Outcome of Percutaneous Fixation of Calcaneal Fractures: A Prospective Analysis in an Indian Population.

Displaced intra-articular calcaneal fractures can be difficult to treat. Open surgical techniques are associated with wound complications, whereas nonoperative management leads to arthrosis. In the present study, 23 displaced intra-articular calcaneal fractures in 19 patients were treated with closed reduction and percutaneous Kirschner wire fixation. Sanders and Essex-Lopresti classification systems were used. We studied anatomical (Gissane and Bohler angles and width of calcaneus) and functional (Maryland Foot Score and American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Score) outcomes after 6, 18, and 26 months. Mechanism of injury, fluoroscopy use, time since injury, time delay to surgery, method of reduction, and number of Kirschner wires used were recorded. The mean participant age was 29.5 (17 to 46) years, mean delay to surgery was 7 (2 to 12) days, mean length of surgery was 61 (range 20 to 175) minutes, and mean fluoroscopy time was 115 (range 20 to 254) seconds. All patients were followed for a minimum of 26 months, and the mean duration of follow-up was 32.4 (26 to 36) months. There were 18 (78.26%) joint depression and 5 (21.74%) tongue-type fractures, whereas there were 2 (8.69%) Sanders type II, 13 (56.52%) Sanders type III, and 8 (34.78%) Sanders type IV fractures. The mean Maryland Foot Score and American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Score at 6 months were 86.7 (81 to 92) and 84.2 (75 to 93), whereas at 26 months, the scores were 87.7 (82 to 93) and 85.1 (75 to 94), respectively. No pin site infections, cases of sural nerve dysfunction, or revision/additional surgery was experienced, and 17 (86.6%) patients were able to return to their original occupation at the end of 26 months.

Longitudinal study of fingerprint recognition.

Human identification by fingerprints is based on the fundamental premise that ridge patterns from distinct fingers are different (uniqueness) and a fingerprint pattern does not change over time (persistence). Although the uniqueness of fingerprints has been investigated by developing statistical models to estimate the probability of error in comparing two random samples of fingerprints, the persistence of fingerprints has remained a general belief based on only a few case studies. In this study, fingerprint match (similarity) scores are analyzed by multilevel statistical models with covariates such as time interval between two fingerprints in comparison, subject's age, and fingerprint image quality. Longitudinal fingerprint records of 15,597 subjects are sampled from an operational fingerprint database such that each individual has at least five 10-print records over a minimum time span of 5 y. In regard to the persistence of fingerprints, the longitudinal analysis on a single (right index) finger demonstrates that (i) genuine match scores tend to significantly decrease when time interval between two fingerprints in comparison increases, whereas the change in impostor match scores is negligible; and (ii) fingerprint recognition accuracy at operational settings, nevertheless, tends to be stable as the time interval increases up to 12 y, the maximum time span in the dataset. However, the uncertainty of temporal stability of fingerprint recognition accuracy becomes substantially large if either of the two fingerprints being compared is of poor quality. The conclusions drawn from 10-finger fusion analysis coincide with the conclusions from single-finger analysis.

Role of p53 in silibinin-mediated inhibition of ultraviolet B radiation-induced DNA damage, inflammation and skin carcinogenesis.

Non-melanoma skin cancers (NMSC) are a growing problem given that solar ultraviolet B (UVB) radiation exposure is increasing most likely due to depletion of the atmospheric ozone layer and lack of adequate sun protection. Better preventive methods are urgently required to reduce UV-caused photodamage and NMSC incidence. Earlier, we have reported that silibinin treatment activates p53 and reduces photodamage and NMSC, both in vitro and in vivo; but whether silibinin exerts its protective effects primarily through p53 remains unknown. To address this question, we generated p53 heterozygous (p53+/-) and p53 knockout (p53-/-) mice on SKH-1 hairless mouse background, and assessed silibinin efficacy in both short- and long-term UVB exposure experiments. In the chronic UVB-exposed skin tumorigenesis study, compared to p53+/+ mice, p53+/- mice developed skin tumors earlier and had higher tumor number, multiplicity and volume. Silibinin topical treatment significantly reduced the tumor number, multiplicity and volume in p53+/+ mice but silibinin' protective efficacy was significantly compromised in p53+/- mice. Additionally, silibinin treatment failed to inhibit precursor skin cancer lesions in p53-/- mice but improved the survival of the mice. In short-term studies, silibinin application accelerated the removal of UVB-induced DNA damage in p53+/+ mice while its efficacy was partially compromised in p53-/- mice. Interestingly, silibinin treatment also inhibited the UVB-induced inflammatory markers in skin tissue. These results further confirmed that absence of the p53 allele predisposes mice to photodamage and photocarcinogenesis, and established that silibinin mediates its protection against UVB-induced photodamage, inflammation and photocarcinogenesis partly through p53 activation.

