control cell lines were injected into the proximal tibia of either NOD-SCID (143b and SaOS-2 xenograft model), or C3H (DLM8-M1 syngeneic model) mice. Local tumor burden was quantitatively assessed using tumor volume caliper measurements and bioluminescence, and qualitatively assessed using post-mortem ex vivo microCT. Lung metastasis was qualitatively assessed by the presence of bioluminescence, and incidence was confirmed using histology. rhBMP-2 soaked absorbable collagen sponges (experimental) and sterile-H₂O soaked absorbable collagen sponges (control) were implanted adjacent to 143b proximal tibial cell line injections to compare the effects of exogenous BMP-2 application with endogenous upregulation.ResultsConstitutive expression of BMP-2 increased the in vitro proliferation of 143b cells (absorbance values 1.2 ± 0.1 versus 0.89 ± 0.1, mean difference 0.36 [95% CI 0.12 to 0.6]; p = 0.01), but had no effect on SaOS-2 and DLM8-M1 cell proliferation. In response to constitutive BMP-2 expression, 143b cells had no differences in osteoblastic differentiation, while DLM8-M1 cells downregulated the early marker connective tissue growth factor (mean ΔCt 0.2 ± 0.1 versus 0.6 ± 0.1; p = 0.002) and upregulated the early-mid range marker Runx-2 (mean ΔCt -0.8 ± 0.1 versus -1.1 ± 0.1; p = 0.002), and SaOS-2 cells upregulated the mid-range marker Osterix (mean ΔCt -2.1 ± 0.6 versus -3.9 ± 0.6; p = 0.002). Constitutive expression of BMP-2 resulted in greater 143b and DLM8-M1 local tumor volume (143b: 307.2 ± 106.8 mm³ versus 1316 ± 387.4 mm³, mean difference 1009 mm³ [95% CI 674.5 to 1343]; p < 0.001, DLM8-M1 week four: 0 mm³ versus 326.1 ± 72.8 mm³, mean difference 326.1 mm³ [95% CI 121.2 to 531]; p = 0.009), but modestly reduced local tumor growth in SaOS-2 (9.5 x 10⁸ ± 8.3x10⁸ photons/s versus 9.3 x 10⁷ ± 1.5 x 10⁸ photons/s, mean difference 8.6 x 10⁸ photons/s [95% CI 5.1 x 10⁸ to 1.2 x 10⁹]; p < 0.001). Application of exogenous rhBMP-2 also increased 143b local tumor volume (495 ± 91.9 mm³ versus 1335 ± 102.7 mm³, mean difference 840.3 mm³ [95% CI 671.7 to 1009]; p < 0.001). Incidence of lung metastases was not different between experimental or control groups for all experimental conditions.ConclusionsAs demonstrated by others, ectopic BMP-2 signaling has unpredictable effects on local tumor proliferation in murine models of osteosarcoma and does not consistently result in osteosarcoma cell line differentiation. Further investigations into other methods of safe bone and soft tissue healing augmentation and the use of differentiation therapies is warranted.Clinical RelevanceOur results indicate that BMP-2 has the potential to stimulate the growth of osteosarcoma cells that are poorly responsive to BMP-2 mediated osteoblastic differentiation. As this differentiation potential is unpredictable in the clinical setting, BMP-2 may promote the growth of microscopic residual tumor burden after resection. Our study provides further support for the recommendation to avoid the use of BMP-2 after limb-salvage surgery in patients with osteosarcoma.     

Design,Synthesis, Biological Screening,and Molecular Docking Studies of Piperazine-Derived Constrained Inhibitors of DPP-IV for the Treatment of Type 2 Diabetes

Novel piperazine-derived conformationally constrained compounds were designed, synthesized, and evaluated for in vitro Dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. From a library of compounds synthesized, 1-(2-(4-(7-Chloro-4-quinolyl)piperazin-1-yl)acetyl)pyrrolidine ( 2g ) was identified as a potential DPP-IV inhibitor exhibiting better inhibitory activity than P32/98, reference inhibitor. The in vivo studies carried out in STZ and db/db mice models indicated that the compound 2g showed moderate antihyperglycemic activity as compared to the marketed drug Sitagliptin. A two-week repeated dose study in db/db mice revealed that compound 2g significantly declined blood glucose levels with no evidence of hypoglycemia risk. Furthermore, it showed improvement in insulin resistance reversal and antidyslipidemic properties. Molecular docking studies established good binding affinity of compound 2g at the DPP-IV active site and are in favor of the observed biological data. These data collectively suggest that compound 2g is a good lead molecule for further optimization studies.     

