The objectives of this paper are: (1) to study the feasibility and relative benefits of integrating the prevention of parent-to-child transmission (PPTCT) component of the National AIDS Control Program with the maternal and child health component of the National Rural Health Mission (NRHM) by offering HIV screening at the primary healthcare level; and (2) to estimate the incremental cost-effectiveness ratio to understand whether the costs are commensurate with the benefits.The intervention included advocacy with political, administrative/health heads, and capacity building of health staff in Satara district, Maharashtra, India. The intervention also conducted biannual outreach activities at primary health centers (PHCs)/sub-centers (SCs); initiated facility-based integrated counseling and testing centers (FICTCs) at all round-the-clock PHCs; made the existing FICTCs functional and trained PHC nurses in HIV screening. All “functional” FICTCs were equipped to screen for HIV and trained staff provided counseling and conducted HIV testing as per the national protocol. Data were collected pre- and post- integration on the number of pregnant women screened for HIV, the number of functional FICTCs and intervention costs. Trend analyses on various outcome measures were conducted. Further, the incremental cost-effectiveness ratio per pregnant woman screened was calculated.An additional 27% of HIV-infected women were detected during the intervention period as the annual HIV screening increased from pre- to post-intervention  among antenatal care (ANC) attendees under the NRHM. A greater increase in HIV screening was observed in PHCs/SCs. The proportions of functional FICTCs increased from 47% to 97% (p < 0.001). Additionally, 93% of HIV-infected pregnant women were linked to anti-retroviral therapy centers; 92% of mother-baby pairs received Nevirapine; and 89% of exposed babies were enrolled for early infant diagnosis. The incremental cost-effectiveness ratio was estimated at INR 44 (less than 1 US$) per pregnant woman tested.Integrating HIV screening with the broader Rural Health Mission is a promising opportunity to scale up the PPTCT program. However, advocacy, sensitization, capacity building and the judicious utilization of available resources are key to widening the reach of the PPTCT program in India and elsewhere. Prevention of parent-to-child transmission(PPTCT) remains one of the key components of global HIV prevention effort . HIV couThe integration of programs working in broadly similar areas is now seen as an important tool for achieving program efficiency. Establishing synergies and linking HIV programs with related health programs can be instrumental in effectively scaling up both programs -10.The global health strategy for HIV and AIDS recommends strengthening health systems by adopting cost-effective, integrated service delivery models focusing on expanding access to quality HIV services . EstimatIn 2010, an estimated 35% of pregnant women received an HIV test in low and middle-income countries, up from 7% in 2005 . In IndiThe objectives of this paper are: (1) to study the feasibility of integrating the PPTCT component of the National AIDS Control Program (NACP) with the MCH component of the National Rural Health Mission (NRHM) by offering HIV screening at the primary health care level and assessing its benefits and impact in increasing HIV reactive diagnoses; and (2) to estimate the incremental cost-effective ratio to understand whether the costs are commensurate with the benefits.Until recently, the PPTCT program , a compoThe Maharashtra State AIDS Control Society (MSACS) , workingThe project was initiated with a situation assessment of HIV in the district, followed by advocacy and sensitization of district political, administrative and health heads. These district leaders mobilized and directed trained staff at PHCs to initiate FICTCs at their centers and to ensure their functionality. A cascade model was adopted for the training and sensitization of health and other staff. A joint plan for outreach activity at each PHC/SC was developed to coincide with the antenatal clinic day/village health and nutrition day. Focused IEC materials were used to create awareness and generate demand among eligible pregnant women . The pilot project was formally launched by the district guardian minister and administrative head. The ASHAs mobilized eligible pregnant women to visit PHCs/SCs where they were provided ANC and voluntary HIV counseling and testing, after obtaining informed consent. Mobile ICTCs were used to facilitate HIV screening in hard-to-reach areas. Post-test counseling was carried out and results were shared on the same day. Early linkages with the nearest anti-retroviral therapy (ART) centers were facilitated through counselors and nurses. MSACS and NRHM officials regularly monitored the process.To garner the benefits of the sensitized system and to ensure sustainability of the integration process, training on HIV screening using rapid testing (based on NACO protocol) was conducted for PHC/SC nurses at the village level following the second phase of outreach activities. The village nurses soon initiated HIV screening at the village level.To summarize, the approach adopted to integrate HIV screening at the primary health level was through advocacy with district political/administrative/health heads, sensitization and capacity building of health staff, generating demand through focused communication, joint micro-planning to ensure better access to HIV counseling and testing, use of rapid HIV testisting at the village level and monitoring the program.The reference period for the intervention was April 2011 to March 2012. The preceding year was considered as the benchmark or the pre-intervention period. Data on outreach activities were collected on a weekly basis and careful expenditure monitoring of all the items were undertaken during the pilot phase. Routine program data on HIV screening with health facility level break-up and cost data collected and compiled by the District AIDS Prevention Control Unit (DAPCU), Satara were used for analysis. The information gathered from the monitoring data used in the current study did not include individual identifiers.The main outcome indicator to measure the feasibility and acceptability of integration was the pre- and post-intervention increase in HIV screening among ANC attendees. The benefits of integration were measured in terms of additional ANC women detected as HIV reactive, responsiveness of the district authorities, sustainability of the intervention and sensitization of health workers. Direct indicators were not available to measure all the benefits; hence, proxy indicators were used. The proportionate increase in HIV-infected pregnant women diagnosed was measured. The responsiveness of the district authorities was measured as the pre- and post-intervention difference in the following variables:i. Number of functional facility-based ICTCs.ii. Number of ANC attendees screened at PHCs/SCs.iii. Number of ANC attendees screened for HIV by nurses at the village level.The proportionate gap between ANC registration and HIV screening measured each month was assumed to reflect the sustainability of the intervention, while the gap in the period excluding outreach activity was used to measure the sensitization of NRHM health staff. Additionally, sensitization was indirectly measured as the proportion of ANC attendees screened for HIV by nurses at the village level.The incremental costs were calculated, and the incremental cost-effectiveness was estimated based on the difference in the number of ANC women screened for HIV before and after the intervention. The major cost items are as follows:•Communication materials– posters, banners and handouts.•Training medical officers – training material and logistics.•Travel–mobile vans deployed, counselors/technicians funded for travel, fuel, and maintenance of mobile vans.•Documentation.additional cost incurred was the temporary deployment of mobile vans, training of medical officers, printing of communication material and documentation.The project did not involve any additional costs for human resources, infrastructure and supplies like HIV testing kits as the resources available with MSACS/DAPCU and district NRHM were utilized. The travel costs of counselors/ laboratory technicians for outreach activities were covered by DAPCU under the routine travel budget. Thus, the only Simple descriptive statistics such as proportions, ratios and means were used to present the results. Differences in proportions were tested using Z-tests and Fisher’s exact test, and the differences in mean values were tested using t-tests. Trend analyses were conducted to measure the proportionate gap between women registered for antenatal care and those screened for HIV, functional FICTCs, ANC attendees screened at PHCs/SCs and village level HIV screening of ANC attendees by NRHM nurses. Cost-effectiveness was analyzed as the incremental cost-effectiveness ratio per pregnant woman screened.A total of 42,120 ANC attendees were screened for HIV at the end of the intervention period, of which 11,223 (27%) were tested through the biannual outreach activity of the program (not shown in tabular format). Annual HIV screening of ANC attendees increased from 55%pre-intervention to 79% post-intervention (p < 0.001)  and the total incremental cost required to implement the project was INR 576,540 , which included training costs , cost of printing and distribution of communication materials , travel costs  for deployed mobile vans inclusive of fuel, vehicle maintenance, and travel allowance for accompanying drivers/counselors/technicians, and documentation costs . Table In addition, as a result of integration where the primary health system was equipped with required resources, 93% of HIV-infected women detected post-intervention were linked to ART centers; 92% of mother-baby pairs received Nevirapine as per the national protocol while 89% of exposed babies were enrolled in a nearby infant diagnosis program (not presented in tabular format).The study results suggest that the integration of HIV screening at the primary health care level as part of a comprehensive MCH program is feasible, beneficial, enhances the uptake of HIV testing, and facilitates wide geographic coverage. In addition, the incremental cost-effectiveness ratio post-intervention of INR 44 (less than US$1) per pregnant woman tested demonstrates that the integration of HIV screening at the primary health care level is a low-cost approach and brings a large number of pregnant women under HIV prevention services. In the absence of alternative cost data for achieving the same target of expanding