Silibinin inhibits hypoxia-induced HIF-1α-mediated signaling, angiogenesis and lipogenesis in prostate cancer cells: In vitro evidence and in vivo functional imaging and metabolomics.

Hypoxia is associated with aggressive phenotype and poor prognosis in prostate cancer (PCa) patients suggesting that PCa growth and progression could be controlled via targeting hypoxia-induced signaling and biological effects. Here, we analyzed silibinin (a natural flavonoid) efficacy to target cell growth, angiogenesis, and metabolic changes in human PCa, LNCaP, and 22Rv1 cells under hypoxic condition. Silibinin treatment inhibited the proliferation, clonogenicity, and endothelial cells tube formation by hypoxic (1% O2 ) PCa cells. Interestingly, hypoxia promoted a lipogenic phenotype in PCa cells via activating acetyl-Co A carboxylase (ACC) and fatty acid synthase (FASN) that was inhibited by silibinin treatment. Importantly, silibinin treatment strongly decreased hypoxia-induced HIF-1α expression in PCa cells together with a strong reduction in hypoxia-induced NADPH oxidase (NOX) activity. HIF-1α overexpression in LNCaP cells significantly increased the lipid accumulation and NOX activity; however, silibinin treatment reduced HIF-1α expression, lipid levels, clonogenicity, and NOX activity even in HIF-1α overexpressing LNCaP cells. In vivo, silibinin feeding (200 mg/kg body weight) to male nude mice with 22Rv1 tumors, specifically inhibited tumor vascularity (measured by dynamic contrast-enhanced MRI) resulting in tumor growth inhibition without directly inducing necrosis (as revealed by diffusion-weighted MRI). Silibinin feeding did not significantly affect tumor glucose uptake measured by FDG-PET; however, reduced the lipid synthesis measured by quantitative 1 H-NMR metabolomics. IHC analyses of tumor tissues confirmed that silibinin feeding decreased proliferation and angiogenesis as well as reduced HIF-1α, FASN, and ACC levels. Together, these findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling. © 2016 Wiley Periodicals, Inc.

Beneficial effects of the naturally occurring flavonoid silibinin on the prostate cancer microenvironment: role of monocyte chemotactic protein-1 and immune cell recruitment.

Tumor microenvironment plays an essential role in prostate carcinogenesis and offers novel opportunities to prevent and treat prostate cancer (PCA). Here, we investigated the ability of cancer-associated fibroblasts (CAFs) to promote PCA progression, and silibinin efficacy to target this response. We collected conditioned media from CAFs treated with vehicle or silibinin, and labeled as control conditioned media (CCM) or silibinin-treatment conditioned media (SBCM), respectively. Next, we characterized the effect of CCM and SBCM treatment in several PCA cell lines (RWPE-1, WPE-1 NA-22, WPE-1 NB-14 and PC3). Result showed that compared with SBCM, CCM significantly reduces E-cadherin expression and increases invasiveness and clonogenicity in PCA cells. Further molecular studies identified monocyte chemotactic protein-1 (MCP-1) as the key component of CCM that promotes PCA invasiveness, whereas silibinin treatment strongly reduced MCP-1 expression in CAFs by inhibiting the DNA-binding activity of MCP-1 transcriptional regulators-nuclear factor-kappaB and AP-1. In vivo, silibinin feeding (200mg/kg body weight) strongly reduced TRAMPC1 allografts growth (by 68%) in syngeneic C57Bl/6 mice. TRAMPC1 tumor analysis showed that silibinin reduced MCP-1 and CAFs' biomarkers (fibroblast activation protein, α-smooth muscle actin, transforming growth factor beta 2, vimentin etc.) and significantly modulated the recruitment of immune cells in the tumor microenvironment. Similar inhibitory effects of silibinin on MCP-1 and immune cells recruitment were also observed in TRAMP PCA tissues with reported silibinin efficacy. Overall, our data suggest that silibinin can target CAF-mediated invasiveness in PCA by inhibiting MCP-1 secretion. This, in turn, was associated with a reduction in immune cell recruitment in vivo along with a marked reduction in tumor growth.

