Chronic pelvic pain in women: comparative study between ultrasonography and laparoscopy as diagnostic tool

Background: Chronic pelvic pain is a major cause of morbidity among the reproductive age group women. The study on patients of chronic pelvic pain aimed to compare the diagnostic accuracy of ultrasonography and laparoscopy in these patientsMethods: The study was conducted on 100 patients of chronic pelvic pain attending the gynaecology outdoor and were subjected to thorough clinical examination followed by ultrasonography and laparoscopic examination.Results: Maximum number of cases of chronic pelvic pain belonged to 25-30 years, were parous with mean duration of pain of 15.2 months. The most common complaint was vaginal discharge (70%) followed by menstrual irregularity. On clinical examination, pelvic tenderness was observed in majority (60%) of cases. USG examination showed chronic pelvic inflammatory disease in 43% cases followed by myoma (8%), ovarian cyst (5%), endometriosis (6%), pelvic congestion (5%) and no abnormal pathology in 25% cases. On laparoscopic examination, chronic pelvic inflammatory disease was present in 47% cases followed by endometriosis (11%), pelvic congestion (8%), myoma (8%), adhesions (7%) while 13% cases showed normal findings.Conclusions: Laparoscopy is more effective than ultrasonography as a diagnostic tool in patients of chronic pelvic pain.

Leprosy drug clofazimine activates peroxisome proliferator-activated receptor-γ and synergizes with imatinib to inhibit chronic myeloid leukemia cells

Leukemia stem cells contribute to drug-resistance and relapse in chronic myeloid leukemia (CML) and BCR-ABL1 inhibitor monotherapy fails to eliminate these cells, thereby necessitating alternate therapeutic strategies for patients CML. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone downregulates signal transducer and activator of transcription 5 (STAT5) and in combination with imatinib induces complete molecular response in imatinib-refractory patients by eroding leukemia stem cells. Thiazolidinediones such as pioglitazone are, however, associated with severe side effects. To identify alternate therapeutic strategies for CML we screened Food and Drug Administration-approved drugs in K562 cells and identified the leprosy drug clofazimine as an inhibitor of viability of these cells. Here we show that clofazimine induced apoptosis of blood mononuclear cells derived from patients with CML, with a particularly robust effect in imatinib-resistant cells. Clofazimine also induced apoptosis of CD34+38− progenitors and quiescent CD34+ cells from CML patients but not of hematopoietic progenitor cells from healthy donors. Mechanistic evaluation revealed that clofazimine, via physical interaction with PPARγ, induced nuclear factor kB-p65 proteasomal degradation, which led to sequential myeloblastoma oncoprotein and peroxiredoxin 1 downregulation and concomitant induction of reactive oxygen species-mediated apoptosis. Clofazimine also suppressed STAT5 expression and consequently downregulated stem cell maintenance factors hypoxia-inducible factor-1α and -2α and Cbp/P300 interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2). Combining imatinib with clofazimine caused a far superior synergy than that with pioglitazone, with clofazimine reducing the half maximal inhibitory concentration (IC50) of imatinib by >4 logs and remarkably eroding quiescent CD34+ cells. In a K562 xenograft study clofazimine and imatinib co-treatment showed more robust efficacy than the individual treatments. We propose clinical evaluation of clofazimine in imatinib-refractory CML

Infective Larvae of Brugia malayi Induce Polarization of Host Macrophages that Helps in Immune Evasion

Filarial parasites suppress, divert, or polarize the host immune response to aid their survival. However, mechanisms that govern the polarization of host MΦs during early filarial infection are not completely understood. In this study, we infected BALB/c mice with infective larvae stage-3 of Brugia malayi (Bm-L3) and studied their effect on the polarization of splenic MΦs. Results showed that MΦs displayed M2-phenotype by day 3 p.i. characterized by upregulated IL-4, but reduced IL-12 and Prostaglandin-D2 secretion. Increased arginase activity, higher arginase-1 but reduced NOS2 expression and poor phagocytic and antigen processing capacity was also observed. M2 MΦs supported T-cell proliferation and characteristically upregulated p-ERK but downregulated NF-κB-p65 and NF-κB-p50/105. Notably, Bm-L3 synergized with host regulatory T-cells (Tregs) and polarized M2 MΦs to regulatory MΦs (Mregs) by day 7 p.i., which secreted copious amounts of IL-10 and prostaglandin-E2. Mregs also showed upregulated expression levels of MHC-II, CD80, and CD86 and exhibited increased antigen-processing capacity but displayed impaired activation of NF-κB-p65 and NF-κB-p50/105. Neutralization of Tregs by anti-GITR + anti-CD25 antibodies checked the polarization of M2 MΦs to Mregs, decreased accumulation of regulatory B cells and inflammatory monocytes, and reduced secretion of IL-10, but enhanced IL-4 production and percentages of eosinophils, which led to Bm-L3 killing. In summary, we report hitherto undocumented effects of early Bm-L3 infection on the polarization of splenic MΦs and show how infective larvae deftly utilize the functional plasticity of host MΦs to establish themselves inside the host

Aged AG129 mice support the generation of highly virulent novel mouse-adapted DENV (1-4) viruses exhibiting neuropathogenesis and high lethality

Dengue virus infection in humans ranges from asymptomatic infection to severe infection, with ∼2.5 % overall disease fatality rate. Evidence of neurological manifestations is seen in the severe form of the disease, which might be due to the direct invasion of the viruses into the CNS system but is poorly understood. In this study, we demonstrated that the aged AG129 mice are highly susceptible to dengue serotypes 1–4, and following the adaptation, this resulted in the generation of neurovirulent strains that showed enhanced replication, aggravated disease severity, increased neuropathogenesis, and high lethality in both adult and aged AG129 mice. The infected mice had endothelial dysfunction, elicited pro-inflammatory cytokine responses, and exhibited 100 % mortality. Further analysis revealed that aged-adapted DENV strains induced measurable alterations in TLR expression in the aged mice as compared to the adult mice. In addition, metabolomics analysis of the serum samples from the infected adult mice revealed dysregulation of 18 metabolites and upregulation of 6-keto-prostaglandin F1 alpha, phosphocreatine, and taurocholic acid. These metabolites may serve as key biomarkers to decipher and comprehend the severity of dengue-associated severe neuro-pathogenesis