Multitarget Mechanisms of Monocarbonyl Curcuminoid Analogues against HL-60 Cancer Cells: In Vitro and Network Pharmacology-Based Approach.

This study addressed the cytotoxic potential of four compounds: monocarbonyl curcuminoid, ethyl (2E)-2-benzylidene-3-oxobutanoate 1, 1,2-dimethoxy-12-methyl-13H- [1,3] benzodioxolo[5,6-c] phenanthridine 2, 3,5-dibenzyloxybenzyl bromide 3, and (E)-4-(4-chlorobenzylidene)-1-(4-nitrophenyl)hexan-3-one 4. In vitro cytotoxic assays were carried out in HL-60 and BJ cells using the MTT assay along with analysis of apoptosis with the annexin V detection kit. Additional network pharmacology and docking analyses were carried out. In the in vitro assays, compounds 2 and 4 displayed significant antiproliferative effects in HL-60 cells, exhibiting IC50 values of 5.02 and 9.50 µM, respectively. Compound 1 showed no activity, and compound 3 displayed toxicity in BJ cells. In addition, both compounds 2 and 4 induced apoptosis in HL-60 cells. Network pharmacology and docking analyses indicated that compounds 2 and 4 had synergistic effects targeting the CASP3 and PARP1 proteins. Notably, these proteins play pivotal roles in cancer-related pathways. Thus, by modulating these proteins, monocarbonyl curcuminoid has the potential to influence various cancer-related pathways. In summary, our novel findings provide valuable insights into the potential of these compounds to serve as novel anticancer therapeutic agents, warranting further mechanistic studies and clinical exploration.

Coverage and predictors of routine immunization among 12-23 months old children in disaster affected communities in Pakistan.

OBJECTIVES: We aimed this study to determine the relationship of various factors related to poor immunization in children in an earthquake affected community. MATERIALS AND METHODS: We conducted this cross-sectional study during 2007-2008 in Muzaffarabad district of Pakistani side of Kashmir. We selected 43 villages as clusters and in the second, 860 children between 12 and 24 months were selected from households through systematic sampling. Mothers of the eligible children were interviewed with a questionnaire. Logistic regression analysis was run to measure the association of various factors with appropriate immunization status of the children. RESULTS: We found that 74% of children had completed their required doses of routine immunization. There were greater odds of a child being unvaccinated if the family lived at a distance that was to be covered in more than 10 min by any transport (odds ratio [OR]: 1.12, confidence interval [CI]: 1.08-1.17), mother of the child was not educated (OR:2.4, 1.3-4.4), child belonged to a low socioeconomic status (OR:3.5, CI: 2.1-6.3), family had any challenge or situation that where they could not take the child to a health facility for vaccination (OR: 2.3, CI: 1.4-3.7) and for a female child that belonged to minority ethnic group (OR: 1.7, CI: 1.0-2.5). CONCLUSION: Improvement in access of communities, especially of minority and poor in disaster-stricken, to immunization services and female education and awareness about the need for immunization in children could play a role in improving immunization coverage in such settings.

Systemic Lupus Erythematosus Presenting as Refractory Thrombotic Thrombocytopenic Purpura: A Diagnostic and Management Challenge. A Case Report and Concise Review of the Literature.

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is one of the thrombotic microangiopathic (TMA) syndromes, caused by severely reduced activity of the vWF-cleaving protease ADAMTS13. Systemic lupus erythematosus (SLE), on the other hand, is an autoimmune disease that affects various organs in the body, including the hematopoietic system. SLE can present with TMA, and differentiating between SLE and TTP in those cases can be very challenging, particularly in patients with no prior history of SLE. Furthermore, an association between these 2 diseases has been described in the literature, with most of the TTP cases occurring after the diagnosis of SLE. In rare cases, TTP may precede the diagnosis of SLE or occur concurrently. CASE REPORT We present a case of a previously healthy 34-year-old female who presented with dizziness and flu-like symptoms and was found to have thrombocytopenia, hemolytic anemia, and schistocytes in the peripheral smear. She was subsequently diagnosed with TTP and started on plasmapheresis and high-dose steroids, but without a sustained response. A diagnosis of refractory TTP was made, and she was transferred to our facility for further management. Initially, the patient was started on rituximab, but her condition continued to deteriorate, with worsening thrombocytopenia. Later, she also fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria for diagnosis of SLE. Treatment of TTP in SLE patients is generally similar to that in the general population, but in refractory cases there are few reports in the literature that show the efficacy of cyclophosphamide. We started our patient on cyclophosphamide and noticed a sustained improvement in the platelet count in the following weeks. CONCLUSIONS Thrombotic thrombocytopenic purpura is a life-threatening hematological emergency which must be diagnosed and treated in a timely manner. Refractory cases of TTP have been described in the literature, but without clear evidence-based guidelines for its management, and is solely based on expert opinion and previous case reports. Further studies are needed to establish guidelines for its management. We present this case to highlight the role that cyclophosphamide might carry in those cases and to be a foundation for these future studies.