Asiatic acid induces endoplasmic reticulum stress and apoptotic death in glioblastoma multiforme cells both in vitro and in vivo.

Glioblastoma multiforme (GBM) is an untreatable malignancy. Existing therapeutic options are insufficient, and adversely affect functional and non-cancerous cells in the brain impairing different functions of the body. Therefore, there is an urgent need for additional preventive and therapeutic non-toxic drugs against GBM. Asiatic acid (AsA; 2,3,23-trihydroxy-12-ursen-28-oic acid, C30 H48 O5 ) is a natural small molecule widely used to treat various neurological disorders, and the present research investigates AsA's efficacy against GBM both in vitro and in vivo. Results showed that AsA treatment (10-100 µM) decreased the human GBM cell (LN18, U87MG, and U118MG) viability, with better efficacy than temozolomide at equimolar doses. Orally administered AsA (30 mg/kg/d) strongly decreased tumor volume in mice when administered immediately after ectopic U87MG xenograft implantation (54% decrease, P ≤ 0.05) or in mice with established xenografts (48% decrease, P ≤ 0.05) without any apparent toxicity. Importantly, AsA feeding (30 mg/kg/twice a day) also decreased the orthotopic U87MG xenografts growth in nude mice as measured by magnetic resonance imaging. Using LC/MS-MS methods, AsA was detected in mice plasma and brain tissue, confirming that AsA crosses blood-brain barrier. Mechanistic studies showed that AsA induces apoptotic death by modulating the protein expression of several apoptosis regulators (caspases, Bcl2 family members, and survivin) in GBM cells. Furthermore, AsA induced ER stress (increased GRP78 and Calpain, and decreased Calnexin and IRE1α expression), enhanced free intra-cellular calcium, and damaged cellular organization in GBM cells. These experimental results demonstrate that AsA is effective against GBM, and advocate further pre-clinical and clinical evaluations of AsA against GBM.

Silibinin prevents prostate cancer cell-mediated differentiation of naïve fibroblasts into cancer-associated fibroblast phenotype by targeting TGF ß2.

Tumor microenvironment (TM) is an essential element in prostate cancer (PCA), offering unique opportunities for its prevention. TM includes naïve fibroblasts that are recruited by nascent neoplastic lesion and altered into 'cancer-associated fibroblasts' (CAFs) that promote PCA. A better understanding and targeting of interaction between PCA cells and fibroblasts and inhibiting CAF phenotype through non-toxic agents are novel approaches to prevent PCA progression. One well-studied cancer chemopreventive agent is silibinin, and thus, we examined its efficacy against PCA cells-mediated differentiation of naïve fibroblasts into a myofibroblastic-phenotype similar to that found in CAFs. Silibinin's direct inhibitory effect on the phenotype of CAFs derived directly from PCA patients was also assessed. Human prostate stromal cells (PrSCs) exposed to control conditioned media (CCM) from human PCA PC3 cells showed more invasiveness, with increased alpha-smooth muscle actin (α-SMA) and vimentin expression, and differentiation into a phenotype we identified in CAFs. Importantly, silibinin (at physiologically achievable concentrations) inhibited α-SMA expression and invasiveness in differentiated fibroblasts and prostate CAFs directly, as well as indirectly by targeting PCA cells. The observed increase in α-SMA and CAF-like phenotype was transforming growth factor (TGF) ß2 dependent, which was strongly inhibited by silibinin. Furthermore, induction of α-SMA and CAF phenotype by CCM were also strongly inhibited by a TGFß2-neutralizing antibody. The inhibitory effect of silibinin on TGFß2 expression and CAF-like biomarkers was also observed in PC3 tumors. Together, these findings highlight the potential usefulness of silibinin in PCA prevention through targeting the CAF phenotype in the prostate TM.

Flavanone silibinin treatment attenuates nitrogen mustard-induced toxic effects in mouse skin.