HIV screening, the incremental cost-effectiveness ratio can be used as a proxy indicator to understand the financial implications of scaling up HIV screening using an integrated approach.Integrating HIV screening with regular village health and nutrition days significantly scaled up HIV screening among pregnant women with the judicious utilization of the available resources within the two vertical health systems. In addition, this approach built the capacity of village-level health care workers, such as PHC/SC nurses and ASHAs, on HIV prevention and PPTCT issues. Sensitization of village-level nurses and health workers along with focused communication activities to generate a demand in the community led to an increase in HIV screening.Advocacy and sensitization of district political, administrative and health heads have led to a more responsive, responsible and sustainable health system. These activities resulted in increasing the number of functional FICTCs, and HIV screenings at PHCs/SCs post-intervention. Further it has led to the initiation of HIV screening by village nurses immediately following their training. The intervention has progressively reduced the gap between the registration of pregnant women for ANC and those screened for HIV.The integration approach also has led to task shifting for HIV screening from MSACS staff to NRHM staff. Several studies in other developing countries indicate that such task shifting –including utilizing primary level staff, such as nurses, for counseling and HIV testing at rural health facilities leads to a higher level of acceptance from the community  and is aIn addition, the intervention has shownd that the integration of health programs results in substantially lower project costs as the major cost items, like infrastructure, supplies and human resources, are already covered within the program. Coordination and collaboration across different authorities is the essence of this program; however unlike other stand-alone programs, such an integrated program uses existing mechanisms and systems to achieve the stated objectives.As shown in this study, it is possible to bring the majority of ANC attendees under the HIV prevention umbrella by integrating vertical government programs (HIV with MCH programs). The main advantage is the early detection of HIV infection among pregnant women, providing them an opportunity to access a range of available HIV care, support and treatment services and eventually preventing the transmission of infection to the next generation. An additional benefit is that all ANC attendees will receive pre-test HIV counseling, thereby empowering women with the knowledge needed to live an HIV-free life.The many gains of such an integrated approach can also be garnered from the fact that based on the same design; the diagnosis and management of sexually transmitted infections were scaled up in Satara district the following year. These results corroborate earlier findings on the integration of such programs -24 and tThis study is important given the lack of evidence demonstrating the integration of the PPTCT program with the broader health mission in India and elsewhere. Thestudy results should be considered in light of certain limitations. First, the use of indirect indicators to measure the benefits of the integrated approach from district authorities and several individuals limits generalizability of the results to a larger population level. Second, it was difficult to measure and attribute the independent effects of multiple intervention strategies used by the program for HIV screening. Third, other events promoting HIV testing that occurred concurrently during the intervention period may have influenced the outcome. Fourth, this design lacks a control group; therefore we could only demonstrate change and not attribution. Despite these limitations, the results show that a low incremental cost can have several advantages for HIV prevention effort with integration.Integrating HIV screening with the broader NRHM is a promising opportunity to scale up the PPTCT program. However, advocacy, sensitization, capacity building and the judicious utilization of available resources are key to widening the reach of the PPTCT program in India and elsewhere.The authors declare that they have no competing interest.RD led the overall strategic planning, costing and implementation. SVB contributed to the customization of the technical design, assisted in the planning, implementation, analyzed data and wrote the manuscript. IG conceptualized and designed the cost analyses and revised the manuscript. NS and VR provided guidance to the analytical approach and revised the manuscript. SR assisted with the analysis and revised the manuscript.DD provided programmatic insight and edited the manuscript. SSG designed the concept for increasing the uptake of HIV screening. All authors have read and approved this final submitted manuscript.


U.S. SEER (Surveillance Epidemiology and End Results) data for age-adjusted mortality rates for all cancers combined for all races show only a modest overall 13% decline over the past 35 years. Moreover, the greatest contributor to cancer mortality is treatment-resistant metastatic disease. The accepted therapeutic paradigm for the past half-century for the treatment of advanced cancers has involved the use of systemic chemotherapy drugs cytotoxic for cycling cells  during DNA synthesis and/or mitosis. The failure of this therapeutic modality to achieve high-level, consistent rates of disease-free survival for some of the most common cancers, including tumors of the lung, colon breast, brain, melanoma, and others is the focus of this paper. A retrospective assessment of critical milestones in cancer chemotherapy indicates that most successful therapeutic regimens use cytotoxic cell cycle inhibitors in combined, maximum tolerated, dose-dense acute treatment regimens originally developed to treat acute lymphoblastic leukemia and some lymphomas. Early clinical successes in this area led to their wholesale application to the treatment of solid tumor malignancies that, unfortunately, has not produced consistent, long-term high cure rates for many common cancers. Important differences in therapeutic sensitivity of leukemias/lymphomas versus solid tumors can be explained by key biological differences that define the treatment-resistant solid tumor phenotype. A review of these clinical outcome data in the context of recent developments in our understanding of drug resistance mechanisms characteristic of solid tumors suggests the need for a new paradigm for the treatment of chemotherapy-resistant cancers. In contrast to reductionist approaches, the systemic approach targets both microenvironmental and systemic factors that drive and sustain tumor progression. These systemic factors include dysregulated inflammatory and oxidation pathways shown to be directly implicated in the development and maintenance of the cancer phenotype. The paradigm stresses the importance of a combined preventive/therapeutic approach involving adjuvant chemotherapies that incorporate anti-inflammatory and anti-oxidant therapeutics. A new paradigm to guide cancer treatment research may be needed in this 21st century, one that builds upon the previous century of research and discovery on the nature of this very complex and still mysterious disease. An exploration of the highlights and difficulties encountered in the long quest to understand the systemic treatment of cancer may provide a necessary perspective so that we can move forward to realize the long anticipated goal of finding a meaningful and permanent solution to the cancer problem. As the so-called “War on Cancer” rapidly approaches the half-century mark, there has been a lot of discussion about its successes and failures. It is not the purpose of this discussion to elaborate on the political or economic aspects of cancer research, but rather to approach the issue from the standpoint of a very basic scientific inquiry of what we have learned from a century of cancer research with respect to future potential translational and clinical applications.Cancer chemotherapy emerged as a means for treating systemic disease in the 1960s. Prior to this time, the primary treatment for cancer involved surgery and radiation. Neither therapeutic modality was designed to treat the problem of systemic diseases due to metastasis. This limitation ultimately became the rationale for a new therapeutic approach to deal with the systemic nature of this disease, eventually involving the use of cytotoxic drugs. Before the advent of systemic treatment, the long-term remission rates for cancers across-the-board could not be pushed beyond approximately 35%, and this difficulty, of course, generated much interest in developing systemic approaches that would produce greater cure rates.The focus of this paper is specifically the biological aspects of cancer therapeutics that comprise the core components of therapeutic responses -both positive and negative- to conventional cytotoxic chemotherapy drugs. This involves an assessment of current chemotherapy modalities and how these therapy approaches may need to be modified in an attempt to develop novel therapeutics for the treatment of refractory cancers.Figures 4). Figure 1 shows the age-adjusted mortality rates for all cancers combined, all ages, all races, and both sexes in the U.S. between 1975 and 2009. The SEER (Surveillance Epidemiology and End Results) data show that the approximate percent decline in mortality rates from all cancers combined has decreased by approximately 13% over the past 40 years  derivatives used in cancer chemotherapy were originally developed as anti-microbial sulfa drugs to treat infectious diseases such as streptococcal infections . This coFigure 5). Other anti-cancer agents developed in this trial and error approach include the vinca alkaloids that function as anti-mitotic agents . Their extraordinary efficacy in the treatment of select cancer types, such as ALL, some types of lymphoma and testicular cancer, is undisputed; nevertheless, the success rate of traditional cytotoxic chemotherapy in producing long-term patient disease-free survival is unpredictable, and in many cancers, unsatisfactory. Based on this clinical record of a half-century of widespread use, it is essential to address the problem of broad-spectrum clinical efficacy of standard chemotherapy in order to maximize its clinical benefit in treatment of cancers most likely to respond to this therapeutic approach.The development of many important cytotoxic drugs was the result of an effort to identify natural and synthetic compounds with anti-cancer activity via mass screenings for their anti-cancer