Development and validation of a questionnaire to assess socio-behavioural impact of COVID-19 on the general population

Background and aimThe aim of the study is to develop a valid and reliable tool to assess sociobehavioural changes due to COVID among the general population.MethodsThis mixed method study has two phases. Phase I for questionnaire development (literature review, focus group discussion, expert evaluation and pilot testing). Phase II for establishing construct validity via factor analysis and internal consistency via Cronbach’s ɑ by administering the questionnaire on 179 participants.ResultsA questionnaire comprising 33 questions and five domains was developed having Cronbach’s α of 0·82.ConclusionThe developed questionnaire is a concise, easy to administer and valid tool to assess socio-behavioural changes.     

Changing perspectives in Japanese encephalitis in India

Japanese encephalitis is a serious public health problem with significant mortality in children and old people. It occurs throughout much of Asia (43 000 cases worldwide per year). In recent years it has caused many epidemics in different parts of the country. In view of the high mortality and severe sequelae which often leaves behind highly dependent and disabled survivors, the disease is assuming great importance. A review of the pathogenesis, epidemiology, management and prevention together with changing perspectives in all these areas is presented.     

High sensitive C-reactive protein-Effective tool in determining postoperative recovery in lumbar disc disease

Background:

It is common in medical practice to see patients having persistent pain and radiculopathy even after undergoing discectomy surgery. Inflammatory cytokines, such as interleukins are produced at the site of disc herniation and are now considered responsible for the pain perceived by the patient. This study has used high sensitive C-reactive protein (HSCRP) assay for predicting inflammation around the nerve roots on very same principle, which has used HSCRP for predicting coronary artery diseases in current clinical practice. Thus, purpose of this study is to test whether HSCRP can stand as an objective tool to predict postoperative recovery in patients undergoing lumbar discectomy. That is, to study association between preoperative HSCRP blood level and postoperative recovery with the help of modified Oswestry Back Disability Score.

Materials and Methods:

A study group consisting of 50 cases of established lumbar disc disease and control group of 50 normal subjects, matched with the study group. Both the study and control groups were subjected to detailed evaluation with the help of modified Oswestry Low Back Pain Scale both pre and postoperatively at 3 months, 6 months and 1-year. The preoperative blood samples were analyzed to assess the HSCRP concentration. All the cases underwent surgery over a period of 1-year by the same surgeon.

Results:

The level of HSCRP in the study group was between 0.050– and 0.710 mg/dL and in the control group, 0.005-0.020 mg/dL. There was highly significant positive correlation between preoperative HSCRP level and postoperative score at P < 0.005. Cases with HSCRP level in the range of 0.1820 ± 0.079 mg/dL, showed better recovery (score improved > 10 points), while those with HSCRP level in the range of 0.470 ± 0.163 mg/dL, showed poor recovery (score improved < 10 points).

Conclusion:

HSCRP will serve as a good supplementary prognostic marker for operative decision making in borderline and troublesome cases of lumbar disc disease.     

Crystallization of Cyclophosphamide Monohydrate During Lyophilization

The purpose of this study was to investigate the phase behavior of cyclophosphamide (CPA) during various stages of lyophilization, with special emphasis on obtaining crystalline CPA monohydrate (CPA-MH) in the lyophilized product. Subambient differential scanning calorimetry and low-temperature X-ray diffractometry (LTXRD) were used to study the phase behavior of CPA solution (3.7% w/v). In situ lyophilization in LTXRD chamber was used to monitor the phase transitions occurring during the drying stages. Finally, the implications of these findings were confirmed by freeze-drying the aqueous solution in a laboratory-scale freeze-dryer. The results suggested that CPA remains amorphous during freeze concentration, with a T_g' of ?50°C. However, its crystallization as CPA-MH can be induced by annealing the frozen solution between ?5°C and ?10°C. In situ lyophilization in LTXRD showed that the CPA-MH crystallized during annealing, rapidly dehydrated during primary drying, thereby causing structural collapse. The dehydration of CPA-MH can be prevented by lowering the escaping tendency of water molecules from the crystal lattice of CPA-MH by maintaining the chamber pressure to 300, 400, or 500 mTorr. This study highlights the relationship of process parameters used during lyophilization with the solid form of lyophilized CPA.     