Currently, there is no effective antidote to prevent skin injuries by sulfur mustard (SM) and nitrogen mustard (NM), which are vesicating agents with potential relevance to chemical warfare, terrorist attacks, or industrial/laboratory accidents. Our earlier report has demonstrated the therapeutic efficacy of silibinin, a natural flavanone, in reversing monofunctional alkylating SM analog 2-chloroethyl ethyl sulfide-induced toxic effects in mouse skin. To translate this effect to a bifunctional alkylating vesicant, herein, efficacy studies were carried out with NM. Topical application of silibinin (1 or 2mg) 30 min after NM exposure on the dorsal skin of male SKH-1 hairless mice significantly decreased NM-induced toxic lesions at 24, 72 or 120 h post-exposure. Specifically, silibinin treatment resulted in dose-dependent reduction of NM-induced increase in epidermal thickness, dead and denuded epidermis, parakeratosis and microvesication. Higher silibinin dose also caused a 79% and 51%reversal in NM-induced increases in myeloperoxidase activity and COX-2 levels, respectively. Furthermore, silibinin completely prevented NM-induced H2A.X phosphorylation, indicating reversal of DNA damage which could be an oxidative DNA damage as evidenced by high levels of 8-oxodG in NM-exposed mouse skin that was significantly reversed by silibinin. Together, these findings suggest that attenuation of NM-induced skin injury by silibinin is due to its effects on the pathways associated with DNA damage, inflammation, vesication and oxidative stress. In conclusion, results presented here support the optimization of silibinin as an effective treatment of skin injury by vesicants.

SNAI1 is critical for the aggressiveness of prostate cancer cells with low E-cadherin.

BACKGROUND: A better molecular understanding of prostate carcinogenesis is warranted to devise novel targeted preventive and therapeutic strategies against prostate cancer (PCA), a major cause of mortality among men. Here, we examined the role of two epithelial-to-mesenchymal transition (EMT) regulators, the adherens junction protein E-cadherin and its transcriptional repressor SNAI1, in regulating the aggressiveness of PCA cells. METHODS: The growth rate of human prostate carcinoma PC3 cells with stable knock-down of E-cadherin (ShEC-PC3) and respective control cells (Sh-PC3) was compared in MTT and clonogenic assays in cell culture and in nude mouse xenograft model in vivo. Stemness of ShEC-PC3 and Sh-PC3 cells was analyzed in prostasphere assay. Western blotting and immunohistochemistry (IHC) were used to study protein expression changes following E-cadherin and SNAI1 knock-down. Small interfering RNA (siRNA) technique was employed to knock- down SNAI1 protein expression in ShEC-PC3 cells. RESULTS: ShEC-PC3 cells exerted higher proliferation rate both in cell culture and in athymic nude mice compared to Sh-PC3 cells. ShEC-PC3 cells also formed larger and a significantly higher number of prostaspheres suggesting an increase in the stem cell-like population with E-cadherin knock-down. Also, ShEC-PC3 prostaspheres disintegration, in the presence of serum and attachment, generated a bigger mass of proliferating cells as compared to Sh-PC3 prostaspheres. Immunoblotting/IHC analyses showed that E-cadherin knock-down increases the expression of regulators/biomarkers for stemness (CD44, cleaved Notch1 and Egr-1) and EMT (Vimentin, pSrc-tyr416, Integrin ß3, ß-catenin, and NF-κB) in cell culture and xenograft tissues. The expression of several bone metastasis related molecules namely CXCR4, uPA, RANKL and RunX2 was also increased in ShEC-PC3 cells. Importantly, we observed a remarkable increase in SNAI1 expression in cytoplasmic and nuclear fractions, prostaspheres and xenograft tissues of ShEC-PC3 cells. Furthermore, SNAI1 knock-down by specific siRNA strongly inhibited the prostasphere formation, clonogenicity and invasiveness, and decreased the level of pSrc-tyr416, total Src and CD44 in ShEC-PC3 cells. Characterization of RWPE-1, WPE1-NA22, WPE1-NB14 and DU-145 cells further confirmed that low E-cadherin is associated with higher SNAI1 expression and prostasphere formation. CONCLUSIONS: Together, these results suggest that E-cadherin loss promotes SNAI1 expression that controls the aggressiveness of PCA cells.

Electronic health records and quality of diabetes care.