effects xantrone . Most ofVery early in the history of cancer chemotherapy, clinical trials producing rapid remissions in patients with ALL and Hodgkin’s disease (HD) were followed by the disappointing recurrence of treatment-resistant disease, soon to be identified as one of the most intractable problems associated with cancer chemotherapy . Just asBacterial drug resistance mechanisms were found to result from antibiotic resistance genes that can spread rapidly in populations of bacterial cells and whose presence can be amplified by the selective destruction of bacteria that do not contain these genes, resulting in the “natural selection” of drug-resistant colonies of infectious agents within the body. The same principle has been observed to be responsible for the development of drug-resistant cancer cells; in some cases, drug resistance appears to result from the selection of tumor phenotypes produced by genetic mutations  that confer resistance to the cell killing effects of specific types anti-cancer drugs, such as the amplification of the mdr-1 gene, associated with a multi-drug-resistant phenotype and the dihydrofolate reductase (DHFR) gene, which specifically confers resistance to the folate antagonists . The concept of dose intensity was based on the observation that patients with HD who received lower dose chemotherapy showed lower cure rates . AdditioThe rationale for these therapeutic approaches was an effort to achieve a maximal and rapid cell killing effect to overwhelm the drug-resistant potential of genetically unstable tumors. To achieve this therapeutic goal, these drugs were delivered at MTDs. This latter approach involves the concept that the higher the dose the greater the therapeutic efficacy and the lower the probability that drug-resistant mechanisms will have the opportunity to develop. This concept led to therapeutic regimens of dose intensity and high-dose chemotherapy in the hope of achieving higher cure rates in advanced cancers of many types . With thAfter a further 25 years of trial and error, it was possible for oncologists to optimize the use of these chemical agents in order to induce long periods of disease-free survival for some types of cancer. High-dose regimens and combined treatment protocols were developed initially for the treatment of childhood leukemia (ALL). The most effective was the VAMP protocol: vincristine, amethopterin, 6-mercaptopurine and prednisone. This therapeutic “cocktail” was administered intermittently to patients to allow for bone marrow recovery. This treatment regimen led to an increase in the rate of remission to 60% by the end of the 1960s .Figure 6).Another cancer to respond to this therapeutic approach was advanced HD. In the 1960s advanced HD was usually fatal. Remissions were attainable in only 25% of patients; however, disease recurrence was the inevitable result using single agent protocols. The development of the MOMP protocol combining nitrogen mustard with vincristine, methotrexate, and prednisone (which became the MOPP program which omitted methotrexate and replaced it with procarbazine) generated complete remissions at a rate of over 80% with 60% of patients avoiding any relapse of this disease. These clinical results were published in 1965–1967 . BeginniWith respect to solid tumor malignancies, it was clear that most patients with local regional disease showing no sign of systemic spread would, nevertheless, inevitably relapse using approaches (surgery and radiation) that target only the site of the original tumor ,b. This Clinical support for the rationale that combined chemotherapy could be useful in the treatment of solid tumors resulted from clinical results obtained in the 1960s and 1970s indicating that combined chemotherapy could cure some types of advanced cancer . TheoretOne of the first adjuvant chemotherapy approaches in the treatment of solid tumors combined cyclophosphamide, methotrexate, and 5-fluorouracil as an adjuvant chemotherapy for patients with metastatic cancer [the CMF (Cyclophosphamide Methotrexate Fluorouracil) regimen]. The overall response rate was over 50%; about 20% of patients showed complete remissions. The CMF study was published in 1976 with positive results .Testicular cancer remissions went from 10 to 60% starting in 1978 using a combination of cisplatin, elastin, and bleomycin , 1979. AFigures 4).The results of over a half-century of clinical trials have shown that the therapeutic approach of combined/dose-dense chemotherapy has not been entirely successful in achieving its primary purpose, which is the induction of long-term disease-free survival in the majority of patients with systemic disease .The mechanism of both phase specific and non-phase specific chemotherapy drugs  is to target dividing cells . Most ofTheir mechanisms of action, therefore, do not distinguish between normal and cancerous proliferating cells, a primary cause of side effects such as bone marrow suppression and dose-limiting toxicities. The net result is a fairly narrow therapeutic window between anti-tumor effect and MTD. These chemotherapy drugs are, therefore, more accurately classified as anti-proliferative, rather than anti-cancer agents. The therapeutic window associated with differential responses between tumor cells and normal dividing cells is based on differences in proliferation rates and recovery parameters that may favor the tumor target, particularly in fast growing malignancies. These differences in normal versus tumor cell sensitivity to agents that block cell division, however, are insufficient to prevent cytotoxic side effects in normal bone marrow and normal dividing epithelial cells. These overlapping sensitivities ultimately limit the MTD, which may be insufficient to destroy all tumor cells without causing irreparable damage to normal host tissue. Moreover, the ablation of the bone marrow has a significant effect on the immune system, at least temporarily decreasing its capacity to defend against the malignant growth within the body.The vast majority of chemotherapy drugs used in “standard of care” oncology practice for the treatment of advanced cancers have a mechanism of action defined by the cell kill paradigm. The cell kill hypothesis originated with Skipper based on studies of L1210 mouse . The celThe narrow therapeutic window limits the MTD of cytotoxic chemotherapy drugs that target dividing cells. A very important side effect of this limitation is that the rate of cell division in the interior regions of solid tumors is frequently extremely low, lower than normal dividing cells, thereby bypassing the cytotoxic effects of these drugs even at their MTDs. What accounts for the low rate of cell division in the solid tumor? The answer can be found in the abnormal microenvironment that develops as the solid tumor mass enlarges.The clinical use of most conventional chemotherapy drugs involves the basic assumption that the cancer phenotype is characterized by continuous dysregulated cell proliferation. However, research on tumor cell biology suggests that many solid tumors of diverse tissue types are heterogeneous collections of cells that are not consistently or uniformly proliferating at any given time , 1988. FFigure 7). This results in regions of hypoxia and acidity that can also influence the sensitivity of the tumor cells to drug treatment  to the treatment of solid tumor malignancies . These tMendelssohn’s concept of defined growth fraction attempts to define the kinetic basis for observed non-exponential growth patterns of many human cancers . This coThis issue of tumor cell division rates and its relationship to cancer drugs that specifically target cycling cells with respect to the problem of drug resistance may, therefore, in part be explained by the growth fraction model that suggests that tumors consist of pools of both proliferating and non-proliferating cells, with only the former category possessing the intrinsic biological capacity to respond to drugs that specifically target dividing cells . In thisin vitro that follow spheroidal growth parameters of volumetric increases that create a changing environment surrounding the cells of the tumor, depending upon their location within the solid tumor  and STAT-3 , major transcription factors that regulate inflammatory pathways . NF-kB wPro-inflammatory stimuli such as TNF, IL-1 and IL-6, cyclo-oxygenase-2 (COX-2), and lipoxygenase (LOX) all regulate NF-kB and are expressed in bronchitis, colitis, gastritis, and hepatitis . MoreoveMuch recent attention has focused on the long-term use of anti-inflammatory drugs such as aspirin as cancer preventives. The association between chronic inflammation and inflammatory pathway activation in the genesis of cancer is supported by clinical research studies that provide evidence for the preventive aspects of long-term aspirin use in the development of some common malignancies, including breast, colon cancer, bladder cancer, melanoma, and other cancers . This prAdditional research studies suggest that suppression of inflammatory pathways may be involved in both the prevention and treatment of cancer . SuppresSeveral recently published studies have provided further evidence for preventive and therapeutic effects of daily aspirin. Longitudinal studies have shown that long-term daily aspirin use for at least 10 years reduces the risk of developing colon cancer and other common cancers. These clinical data indicated that low-dose aspirin use for at least 3 years can reduce the risk of cancer incidence by about 25% and the risk of dying from cancer by about 15%. The statistic increases from 25 to 37% for those who take aspirin for longer than 5 years . The resAdditional natural products with demonstrated anti-cancer activity that also block inflammation via NF-kB pathway inhibition include curcumin, resveratrol, ursolic acid, and others . For exaThe potential preventive anti-cancer effects of anti-oxidants found in high concentrations in many phytochemicals have become a major focus of research in recent years. Despite accumulating evidence to suggest an important role in cancer prevention, there has been much controversy over their potential therapeutic applications based on the fact that these agents block free radical formation as an important mediator of their anti-cancer effects . AlthougTo address this question, it is necessary to explore the biological basis of the potential anti-cancer therapeutic effects of anti-oxidants. Of particular importance is the question of whether anti-oxidants can prevent the formation of incipient tumors and/or affect parameters of tumor growth behavior involving ROS . AbnormaMoreover, based on their effects on mitochondrial function, it is entirely possible that the formation of oxygen free radicals may contribute to the development of tumor-associated hypoxia as a result of mitochondrial dysfunction. Normal PO2 oxygen ranges between 10 and 80 mmHg; many solid tumors contain PO2 at less than 5 mmHg. Elevated tumor acidity compared to normal tissues is associated with lactate accumulation due to the spacio-temporal pH gradients resulting from the metabolic state of tumor cells and the ion pumping mechanisms that vary significantly in tumors . The res2O2, hydroxyl radicals, and other ROS. Within specific concentration limits, ROS regulate cell functions, acting as a second messenger to activate transcription factors NF-kB and activator protein 1 (AP-1). Excess ROS production, however, is destructive. Overproduction of ROS by damaged mitochondria may activate inflammatory pathways linked to cancer . Harman suggested that mitochondria are major targets of free radical attack that leads to aging, a concept embodied in the “free radical theory of aging.” Thus, there appears to be a cyclical interaction between mitochondrial respiration, which is an important source of ROS due to electron leakage from the respiratory chain, and the destructive effects of excessive ROS production on mitochondrial function  has been linked to a “reverse Warburg effect” , resulti systems .