High-resolution solid-state 2H NMR spectroscopy of polymorphs of glycine.

High-resolution solid-state (2)H MAS NMR studies of the α and γ polymorphs of fully deuterated glycine (glycine-d(5)) are reported. Analysis of spinning sideband patterns is used to determine the (2)H quadrupole interaction parameters, and is shown to yield good agreement with the corresponding parameters determined from single-crystal (2)H NMR measurements (the maximum deviation in quadrupole coupling constants determined from these two approaches is only 1%). From analysis of simulated (2)H MAS NMR sideband patterns as a function of reorientational jump frequency (κ) for the -N(+)D(3) group in glycine-d(5), the experimentally observed differences in the (2)H MAS NMR spectrum for the -N(+)D(3) deutrons in the α and γ polymorphs is attributed to differences in the rate of reorientation of the -N(+)D(3) group. These simulations show severe broadening of the (2)H MAS NMR signal in the intermediate motion regime, suggesting that deuterons undergoing reorientational motions at rates in the range κ ≈ 10(4)-10(6) s(-1) are likely to be undetectable in (2)H MAS NMR measurements for materials with natural isotopic abundances. The (1)H NMR chemical shifts for the α and γ polymorphs of glycine have been determined from the (2)H MAS NMR results, taking into account the known second-order shift. Further quantum mechanical calculations of (2)H quadrupole interaction parameters and (1)H chemical shifts reveal the structural dependence of these parameters in the two polymorphs and suggest that the existence of two short intermolecular C-H···O contacts for one of the H atoms of the >CH(2) group in the α polymorph have a significant influence on the (2)H quadrupole coupling and (1)H chemical shift for this site.

Is procalcitonin better than C-reactive protein for early diagnosis of bacterial pneumonia in children?

Early diagnosis of bacterial pneumonia plays a pivotal role in the management. We evaluated the diagnostic accuracy of procalcitonin (PCT) as compared with C-reactive protein (CRP) for the early diagnosis of bacterial pneumonia in children. In total, 92 children consisting of 46 patients of bacterial pneumonia were admitted in the Military hospital, Rawalpindi, Pakistan and equal number of controls were included. Patient's investigations were carried out at admission. PCT and CRP were analyzed on Vidas analyzer and Immulite 1000, respectively. Out of 46 pneumonia patients, 28 were male and 18 female, with a median age of 4 years. PCT levels were significantly high median (range) of 2.69 ng/ml (0.30-13.00) vs. 0.45 ng/ml (0.10-2.00) in controls. Serum CRP levels were moderately elevated with median (range) 6.5 mg/l (0.30-60) vs. 0.30 mg/l (0.30-5.0) in controls. The area under receiver characteristic curves for PCT and CRP were 0.89 (95% CI=0.83-0.96) and 0.79 (95% CI=0.70-0.88), respectively. In total, 38 patients were diagnosed to have bacterial pneumonia with PCT (sensitivity 83% at cutoff > or = 1 ng/ml) and 26 children with CRP (sensitivity 57% at cutoff > or = 6 mg/L). PCT has better diagnostic accuracy than CRP and can be utilized for early diagnosis of bacterial pneumonia in children.

Characteristics of patients with Guillain Barre Syndrome at a tertiary care centre in Pakistan, 1995-2003.

OBJECTIVE: To study the clinical presentation, hospital course and outcome of patients admitted with Guillain Barre Syndrome (GBS) to a tertiary care hospital in Karachi, Pakistan. METHODS: The charts of patients conforming to International Classification of Diseases (ICD) code 9.0, for GBS, from September 1995 to January 2003 were reviewed. Clinical data was recorded on a standardized questionnaire, which included patients' age, sex, antecedent events, neurological signs and symptoms and ventilation requirement. The hospital course was analyzed, including nosocomial infections, therapy given and the functional status of patients, using the Rankin scale (0-6). Standard SPSS 11.5 software (Windows) was used for data analysis. RESULTS: Thirty-four cases of GBS were admitted to the hospital during the study period, with an age range of 3 to 70 years. The mean age for disease onset was 35.2 years for female patients, compared to 30 years for males; the male/female ratio was 1.6:1.Gastrointestinal infections (12/22, 54.6%) were the most common antecedent event, followed by upper respiratory tract infections (9/22, 40.9%) and skin lesions (1/22, 4.5%). Most patients developed GBS within one month of the preceding infection. Cranial nerve abnormalities (30/34, 88.2%), autonomic dysfunction (21/34, 61.8%) and respiratory failure requiring intubation (19/34, 55.9%) were also common. The median Rankin score of patients at admission, and at 30 and 60 days thereafter was 5, 4 and 3.5 respectively. The in-patient mortality was 1 of 34 (2.4%). CONCLUSION: We found that GBS occurred at all ages and was slightly more common in males. Majority of patients had an antecedent history of infection and had severe disease on presentation. The patients were treated with either plasmapheresis or intravenous immunoglobulins and there was no significant difference in outcome in the two groups. Despite severe persistent disability, in-hospital mortality was low.