BACKGROUND: Available studies have shown few quality-related advantages of electronic health records (EHRs) over traditional paper records. We compared achievement of and improvement in quality standards for diabetes at practices using EHRs with those at practices using paper records. All practices, including many safety-net primary care practices, belonged to a regional quality collaborative and publicly reported performance. METHODS: We used generalized estimating equations to calculate the percentage-point difference between EHR-based and paper-based practices with respect to achievement of composite standards for diabetes care (including four component standards) and outcomes (five standards), after adjusting for covariates and accounting for clustering. In addition to insurance type (Medicare, commercial, Medicaid, or uninsured), patient-level covariates included race or ethnic group (white, black, Hispanic, or other), age, sex, estimated household income, and level of education. Analyses were conducted separately for the overall sample and for safety-net practices. RESULTS: From July 2009 through June 2010, data were reported for 27,207 adults with diabetes seen at 46 practices; safety-net practices accounted for 38% of patients. After adjustment for covariates, achievement of composite standards for diabetes care was 35.1 percentage points higher at EHR sites than at paper-based sites (P<0.001), and achievement of composite standards for outcomes was 15.2 percentage points higher (P=0.005). EHR sites were associated with higher achievement on eight of nine component standards. Such sites were also associated with greater improvement in care (a difference of 10.2 percentage points in annual improvement, P<0.001) and outcomes (a difference of 4.1 percentage points in annual improvement, P=0.02). Across all insurance types, EHR sites were associated with significantly higher achievement of care and outcome standards and greater improvement in diabetes care. Results confined to safety-net practices were similar. CONCLUSIONS: These findings support the premise that federal policies encouraging the meaningful use of EHRs may improve the quality of care across insurance types.

Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-κB, and AP-1 activation in RAW264.7 cells.

Currently, there are limited therapeutic options against bone metastatic prostate cancer (PCA), which is primarily responsible for high mortality and morbidity in PCA patients. Enhanced osteoclastogenesis is an essential feature associated with metastatic PCA in the bone microenvironment. Silibinin, an effective chemopreventive agent, is in phase II clinical trials in PCA patients but its efficacy against PCA cells-induced osteoclastogenesis is largely unknown. Accordingly, here we examined silibinin effect on PCA cells-induced osteoclastogenesis employing human PCA (PC3MM2, PC3, and C4-2B) and murine macrophage RAW264.7 cells. We also assessed silibinin effect on receptor activator of nuclear factor κB ligand (RANKL)-induced signaling associated with osteoclast differentiation in RAW264.7 cells. Further, we analyzed silibinin effect on osteomimicry biomarkers in PCA cells. Results revealed that silibinin (30-90 µM) inhibits PCA cells-induced osteoclast activity and differentiation in RAW264.7 cells via modulating expression of several cytokines (IGF-1, TGF-ß, TNF-α, I-TAC, M-CSF, G-CSF, GM-CSF, etc.) that are important in osteoclastogenesis. Additionally, in RAW264.7 cells, silibinin decreased the RANKL-induced expression and nuclear localization of NFATc1, which is considered the master regulator of osteoclastogenesis. Furthermore, silibinin decreased the RANKL-induced DNA binding activity of NFATc1 and its regulators NF-κB and AP1, and the protein expression of osteoclast specific markers (TRAP, OSCAR, and cathepsin K). Importantly, silibinin also decreased the expression of osteomimicry biomarkers (RANKL, Runx2, osteocalcin, and PTHrP) in cell culture (PC3 and C4-2B cells) and/or in PC3 tumors. Together, our findings showing that silibinin inhibits PCA cells-induced osteoclastogenesis, suggest that silibinin could be useful clinically against bone metastatic PCA.

Chronic kidney disease in an electronic health record problem list: quality of care, ESRD, and mortality.

BACKGROUND: Whether chronic kidney disease (CKD) recognition in an electronic health record (EHR) problem list improves processes of care or clinical outcomes of end-stage renal disease (ESRD) and death is unclear. METHODS: We identified patients who had at least 1 year of follow-up (2005-2009) in our EHR-based CKD registry (n = 25,742). CKD recognition was defined by having ICD-9 codes for CKD, diabetic kidney disease, or hypertensive kidney disease in the problem list. We calculated proportions of patients with and without CKD recognition and examined differences by demographics, clinical factors, and development of ESRD or mortality. We evaluated differences in the proportion of patients with CKD-specific laboratory results checked before and after recognition among cases and propensity-matched controls. RESULTS: Only 11% (n = 2,735) had CKD recognition in the problem list and they were younger (68 vs. 71 years), a higher proportion were male (61 vs. 37%) and African-American (21 vs. 10%) compared to those unrecognized. CKD-specific laboratory results for patients with estimated glomerular filtration rate (eGFR) 30-59 including intact parathyroid hormone (23 vs. 6%), vitamin D (22 vs. 18%), phosphorus (29 vs. 7%), and a urine check for proteinuria (55 vs. 36%) were significantly more likely to be done among those with CKD recognition (all p < 0.05). Similar results were found for eGFR <30 except for proteinuria and in our propensity score-matched control analysis. There was no independent association of CKD recognition with ESRD or mortality. CONCLUSIONS: CKD recognition in the EHR problem list was low, but translated into more CKD-specific processes of care; however ESRD or mortality were not affected.