++SOD overexpression has been reported , the observed cytotoxic effects of aspirin in cultured tumor cells, and physiological assessments of the presence of elevated levels of several biomarkers for inflammation in patients with many types of advanced cancer. It is entirely possible that some of the apparent chemopreventive properties of anti-inflammatory agents may be operating at the level of pre-established incipient malignancies in which further tumor progression and the onset of overt disease are significantly delayed or do not occur at all. It is important to carry out studies to establish this possibility as a rationale for the use of this approach in long-term, preventive modalities. If so, then anti-inflammatory agents might be developed for use in long-term maintenance therapeutic approaches in the management of malignant disease as well as in cancer prevention.The inclusion of long-term maintenance therapy involving the use of any anti-inflammatories must be evaluated in this context. The concept of long-term maintenance therapy approaches to prevent disease recurrence is further supported by longitudinal studies on the long-term use of tamoxifen and aromatase inhibitors in the management of breast cancer . The conAnother point that should be emphasized involves the fact that successful therapy with gene-targeted drugs such as Gleevec, tamoxifen, and aromatase inhibitors requires ongoing treatment involving a continuous dosing regimen that follows a very different protocol from that generally followed in cytotoxic chemotherapy. In the case of gene-targeted drugs such as Gleevec, the patient will receive the drug on a long-term basis as a form of maintenance therapy to prevent the establishment of drug-resistant clones. The need for continuous maintenance therapy in the successful management of patients with chronic myelogenous leukemia (CML) using Gleevec suggests that successful cancer management in general may require long-term maintenance therapy in order to achieve stable remissions and to prevent the development of acquired drug resistance. These clinical successes in long-term cancer management underscore the importance of developing therapeutic approaches that can be used in long-term maintenance therapy to prevent disease recurrence.This approach, of course, is not possible using conventional chemotherapeutics; due to their high-level toxicity, it would be impossible to use cytotoxic drugs for long-term maintenance therapy regimens. This, therefore, represents a basic therapeutic modality that cannot be entertained in the context of conventional chemotherapy drugs. Nevertheless, the successful management of many types of cancer may require an approach that involves some type of long-term maintenance therapy in order to prevent disease recurrence. An important therapeutic goal for future research, therefore, may involve the development of therapeutics designed for use in long-term maintenance therapy. These agents, though specific in their cell-targeted inhibitory effects, nevertheless impact essential pathways that drive the malignant phenotype. Perhaps nothing less will do.The concepts of anti-inflammatory and anti-oxidant approaches to cancer therapy involve a very basic hypothesis, that similar mechanisms may be associated with their cancer preventive effects and therapeutic effects. In other words, prevention and treatment may not be two different entities but rather may be multifaceted components necessary to create a systemic environment that prevents both the development and spread of malignancies within the body. By altering the tumor-promoting environment, either in pre-malignant, active or post-malignant conditions, these so-called preventive agents may help to maintain a system equilibrium that is resistant both to tumor development and disease recurrence. The paradigm that prevention and treatment are interconnected therapeutic approaches is based on the proposed interrelationship between physiological conditions associated with the development of incipient cancer and the progression to systemic disease. This paradigm suggests that the treatment of cancer is not simply regarded as a short-term effort to destroy tumor cells in patients with diagnosed disease but rather as both a preventive approach in healthy individuals to protect against the development of incipient cancers and also as a therapeutic approach in diagnosed patients to modify the system in such a way that the host no longer serves to support tumor growth within the body.For the past several decades, the prevailing therapeutic paradigm for the treatment of both disseminated leukemias/lymphomas as well as almost all solid tumor malignancies has involved the use of dose-dense, combined MTD cytotoxic chemotherapy. Current therapeutic protocols for the treatment of most cancers were developed initially in the context of treating childhood leukemias and lymphomas; their extended clinical applications to the treatment of solid tumor malignancies were based largely on the therapeutic successes observed, for example, in the treatment of HD and acute lymphoblastic childhood leukemia (ALL).Despite these broad-spectrum applications to almost all currently used chemotherapy regimens, in only a few types of cancer do we see curative responses such as have been consistently observed in the treatment of childhood ALL and HD. Thus, the results of over a half-century of clinical trials have shown that the therapeutic approach of combined/dose-dense chemotherapy has not been successful in achieving its primary purpose, which is the induction of long-term disease-free survival in the majority of patients with systemic disease.The clinical use of most conventional chemotherapy drugs involves the basic assumption that the cancer phenotype is characterized by continuous dysregulated cell proliferation. Therapeutic modeling in solid tumors was largely based on the growth parameters defined by the growth of leukemia cells; however, the vast differences in growth properties that distinguish solid tumor growth from that of leukemias and some lymphomas made this translational approach inappropriate. Research on tumor biology suggests that many solid tumors of diverse tissue types are heterogeneous collections of cells that are not consistently or uniformly proliferating at any given time. Fundamental differences between the growth properties of leukemias/lymphomas and solid tumors may thus explain key differences in chemotherapy sensitivities.The association between chronic inflammation and ROS activity in the genesis of cancer is supported by clinical research studies that provide evidence for the preventive aspects of the long-term use of aspirin and anti-oxidants in the development of some common malignancies. Moreover, based on their effects on mitochondrial function, it is entirely possible that inflammation/ROS may contribute to abnormal tumor physiology that promotes tumor progression and metastasis.The concept of long-term anti-inflammatory/anti-oxidant maintenance approaches to cancer therapy involves a very basic hypothesis, that similar physiological mechanisms may be responsible for both cancer preventive and therapeutic effects. Prevention and treatment may not be two different entities but rather may be multifaceted components necessary to create a systemic environment that prevents both the development and spread of malignancies within the body. By altering the tumor-promoting environment, either in pre-malignant, active or post-malignant conditions, these so-called preventive agents may help to maintain a system equilibrium that is resistant both to tumor development and disease recurrence.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The influence of feed restriction and different diet's caloric value on the aerobic and anaerobic capacity is unclear in the literature. Thus, the objectives of this study were to determine the possible influences of two diets with different caloric values and the influence of feed restriction on the aerobic (anaerobic threshold: AT) and anaerobic (time to exhaustion: Tlim) variables measured by a lactate minimum test (LM) in rats.ad libitum commercial Purina® diet  (ALP), restricted commercial Purina® diet (RAP), ad libitum semi-purified AIN-93 diet  (ALD) and restricted semi-purified AIN-93 diet (RAD). The animals performed LM at the end of the experiment, 48 h before euthanasia. Comparisons between groups were performed by analysis of variance .We used 40 adult Wistar rats. The animals were divided into four groups: ad libitum diet intakes. In addition, the ALD group had higher amounts of adipose tissue. With respect to energetic substrates, the groups subjected to diet restriction had significantly higher levels of liver and muscle glycogen. There were no differences between the groups with respect to AT; however, the ALD group had lower lactatemia at the AT intensity and higher Tlim than the other groups.At the end of the experiment, the weights of the rats in the groups with the restricted diets were significantly lower than those in the groups with ad libitum intake of a semi-purified AIN-93 diet results in an increase in adipose tissue, likely reducing the density of the animals in water and favouring their performance during the swimming exercises.We conclude that dietary restriction induces changes in energetic substrates and that  All authors worked read and approved the final manuscript.