Gynaecomastia correction: A review of our experience

Introduction:

Gynaecomastia is a common problem in the male population with a reported prevalence of up to 36%. Various treatment techniques have been described but none have gained universal acceptance. We reviewed all gynaecomastia patients operated on by one consultant over a 7-year period to assess the morbidity and complication rates associated with the procedure.

Materials and Methods:

Clinical notes and outpatient records of all patients who underwent gynaecomastia correction at University Hospital North Staffordshire between 01/10/2001 to 01/10/2009 were retrospectively reviewed. A modified version of the Breast Evaluation Questionnaire was used to assess patients satisfaction with the procedure.

Results:

Twenty-nine patients and a total of 53 breasts were operated on during the study period. Patients underwent either liposuction alone (6 breasts - 11.3%), excision alone (37 breasts - 69.8%) or both excision and liposuction (10 breasts - 18.9%). Twelve operated breasts (22.6%) experienced some form of complication. Minor complications included seroma (2 patients), superficial wound dehiscence (2 patients) and minor bleeding not requiring theatre (3 patients). Two patients developed haematomas requiring evacuation in theatre. No cases of wound infection, major wound dehiscence or revision surgery were encountered. Twenty-six patients (89.7%) returned the patient satisfaction questionnaire. Patients scored an average 4.12 with regards comfort of their chest in different settings, 3.98 with regards chest appearance in different settings, and 4.22 with regards satisfaction levels for themselves and their partner/family. Overall complication rate was 22.6%. Grade III patients experienced the highest complication rate (35.7%), followed by grade II (22.7%) and grade I (17.6%). Overall complication rates among the excision only group was the highest (29.8%) followed by the liposuction only group (16.7%) and the liposuction and excision group (10.0%). There were high satisfaction rates amongst both patients and surgeon. Eleven patients (37.9%) had their outcome classified as ‘excellent’ by the operating surgeon, 16 patients (55.2%) as ‘good’, 1 (3.4%) as ‘satisfactory’ and 1(3.4%) as ‘poor’.

Conclusion:

Gynaecomastia is a complex condition which poses a significant challenge to the plastic surgeon. Despite the possible complications our case series demonstrates that outcomes of operative correction can be favourable and yield high levels of satisfaction from both patient and surgeon.KEY WORDS: Plastic Surgery, University Hospital North Staffordshire, Correction, gynaecomastia, surgery     

Identification and molecular characterization of a single-stranded circular DNA virus with similarities to Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1

A putative circular single-stranded DNA (ssDNA) virus was recovered from Hypericum japonicum collected in Vietnam. The viral isolate was tentatively named Hypericum japonicum-associated circular DNA virus (HJasCV). HJasCV shares 58.7-65.4% nucleotide sequence identity with Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 (SsHADV-1) and SsHADV-1-like viruses. Like this group of viruses, the genome of HJasCV (2 200 nt) has two large ORFs, one in the virion-sense and the other in the complementary-sense DNA. The proteins encoded in the virion-sense and complementary-sense ORFs share 39-46 % and 45-67 % amino acid sequence identity with the putative capsid and replication-associated proteins (Reps), respectively, of SsHADV-1 and SsHADV-1-like viruses. The putative Rep of HJasCV contains all of the motifs related to rolling-circle replication. Its 111-bp intergenic region (IR) contains a hairpin structure with a geminivirus-like nonanucleotide sequence, TAATGTTAT, at the apex of the loop. Phylogenetic analysis revealed that HJasCV forms a monophyletic clade with SsHADV-1 and SsHADV-1-like viruses.