Cervicodorsal spine tuberculosis-- surgical approach.

Background: Tuberculosis (TB) of CT junction is uncommon (5 % of all spinal TB), and difficult to approach surgically in view of its deep location with sternum in front and scapula in the back. We present 7 consecutively treated cases of cervico-thoraccic TB for outcome of treatment and discuss rationale of choosing surgical approach. Methods: Present study includes 7 freshly diagnosed cases of CT junction TB. Plain radiographs, sagittal reconstruction of CT spine that included sternum on CT/MRI was performed in all cases. Disc space below the distal healthy vertebrae was identified and a line parallel to disc space was drawn. If this line passes above suprasternal notch, it was inferred that this VB can be accessed by anterior cervical approach. If disease focus was at or below suprasternal notch level, manubriotomy/sternotomy was added for better visualization of the lesion. Results: All seven cases were female, with mean age of 20 years (9-45 years). The vertebral lesion involved 2VB (n = 3), 3VB (n = 2) and >3 VB (n = 2). The average Cervico-thoracic kyphosis was 15° (range 10-25°). All 7 cases were operated for anterior decompression, kyphotic deformity correction and instrumented stabilization. Anterior cervical approach and manubriotomy/sternotomy approach was performed in three cases each. In two pan-vertebral cases we performed 360° procedure. Six cases have shown first sign of neural recovery within 3 weeks of surgery and almost complete neural recovery at 3 months follow-up while one case showed partial recovery. ATT was stopped after 12 months once healed stage was demonstrated on contrast MRI in all. Conclusions: CT junction TB usually presents with severe kyphotic deformity/neural deficit. These cases require anterior decompression/corpectomy, deformity correction, gap grafting and instrumented stabilization with anterior cervical plate. Lesion with pan-vertebral disease is stabilized 360°. These lesions can be decompressed by lower anterior cervical approach with/without manubriotomy. The Karikari method was useful in deciding the need for manubriotomy to decompress the lesion.

Treatment Outcome of Drug-Resistant Skeletal Tuberculosis: A Retrospective Analysis.

Background: Management outcomes of drug-resistant (DR) osteoarticular tuberculosis (OATB) is dismal as in pre-ATT era (1905). The studies documenting treatment outcome of DR-OATB are scarce; hence, present retrospective analysis was conducted to evaluate outcome of consecutive cases of DR-OATB. Methods: 45 consecutive patients of suspected DR-OATB were treated from 2010 onwards. Tissue samples were submitted for AFB smear, cytology/histology, liquid culture, CBNAAT/LPA besides gram's staining and aerobic/anaerobic culture. Patients were treated by individualized second-line ATT till documenting healed status by contrast MRI/PET. The changes in neurological deficit, deformities, and drug-induced adverse events were documented. Results: 37/45 patients, 15 males and 22 females, mean age 26.89 years were followed. DR was suspected observing poor clinico-radiological response/appearance of fresh lesions on ATT. All showed no growth on aerobic/anaerobic pyogenic culture. 29 (78%) had microbiologically proven drug resistance and 8 (22%) were labeled as clinical drug resistance (CDR). 18/29 had multi-drug resistance. Mean prior ATT intake was 12.03 months 15 (40%) underwent surgical decompression. Mean duration of second-line ATT was 22.5 months (9-36 months). All patients achieved healed status with 8 (21%) developed side effects, most commonly hepatotoxicity, ototoxicity, and psychiatric disturbances. Average follow-up after completion of ATT was 40.5 months. Conclusion: We report a large series where patients of DR-OATB were suspected on clinical criteria, investigated by DST, and treated. Patients with proven drug resistance were treated by individualized second-line ATT. CDR cases were treated by MDR protocol. Genotypic DST (CBNAAT/LPA) improved demonstration of DR. We demonstrated healed status on MRI/PET with no recurrence at minimum 2-year follow-up.