Because of the increasing age of the population, critical care and emergency medicine physicians have seen an increased number of critically ill patients over the last decade. Moreover, the trend of hospital closures in the United States t imposes a burden of increased efficiency. Hence, the identification of devices that facilitate accurate but rapid assessments of hemodynamic parameters without the added burden of invasiveness becomes tantamount. The purpose of this review is to understand the applications and limitations of these new technologies. The derived hemodynamic variables are systemic and pulmonary vascular resistances. The major obstacle for the use of PAC has been the lack of demonstrating patient benefit and its level of invasiveness. Several prospective trials have demonstrated the lack of benefit from PACs. The PAC-man trial indicated that the routine placement of PACs had no effect on morbidity or mortality, and the ESCAPE trial found no difference in mortality or length of hospital stay when PAC parameters were compared with clinical assessment in the management of severe congestive heart failure patients [The ultimate goal of any hemodynamic monitoring system is to provide the clinicians with additional information on the underlying pathological condition and to guide fluid or vasopressor therapy. Cardiac output measurement and its response to therapeutic interventions are frequently used in critically ill patients. As the use of CO monitoring devices increases today, it is necessary to understand the application of such devices in different clinical settings. For many years pulmonary artery catheter (PAC) thermodilution cardiac output assessment was the monitor of choice for the management of critically ill patients. Thermodilution is a modification of the original indicator dilution techniques in which the injectate has a defined volume and temperature from which the thermodilution curve is generated . As withpatients -6. FurthCO monitors use different principles for measuring CO. They include Doppler technology, echocardiography, pulse contour analysis, transpulmonary thermodilution, bioimpedance, bioreactance and Fick's principle.Esophageal Doppler (ED) measuring aortic blood flow velocity was first introduced in 1971 . This meEchocardiography has been used in the ICU and emergency medicine for many years to diagnose the underlying cause of hemodynamic instability. Like ED, echocardiography uses Doppler technology, but it relies on direct visualization of the cardiac anatomy and flow dynamics. The American College of Emergency Physicians encourages emergency medicine physicians to be able to rapidly diagnose pericardial tamponade and electromechanical dissociation, which represent truly emergent and potentially lethal cardiovascular conditions. A focused point of care exam will enable the emergency medicine physician to quickly assess: hemodynamic states  and unex1. Wall motion abnormality for the diagnosis of myocardial injury  and eval2. Ventricular systolic dysfunction  and cardOne potential disadvantage of this device is the additional training required to make a proper diagnosis. Detailed cardiac echocardiography for diagnosis of complex cardiac diseases requires more advance training. Echocardiography measures CO only in a single point in time and is not suitable for trend analysis.Pulse contour analysis of cardiac output is based on the principles that stroke volume can be continuously estimated by analyzing the arterial pressure waveform obtained from an arterial line. The origin of the pulse contour method for estimation of the beat-to-beat stroke volume is based on the Windkessel model described by Otto Frank in 1899. In 1974, Wesseling et al. developed an algorithm that can be used to monitor stroke volume (SV) . CO is cThe most frequently used ones are the calibrated PiCCO monitor system , the LiDCO monitoring system , which is available as either a calibrated (LiDCOplus) or uncalibrated device (LiDCOrapid), and the uncalibrated FloTrac/Vigileo device . The pulse contour devices are utilized with greater frequency in our local practice; hence, they are covered in more detail.The PiCCO system uses the pulse contour method based on the Wesseling algorithm for the calculation of CO. The system is periodically calibrated via the thermodilution method to calibrate the pulse pressure algorithm. PiCCO is a cardiac monitor that measures cardiac output and several volumes such as intrathoracic blood volume (ITBV), global end diastolic volume (GEDV), and extra vascular lung water (EVLW) . PiCCO cPiCCO has the ability to measure (ITBV), (EVLW), and cardiac function index (CFI). These parameters are of interest as they are considered to be the most specific measures of cardiac preload, pulmonary edema, contractility, and a global indicator of cardiac performance. Therefore, PiCCO may give an emergency medicine physician a powerful tool for managing critically ill patients .Flo-Trac is another pulse contour CO monitoring system  that was introduced in 2005. A special blood flow sensor, which is connected to an arterial line , is needed. No external calibration is necessary -35. ThisThe technique of using lithium dilution to measure CO was first described in 1993 by Linton et al. . This teThe use of the electrical signal across the thorax to measure CO goes back to early 1970 . BioimpeBioreactance  is a unique technology for assessment of cardiac output . It is s2) production and exhaled or end tidal CO2 at baseline and during a brief period of rebreathing. This will allow calculation of pulmonary artery blood flow. A new monitor called the NICO system  uses Fick's equation for CO2 elimination. It is relatively noninvasive. Its principle states that over a fixed period of time the amount of CO2 leaving the lungs in the arterial blood is equal to the amount brought into the lungs in the venous blood minus the amount eliminated through the lungs. With this method, the CO is computed on breath-by-breath measurements of CO2 elimination. CO is proportional to the change in CO2 elimination divided by the change in end tidal CO2 resulting from a brief rebreathing period. Rebreathing measurements are made every 3 min for 35 s. The main drawback to this system is the assumption about the shunt fraction and arterial CO2 being equal to end-tidal CO2. Clinical and experimental data for CO determinations with the NICO monitor [2 concentration reflects the level of CO2 stored in the body. Therefore, any changes in metabolism or ventilation may alter the reliability of this monitor. Pulmonary shunting and heterogeneous ventilation decrease the precision of this device in acute lung injury since the shunt fraction is estimated from the concentration of the inspired fraction of oxygen and arterial oxygen saturation. Its main area of use has been in stable cardiac patients. This device can be utilized in the busy emergency medicine environment for evaluation of low cardiac output states if a patient is already intubated and on mechanical ventilation.Adolf Fick spent most of his life studying muscle metabolism, but in a brief publication in 1870, he described how mass balance might be used to measure cardiac output . Later G monitor  give a b monitor . AdvantaWith an increasing need for utilization of hemodynamic monitoring due to the aging population, increased comorbidities and increasingly complex interventions and monitoring are becoming incorporated into the standard of care, and the need for hemodynamic monitoring is likely to increase. Because of the inherent limitations and complications of PAC in the busy emergency department, physicians are looking for less invasive devices to measure CO. There is no gold standard for the clinical measurement of CO. Therefore, comparison of these new technologies is somewhat challenging Table . The levThe authors do not have any financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.JP drafted the manuscript. GZ drafted the manuscript and made significant contributions to the revision. SC drafted the manuscript and made significant contributions to the revision. NN drafted the manuscript and provided figures. All authors read and approved the final manuscript.


Neuroimaging has improved our understanding of the evolution of stroke at discreet time points helping to identify irreversibly damaged and potentially reversible ischemic brain. Neuroimaging has also contributed considerably to the basic premise of acute stroke therapy which is to salvage some portion of the ischemic region from evolving into infarction, and by doing so, maintaining brain function and improving outcome. The term neurovascular unit (NVU) broadens the concept of the ischemic penumbra by linking the microcirculation with neuronal-glial interactions during ischemia reperfusion. Strategies that attempt to preserve the individual components  of the NVU are unlikely to be helpful if blood flow is not fully restored to the microcirculation. Magnetic resonance imaging (MRI) is the foremost imaging technology able to bridge both basic science and the clinic via non-invasive real time high-resolution anatomical delineation of disease manifestations at the molecular and ionic level. Current MRI based technologies have focused on the mismatch between perfusion-weighted imaging (PWI) and diffusion weighted imaging (DWI) signals to estimate the tissue that could be saved if reperfusion was achieved. Future directions of MRI may focus on the discordance of recanalization and reperfusion, providing complimentary pathophysiological information to current compartmental paradigms of infarct core (DWI) and penumbra (PWI) with imaging information related to cerebral blood flow, BBB permeability, inflammation, and oedema formation in the early acute phase. In this review we outline advances in our understanding of stroke pathophysiology with imaging, transcending animal stroke models to human stroke, and describing the potential translation of MRI to image important interactions relevant to acute stroke at the interface of the neurovascular unit. The sece points ,14,68. TThe Apparent Diffusion Coefficient (ADC) quantifies the diffusibility of water and absolute thresholds of ADC reduction have been quoted as an absolute viability threshold in the controlled environment of animal stroke models but not humans. Clinically the timing of the ADC measurement is critical to its interpretation as it normalizes and then increases over time. It is also recognized that there is regional tissue susceptibility reflected by a variance of vulnerabilities; reduction of ADC in the striatum correlated with reduced ATP and tissue necrosis. The response of ADC upon reperfusion is an observed return of the ADC toward normal values ,70. TherT2-weighted imaging is sensitive to inter-parenchymal water accumulation, and increased T2 becomes apparent within several hours. T2 has become generally accepted as a reliable technique to predict an ischemic lesion beyond the acute stages. It correlates with histological measures of hemispheric swelling and the area of infarction by TTC and H&E histological sections . The detMAX) most accurately identifies hypoperfusion and infarct growth or response to thrombolysis [Dynamic contrast perfusion-weighted imaging uses bolus tracking techniques and intravenous administration of paramagnetic contrast agents. Different curve patterns can be derived with or without deconvolution using an arterial input function obtained from large intracranial vessels such as the middle cerebral artery . There ambolysis . Also, smbolysis ,80.MAX [To differentiate penumbra from benign hypoperfusion (oligemia) a visual analysis is inadequate. Numerous MRI thresholds have been used, including relative TTP, relative MTT, CBF and TMAX ,79–81. SMAX ,82. A reMAX . ComparaMAX ,82. TherMAX . This isMAX ,84.5.It has been acknowledged that understanding injury at the NVU following ischemia reperfusion is fundamental to therapeutic advancement for stroke. To date, tissue plasminogen activator (tPA) is an effective yet vastly underused treatment for acute ischemic stroke associated with several limitations to its use. First, the six-fold increase in morbidity and four-fold increase in fatality related to tPA-induced hemorrhagic transformation have deterred physician use of the therapy . Second,vs. irreversible during ischemia, the use of MR paramagnetic contrast agents allows complimentary assessments of vascular flow, tissue perfusion and BBB integrity. Relevant mechanisms of injury to tissue viability and the ischemic penumbra that can be imaged are the early inflammatory responses to ischemia in the microvasculature, BBB dysfunction and CBF/neuronal changes .While our understanding of molecular and biochemical responses that ensue following cerebral ischaemia in individual cell types  has grown appreciably there is a demand to understand these processes together at the microvascular level. MRI has allowed us to study animals over time, increasing our understanding of the temporal and spatial evolution of ischemic brain injury, while also reducing