Tubercular Osteomyelitis of Navicular Bone: A Rare Site for Bone Tuberculosis.

Introduction: Tuberculosis (TB) is a global public health problem, endemic to India. Osteoarticular TB uncommonly presents in the foot, navicular osteomyelitis is an extremely rare entity. Case Report: We report a rare case of navicular osteomyelitis caused by TB in a 37-year-old man who presented to OPD with swelling and dull aching pain over the dorsum of his left foot. A radiograph of the foot showed a lytic lesion in the navicular bone. Further investigations in the form of aspiration cytology, cartridge-based nucleic acid amplification test, and acid-fast bacilli culture confirmed TB. Category-1 anti-tubercular therapy was started immediately and the patient was treated conservatively. Four drugs (HRZE) were given for 2 months and 3 drugs (HRE) for 9 months, after which the patient stopped his medications on his own. Radiographs and CEMRI at 14-month follow-up showed a healed lesion. Conclusion: This case illustrates an exceptional location of osteoarticular TB and shows that Navicular TB can be treated conservatively with near-complete function and recovery if diagnosed early.

Drug-Resistant Bone, Joint and Spine Tuberculosis: Evolution of Diagnosis and Treatment.

Background: Drug resistant (DR) osteoarticular TB (OATB) is a challenge in view of it being deep seated lesion and paucibacillary disease. Case definition, investigation protocol, treatment of proven DR and those cases where DR could not be demonstrated lacks clarity and evidence. Hence, a series of studies were conducted to develop an algorithm to investigate and treat therapeutically refractory disease (TRD) or presumptive drug resistance (PDR) cases of OATB. Patients and methods: 6 studies were conducted. Study one and two evaluated criteria to label TRD/PDR. Three subsequent studies were conducted where TDR/PDR or fresh cases of OATB cases were investigated by AFB smear, Bactec/liquid culture, histology and genotypic DST by CBNAAT & LPA. Sixth study was a retrospective evaluation of all DR cases treated for proven or clinical drug resistance (CDR). Results: Patient of bone/spine TB on ATT for 5 months or more show poor clinico-radiological treatment response as worsening of lesion, increased spinal deformity, persistent discharging sinus/ulcer, appearance of fresh lesion, recurrence of previous lesion, wound dehiscence of post-operative surgical scar cab labelled as PDR cases. These cases on histology ascertained TB and were proven DR on genotypic and phenotypic DST and are treated successfully. The patients of histologically ascertained TB and no/indeterminate phenotypic and genotypic DST were successfully treated as clinical drug resistance on MDR protocol. Conclusions: We described an algorithm. We must suspect PDR(TRD) based on criteria described. The tissue must be procured and submitted for AFB smear, histology and phenotypic and genotypic DST for diagnosis of TB. Genotypic and phenotypic DST will be useful to prove (90% instances) type of drug resistance. Remaining on strong clinical suspicion of DR and yet inconclusive on phenotypic/genotypic DST (<10%), may be treated as CDR as MDR. The adverse drug reactions and hepatic side-effects should be monitored diligently and these cases to be treated till healed status is demonstrated.

Bitter melon juice activates cellular energy sensor AMP-activated protein kinase causing apoptotic death of human pancreatic carcinoma cells.

Prognosis of pancreatic cancer is extremely poor, suggesting critical needs for additional drugs to improve disease outcome. In this study, we examined efficacy and associated mechanism of a novel agent bitter melon juice (BMJ) against pancreatic carcinoma cells both in culture and nude mice. BMJ anticancer efficacy was analyzed in human pancreatic carcinoma BxPC-3, MiaPaCa-2, AsPC-1 and Capan-2 cells by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide, cell death enzyme-linked immunosorbent assay and annexin/propidium iodide assays. BMJ effect on apoptosis regulators was assessed by immunoblotting. In vivo BMJ efficacy was evaluated against MiaPaCa-2 tumors in nude mice, and xenograft was analyzed for biomarkers by immunohistochemistry (IHC). Results showed that BMJ (2-5% v/v) decreases cell viability in all four pancreatic carcinoma cell lines by inducing strong apoptotic death. At molecular level, BMJ caused caspases activation, altered expression of Bcl-2 family members and cytochrome-c release into the cytosol. Additionally, BMJ decreased survivin and X-linked inhibitor of apoptosis protein but increased p21, CHOP and phosphorylated mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2 and p38) levels. Importantly, BMJ activated adenosine monophosphate-activated protein kinase (AMPK), a biomarker for cellular energy status, and an AMPK inhibitor (Compound C) reversed BMJ-induced caspase-3 activation suggesting activated AMPK involvement in BMJ-induced apoptosis. In vivo, oral administration of lyophilized BMJ (5mg in 100 µl water/day/mouse) for 6 weeks inhibited MiaPaCa-2 tumor xenograft growth by 60% (P < 0.01) without noticeable toxicity in nude mice. IHC analyses of MiaPaCa-2 xenografts showed that BMJ also inhibits proliferation, induces apoptosis and activates AMPK in vivo. Overall, BMJ exerts strong anticancer efficacy against human pancreatic carcinoma cells, both in vitro and in vivo, suggesting its clinical usefulness.