the large number of animals that are required for traditional histological experiments. In addition to making assessments of what injury might be reversible The potential of imaging molecular and cellular events that are critically involved in stroke pathophysiology and infarct evolution at the neurovascular level has capitalized on advancements in contrast agent design and synthesis. Cellular labeling and molecular targeting with contrast agents may enable both detection and quantification of neuroinflammatory processes such as infiltration of leukocytes and upregulation of markers of endothelial activation ,87. ThesIn the pursuit of determining specific disease process, the evolving field of molecular imaging requires the development of novel classes of MR detectable agents with improved image contrast. The aim of Magnetic Resonance Molecular Imaging is to provide an anatomical visualization of specific molecular processes ideally with high temporal and spatial resolution. There are some basic imaging requirements of Magnetic Resonance Molecular Imaging that should be considered: (1) the imaging target should be well-characterized with respect to its anatomical localization, the time course and the extent of expression; (2) the targeting ligand should be able to access the target, have high binding affinity and a pharmacokinetic profile suited for the needs of the imaging: (3) the signal should unambiguously be a consequence of ligand-target binding, representing specific binding.Currently two major classes of contrast agents exist: paramagnetic (gadolinium based); and super-paramagnetic agents . The parTechniques capable of characterizing BBB integrity may prove particularly valuable because there is a credible association between BBB disruption and risk of hemorrhagic transformation with thrombolytic therapy. For the assessments of BBB permeability paramagnetic contrast agent is administered intravenously using a bolus injection. With an intact blood brain barrier the contrast agent passes through the microvasculature of the brain, being contained to the intravascular space. During stroke there are areas of the brain that are associated with BBB breakdown and it is in these areas that the contrast agent can extravasate into the interstitium. There are two methods of detecting BBB breakdown: (1) static T1-weighted MR imaging; and, (2) dynamic contrast enhanced MRI (DCE MRI) . Post coet al. showed that DCE MRI in a rat model of progressive parenchymal enhancement was highly correlated with the presence of hemorrhagic transformation [More research is required in this area but it is hypothesized that dynamic contrast MRI or CT may be useful in the prediction of hemorrhagic transformation in acute ischemic stroke. It has been proposed that measurements of BBB permeability in acute stroke may aid in selecting acute ischemic stroke patients for treatment based on imaging criteria of BBB integrity, avoiding the restrictive eligibility criteria mandated by the time window paradigm. Knight ormation ,103. Theormation . Such te6.i.e., brain with reduced blood flow at risk of infarction. PET is considered to be the gold standard for CBF quantification with the additional parameter of tissue viability in terms of maintained rates of cerebral oxygen metabolism. MR diffusion and perfusion-weighted imaging have been used to translate the imaging concept of penumbra to one of diffusion-perfusion mismatch. This conceptual framework of penumbra is not absolute and controversies remain regarding whether diffusion can correctly identify infarct core and perfusion-weighted imaging can identify tissue at risk outside the DWI lesion. Other problems exist regarding consensus over definitions of penumbra, the consistency of post-processing software used between research groups, and, mismatch has not been shown to be a reliable surrogate to target patient populations in prospective studies. There remain several voids clinically of what we understand of reversible and irreversible injury from the imaging technology and what we understand of the disease at the microscopic level, specifically our concept of the neurovascular unit, its cellular interrelationships and clinical importance in terms of its dependence of tissue viability on blood flow return. The combination of neuroimaging modalities that include biomarkers of both blood flow, metabolism and blood brain barrier breakdown along with molecular imaging markers of cell injury may clearly delineate reversible vs. irreversible and potentially salvageable tissue in the penumbra. This will also expand our perspective that the identification of tissue at risk is only one of many predictors of therapeutic success. The treatment related risks have to be considered and limit therapeutic options for instance related to intracerebral hemorrhage with thrombolysis. Therefore the mismatch concept has to be extended to the assessment of the regional integrity of the neurovascular unit to estimate the response and risk associated with treatment. Under certain therapeutic situations the response of ischemic tissue to reperfusion is likely to exacerbate injury and therefore BBB integrity may provide a useful surrogate to assess ability to rescue tissue. A more physiological based approach complementary to our current understanding of the biological mechanisms, should allow decision processes that alleviate our dependence on the current time based treatment window to an imaging based treatment window [Neuroimaging has been fundamental to translating pathophysiological concepts to clinical trials. The target for stroke therapy remains the ischemic penumbra, t window ,105. Fut


Several lines of evidence implicate orbitofrontal cortex dysfunction in the pathophysiology of obsessive-compulsive disorder (OCD). The purpose of this study was to investigate neuropsychological dysfunction of the orbitofrontal cortex in children with OCD.The Iowa Gambling Task (IGT), which reflects orbitofrontal cortex function, and the Wisconsin Card Sorting Test (WCST), which is associated with functioning of the dorsolateral prefrontal cortex, were administered to 22 children with OCD and 22 healthy controls matched for gender, age, and intelligence.OCD patients displayed poor performance on the IGT. In contrast, performance on the WCST was not impaired in OCD patients compared to controls.These findings are in line with previous studies demonstrating that OCD in childhood is associated with a dysfunction of orbitofrontal-striatal-thalamic circuitry. The current dominant model of obsessive-compulsive disorder (OCD) focuses on abnormalities in cortico-striatal circuitry, with particular emphasis on the orbitofrontal-striatal-thalamic circuit ,2. In paPerformance on the Iowa Gambling Task (IGT), which evaluates real-life decision-making abilities under conditions of ambiguity, is particularly sensitive to alterations in OFC function ,5. In coIn the present study, to test this hypothesis, we measured IGT and WCST performance in children with OCD and compared these results with those of gender-, age-, and intelligence-matched healthy, non-clinical controls. We excluded OCD patients comorbid with pervasive developmental disorder (PDD) or attention-deficit/hyperactivity disorder (ADHD) because a comorbidity of these disorders is known to affect performance on neuropsychological tests ,15.The study sample consisted of 22 Japanese OCD patients (between the age of 10 and 15 years). They were admitted as inpatients or outpatients at Kohnodai Hospital, National Center for Global Health and Medicine. Two trained child and adolescent psychiatrists made diagnoses following DSM-IV-TR  criteriaNormal healthy controls were recruited from 2 local public schools by word of mouth. A total of 47 students volunteered to participate, of which 2 were excluded due to obsessive symptoms, 1 due to tic disorder, and 3 due to pervasive developmental disorder. After matching for gender, age, handedness, and intelligence with the patient group, 22 were included in the analyses. Those with a current or past history of psychiatric diagnosis, psychiatric or psychological treatment, or absenteeism from school were excluded from the control group. A child psychiatrist conducted a 30-minute clinical interview with each control subject to rule out any current or past history of psychiatric disorders.Two trained child and adolescent psychiatrists assessed the severity of OCD symptoms using the NIMH-Global Obsessive Compulsive Scale (NIMH-OCS)  in both The Iowa Gambling task (IGT)  was admiFour clinical psychologists individually administered the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) and the Keio version of the Wisconsin Card Sorting Test (WCST) . WCST isData were analyzed using the Statistical Package for the Social Sciences (SPSS) Version 20 for Mac. T-tests were used to compare continuous variables , and Mann–Whitney tests were used to compare ordinal variables. The results were considered significant at p < 0.05.This study was designed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the National Center for Global Health and Medicine. All participants gave written informed assent and their parents gave written informed consent after the procedure had been explained to them.Demographic and clinical characteristics are summarized in Table In the last section of the IGT (selections 81–100), the number of disadvantageous card selections was significantly higher in the OCD group compared to the controls . However, the CY-BOCS score during the period with the most severe symptoms in children with OCD significantly and positively correlated with the number of disadvantageous cards selected in the last block . The number of disadvantageous cards selected in the last block was also significantly greater in patients on antidepressant medications compared to patients not taking an antidepressant . Total number of errors in the WCST was negatively correlated with current age in OCD patients  and with performance IQ in the controls ; however, no other significant correlations were observed between WCST scores and the clinical parameters .To the best of our knowledge, this is the first report on IGT performance in children and adolescents with OCD. The observed poor IGT performance suggests impaired decision-making function in OCD patients. Previous studies have described poor IGT performance in adult OCD patients -11 and oElectrophysiological recordings of the OFC have revealed that orbitofrontal neurons play an important role in processing the motivational value of rewarding outcomes -32. ThisThe present findings that IGT performance correlated significantly with the CY-BOCS score during the period with the most severe symptoms but not with the CY-BOCS score at the time of the assessment suggest that IGT performance may be associated with the potential severity of OCD rather than the state of present symptom exacerbation. We infer that the poor performance on IGT in antidepressant users may be because antidepressants were more likely to be chosen as a treatment for those with severe symptoms during the initial clinical assessment. However, an alternative explanation may be that the negative effects of antidepressants on cognitive performance result in poor IGT performance. Further studies are needed to elucidate what factors influence IGT performance in children with OCD.The current study showed no significant differences in performance on the WCST between OCD patients and controls. WCST performance is specifically related to function of the DLPFC , a regioThe only previous study which examined WCST performance in children with OCD  reportedThere are numerous studies on WCST performance in adult OCD patients; however, results are inconsistent across studies. Several groups reported a reduced performance in OCD patients ,36-38, wThere are several limitations to the current study. First of all, the number of participants was too small to draw definitive conclusions. Secondly, some children with OCD were on medication, which may have affected the results. Finally, we did not use neuroimaging methods such as fMRI to confirm our inference that the function of the OFC was associated with the results obtained in our study.In summary, children with OCD displayed poor performance on IGT but did not differ on WCST scores compared to controls. These findings are in line with the hypothesis that OCD is associated with dysfunction of orbitofrontal-striatal-thalamic circuitry. However, large-scale studies combined with fMRI are needed to confirm the role of the orbitofrontal cortex in the pathophysiology of childhood OCD.The authors declare that they have no competing interests.MaK designed the study and wrote the manuscript. MaK, YI, HU, MU and KW recruited and screened the study participants. MaK and YI diagnosed the study participants. MaK administered the IGT. MaK undertook the statistical analysis. AO and KS supervised the data analysis and writing of the paper. MoK, NS, and DS gave critical comments on the manuscript. All authors contributed to and have approved the final manuscript.