Tuberculosis of spine: neurological deficit.

The most dreaded neurological complications in TB spine occur in active stage of disease by mechanical compression, instability and inflammation changes, while in healed disease, these occur due to intrinsic changes in spinal cord secondary to internal salient in long standing kyphotic deformity. A judicious combination of conservative therapy and operative decompression when needed should form a comprehensive integrated course of treatment for TB spine with neurological complications. The patients showing relatively preserved cord with evidence of edema/myelitis with predominantly fluid collection in extradural space on MRI resolve on non-operative treatment, while the patients with extradural compression of mixed or granulomatous nature showing entrapment of spinal cord should be undertaken for early surgical decompression. The disease focus should be debrided with removal of pus caseous tissue and sequestra. The viable bone should only be removed to decompress the spinal cord and resultant gap should be bridged by bone graft. The preserved volume of spinal cord with edema/myelitis and wet lesion on MRI usually would show good neural recovery. The spinal cord showing myelomalacia with reduced cord volume and dry lesion likely to show a poor neural recovery. The internal kyphectomy is indicated for paraplegia with healed disease. These cases are bad risk for surgery and neural recovery. The best form of treatment of late onset paraplegia is the prevention of development of severe kyphosis in initial active stage of disease.

Transfer Learning in Deep Reinforcement Learning: A Survey.

Reinforcement learning is a learning paradigm for solving sequential decision-making problems. Recent years have witnessed remarkable progress in reinforcement learning upon the fast development of deep neural networks. Along with the promising prospects of reinforcement learning in numerous domains such as robotics and game-playing, transfer learning has arisen to tackle various challenges faced by reinforcement learning, by transferring knowledge from external expertise to facilitate the efficiency and effectiveness of the learning process. In this survey, we systematically investigate the recent progress of transfer learning approaches in the context of deep reinforcement learning. Specifically, we provide a framework for categorizing the state-of-the-art transfer learning approaches, under which we analyze their goals, methodologies, compatible reinforcement learning backbones, and practical applications. We also draw connections between transfer learning and other relevant topics from the reinforcement learning perspective and explore their potential challenges that await future research progress.

PrintsGAN: Synthetic Fingerprint Generator.

A major impediment to researchers working in the area of fingerprint recognition is the lack of publicly available, large-scale, fingerprint datasets. The publicly available datasets that do exist contain very few identities and impressions per finger. This limits research on a number of topics, including e.g., using deep networks to learn fixed length fingerprint embeddings. Therefore, we propose PrintsGAN, a synthetic fingerprint generator capable of generating unique fingerprints along with multiple impressions for a given fingerprint. Using PrintsGAN, we synthesize a database of 525k fingerprints (35K distinct fingers, each with 15 impressions). Next, we show the utility of the PrintsGAN generated dataset by training a deep network to extract a fixed-length embedding from a fingerprint. In particular, an embedding model trained on our synthetic fingerprints and fine-tuned on a small number of publicly available real fingerprints (25K prints from NIST SD 302) obtains a TAR of 87.03% @ FAR=0.01% on the NIST SD4 database (a boost from TAR=73.37% when only trained on NIST SD 302). Prevailing synthetic fingerprint generation methods do not enable such performance gains due to i) lack of realism or ii) inability to generate multiple impressions per finger. Our dataset is released to the public: https://biometrics.cse.msu.edu/Publications/Databases/MSU_PrintsGAN/.