The lithic assemblage of the Early Pleistocene site of Bizat Ruhama, Israel demonstrates the earliest evidence for systematic secondary knapping of flakes. The site, dated to the Matuyama chron, is one of the earliest primary context Oldowan occurrences in Eurasia. According to the experimental replication of the stone-tool production sequence, the secondary knapping of flakes was a part of a multi-stage operational sequence targeted at the production of small (<2 cm) flakes. This sequence included four stages: acquisition of chert pebbles, production of flakes, deliberate selection of flakes of specific morphologies, and their secondary knapping by free-hand or bipolar methods. The results suggest that flakes with retouch-like scars that were produced during this sequence and which commonly are interpreted as shaped tools are unintentional waste products of the small flake production. The intentional manufacture of very small flakes at Bizat Ruhama was probably an economic response to the raw material constrains. Systematic secondary knapping of flakes has not yet been reported from other Early Pleistocene sites. Systematic secondary knapping for small flake production became increasingly important only in the lithic industries of the second half of the Middle Pleistocene, almost a million years later. The results from Bizat Ruhama indicate that Oldowan stone-tool production sequence was conceptually more complex than previously suggested and offer a new perspective on the capabilities for invention and the adaptive flexibility of the Oldowan hominins. The lithic industries assigned to the Oldowan techno-complex are characterized by production of unmodified sharp-edged flakes This paper reports on systematic secondary flake knapping recorded at the Early Pleistocene site of Bizat Ruhama, Israel, indicating that Oldowan hominins employed more complex operational schemes than previously suggested. The site of Bizat Ruhama, currently dated to 1.6-1.2 Ma on the basis of biochronological and paleomagnetic considerations Approximately half of the flakes that were produced during core reduction were subsequently further flaked, broken or notched, most commonly resulting in Clactonian notches or flakes with retouch-like abrupt scars. These types of thick modified flakes are the most distinct product of the Bizat Ruhama industry, distinguishing it from other Early Pleistocene assemblages. Originally the modified flakes in Bizat Ruhama were interpreted as retouched tools An experimental study was therefore undertaken in order to test the hypothesis that an anvil have been used in the modification of flakes at Bizat Ruhama. Flakes were detached from local pebbles, and then further knapped on an anvil. The results of the experimental knapping suggest that the majority of the modified flakes at Bizat Ruhama are waste products of the process of manufacturing small, thin and sharp flakes on an anvil. The results indicate that the production sequence at Bizat Ruhama consisted of more stages and was conceptually more complex than previously reported for Oldowan sites. The study points to a high level of technological and adaptive flexibility of the Early Pleistocene hominins on the threshold of Eurasia.hamra in an undulating inter-dune depression. The clayey sand of the archaeological layer represents input of locally reworked sand and soil aggregates from the hamra topsoil by low energy deposition, possibly through wind and overland flow. According to micromorphological studies the archaeological assemblages are in primary context and represent either a single occupation or several occupation events within a relatively short period of time Bizat Ruhama is a single-horizon open-air site on the fringe of the Negev Coastal Plain, 25 km east of the present-day Mediterranean coastline of Israel . The arcEquus cf. tabeti), followed by antelopes (Pontoceros ambiguous/Spirocerus sp.), bovids (cf. Bison sp.) and gazelles (Gazella gazella), all representative of an open environment with patchy water sources The faunal assemblage at Bizat Ruhama includes mainly equids . The majority of the artifacts (N = 1694) derive from excavation areas BRAT5 and BR1996, and the rest were unearthed in three excavated trenches: BRT1, BRT2 and BRT3 . A largeThe raw material used at the site consists of small, rounded chert pebbles from the nearby Pleshet Formation The Bizat Ruhama lithic industry was studied using experimental and technological approaches. The comprehensive experimental knapping program at the site included free-hand hard hammer and bipolar flaking of pebbles, an anvil breakage of flat pebbles and free-hand and anvil knapping/breakage of flakes For the controlled knapping experiments, 65 flakes were selected among the flakes produced during the experimental pebble reduction. The selection criteria were based on the features of secondary knapped flakes in the archaeological assemblages. Thus, large and thick flakes, whose lateral edges had an angle of 50–80 degrees, were selected. The bipolar reduction procedure followed the general rules recorded in ethnographic and experimental studies. The bipolar technique consists of placing the core/flake on an anvil and striking it along a roughly perpendicular plane The products of experimental knapping were compared to secondary knapped flakes in archaeological assemblages using the same list of technological, morphological and metrical attributes .Apart from a small number of flakes that were used as simple cores, from which 1–4 small flakes were removed , the flaThe secondary knapped flakes often show impact marks at the intersection between the dorsal surface and the lateral or broken surfaces. The most frequent impact marks on the dorsal surfaces are points of percussion, crushing of the dorsal edges and crack lines .Flakes selected for secondary knapping are considerably thicker than complete flakes. Flakes thinner than 7 mm constitute approximately 45% of the complete flakes, but only 11.5% of secondary knapped flakes . These nBetween 83 and 95% of the secondary knapped flakes from different excavation areas are fresh and unrolled Bipolar technique flaking conceived as having fracture mechanics associated with the type of initiation called wedging Wedging initiation, however, will not necessary be generated while applying bipolar loading. According to Cotterell and Kamminga Another defining feature of bipolar flaking is that the loading is applied to two opposite surfaces and may result in fractures in opposite directions – the flake can be detached by either a blow from a hammer or a counterblow from an anvil In the current experiment, the morphology of the knapped blank dictated different fracture mechanics. The angle between the ventral surface of the flake resting on an anvil and the flake edges was less than 90 degrees and the fracture was initiated mostly by anvil impact, usually close to the flake edge. The bipolar loading did not split or break the flake; rather, the flake functioned as a core and flakes and fragments were detached from its edges . The scaDuring the experiments a series of flakes was produced by a sequence of 3–4 blows. The detachment of the flakes often formed scars in the form of Clactonian notches or of retouch by large removals ; 8; 9. SAltogether, Clactonian notches, flakes with retouch-like scars and broken flakes constitute 21.1% of the assemblage, while small flakes and fragments detached from their edges account for 78.9%. Each knapping sequence produced on average 2.18 artifacts of the first group, and 8.01 of the second. In total the 65 flakes that were knapped on an anvil yielded 667 artifacts .Hammerstone impact marks occur on 54% of the flakes with retouch-like scars, 35.7% of the Clactonian notches and 45.8% of the broken flakes. The impact marks usually occur on the ridges at the contact between the dorsal and lateral or broken surfaces. They are localized and pronounced, indicating a small contact area. Crushing and small scars are the most frequent, followed by points and cones of percussion and then by various combinations of crushing marks, cones of percussion and wedge-shaped crack lines ; Table 3Anvil impact marks occur at various points along the circumference of the experimental items, indicating a large contact area between anvil and artifact. The anvil impact is evident on 59% of the experimental flakes that underwent further knapping. The anvil impact can be identified by the following:Crushing. These are most commonly found on broken flakes and are often associated with crack-lines, points of percussion and isolated scars Click here for additional data file.Table S2Full list of attributes applied to experimental and archaeological secondary knapped flakes.(DOCX)Click here for additional data file.


National Rural Health Mission (NRHM) was launched to address with a mission approach all components of functional systems; infrastructure, human resources, logistics and participation of the community through increasing government investment in healthcare and addressing managerial weaknesses in the system.Before the launch of NRHM, in order to bring the states that were performing poorly in terms of health indicators at par with the better performing states, the empowered action group of eight states was constituted in 2001. The failure to achieve desirable improvement in health indicators led the NRHM to focus on 18 poorly performing states, which included eight northeastern states of Assam, Meghalaya, Tripura, Manipur, Nagaland, Mizoram, Arunachal Pradesh and Sikkim.Our consultancy organisation got an opportunity to be part of the decentralised planning process in three high focus northeastern states of Meghalaya (2006-2007), Tripura (2006-2007) and Sikkim (2007-2008) under NRHM. After five year's journey of NRHM, this study aims at revisiting the situation in the light of the performance of these three states in three identified components of structural correction of the health system.We collected primary information through in-depth interviews of key functionaries. We also did a desk review of secondary literature.Shortage of human resource in the three states is a major problem in health sector in explaining ineffective and inefficient health outputs. Tripura is yet to appoint Auxiliary Nurse Midwives (ANM) in about 8.5% of health sub-centres in order to make them functional. The placement of a proposed second ANM at health sub-centre is a mammoth challenge. All the primary health centres (PHC) in Sikkim and 13% of PHCs in Meghalaya do not have staff nurse. In Meghalaya 13% of its PHCs offer services round the clock.The presence of the medical care is concentrated in and around semi-urban and urban conglomerates as the overall development issues are yet to be addressed for the hilly areas. The availability of clinical cadre is often in papers. The demand by Accredited Social Health Activists (ASHA), recently introduced female health workers at village levels, for being included in the mainstream is adding to the human resource issues to be resolved. It has remained a challenge to find clinical specialists for placements at community health centres .Janani Suraksha Yojana (Maternity protection scheme) has enabled Meghalaya to achieve 10% increase in institutional deliveries, the highest among the three states, but failed in assuring 48 hours of recommended stay of women in PHCs mainly due to unavailability of manpower, lack of electricity, and related amenities. Political unrest and inaccessible geographic terrains of three states often add to the multitude of the problem.Development of Indian Public Health Standards (IPHS) under NRHM has been an important effort towards assuring quality healthcare services. However none of the healthcare facilities in the three states have achieved these standards.In regard to flexible financing under NRHM all the three states exhibited gradual increase in expenditure pattern till the year 2008-2009 with a fall in the year 2009-2010. The gradual increase in financial allocation and disbursements with reduction in expenditure implies inability of the states to spend the available fund. The utilisation of untied fund available with health sub-centres and village level committees increased from the year 2005 to 2010. However they exhibited inability to submit utilisation certificates for finances expended.If we remove the performance indicators pertaining to Assam from the northeastern states, the non-performance of other northeastern states becomes apparent. Also the financial allocation is skewed if Assam is seen in along with other northeastern states. The uniqueness and variety of northeastern states cannot fall into the “one size fit all” interventions and strategies. For example, appointment of ASHAs has led to resentment among trained birth assistants supporting home deliveries in hilly terrain and led to confusion in a successful service delivery mechanism.We feel that the norms relating to two ANMs at health sub-centres and having healthcare facilities functioning round the clock can be relaxed and more attention need to be given on integration of local and other healing traditions into present healthcare services. NRHM has provided an impetus to utilisation of healthcare services but lack of concurrent development has affected the impression of the user negatively.


Neither indoor residual spraying (IRS) nor long-lasting insecticidal nets (LLINs) are able to fully interrupt transmission in holoendemic Africa as single interventions. The combining of IRS and LLINs presents an opportunity for improved control and management of pyrethroid resistance through the simultaneous presentation of unrelated insecticides.Anopheles gambiae and Culex quinquefasciatus. The bed nets were deliberately holed with either six or 80 holes to examine the effect of increasing wear and tear on protectiveness. Anopheles gambiae were genotyped for the kdr gene to assess the combination's potential to prevent the selection of pyrethroid resistance.Chlorfenapyr IRS and a pyrethroid-impregnated polyester LLIN (WHO approved) were tested separately and together in experimental huts in southern Benin against pyrethroid resistant kdr was 84%. The overall mortality rates of An. gambiae were 37% and 49% with the six-hole and 80-hole LLINs, respectively, and reached 57% with chlorfenapyr IRS. Overall mortality rates were significantly higher with the combination treatments (82-83%) than with the LLIN or IRS individual treatments. Blood feeding (mosquito biting) rates were lowest with the 6-hole LLIN (12%), intermediate with the 80-hole LLIN (32%) and highest with untreated nets (56% with the 6-hole and 54% with the 80-hole nets). Blood feeding (biting) rates and repellency of mosquitoes with the combination of LLIN and chlorfenapyr IRS showed significant improvement compared to the IRS treatment but did not differ from the LLIN treatments indicating that the LLINs were the primary agents of personal protection. The combination killed significantly higher proportions of Cx. quinquefasciatus  than the LLIN  or IRS (32%) treatments.The frequency of The chlorfenapyr IRS component was largely responsible for controlling pyrethroid-resistant mosquitoes and the LLIN component was largely responsible for blood feeding inhibition and personal protection. Together, the combination shows potential to provide additional levels of transmission control and personal protection against pyrethroid-resistant mosquitoes, thereby justifying the additional resources required. Chlorfenapyr has potential to manage pyrethroid resistance in the context of an expanding LLIN/IRS strategy. Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are the most widely implemented methods of malaria vector control . Owing tAs more resources are made available for malaria control through the Global Fund and President's Malaria Initiative, there is growing opportunity for deploying LLINs and IRS as a combination intervention ,3. A recAnopheles gambiae populations  of the dead mosquitoes had blood-fed beforehand), only a minority of dead mosquitoes had managed to blood feed when a LLIN was present in the IRS treated hut (i.e. 9.2% [8/87] of the dead mosquitoes had blood fed beforehand through the 6-hole nets and 26.3% [17/65] through the 80-hole nets). This indicates that in the absence of a LLIN the mosquitoes will blood feed on the sleeper before alighting on the insecticidal wall. But in the presence of an LLIN many mosquitoes alight on the wall and are killed before managing to feed.Cx. quinquefasciatus are presented in Table Cx. quinquefasciatus than untreated nets with six holes (P = 0.0001). In the absence of any net a higher proportion of mosquitoes were able to blood feed (77% managed to blood feed in the huts with chlorfenapyr IRS and no net), indicating that the holed net was a partial barrier to Culex biting and feeding. The pyrethroid on the LLIN was highly protective and the level of blood feeding inhibition by the insecticide was higher for Cx. quinquefasciatus than for An. gambiae. However, only a small proportion of Cx. quinquefasciatus were killed by the pyrethroid (~15%), and this proportion was smaller than the proportion of An. gambiae killed by the same treatment. Chlorfenapyr IRS killed 32.3% of Cx. quinquefasciatus. The combination of IRS and LLIN was additive, killing in the range of 40-50%. As was observed with An. gambiae, the combination was protective against Cx. quinquefasciatus (mostly due to the LLIN component) and also succeeded in killing many Cx. quinquefasciatus (mostly due to the IRS component). As with An. gambiae, the proportion of Cx. quinquefasciatus blood feeding was dependent on the number of holes in the LLIN, irrespective of whether chlorfenapyr IRS was present or not.The effects of the treatments on kdr allele did not differ between the survivor and dead collections of An. gambiae at the 5% significance level. These results did not show any selective advantage to kdr in the presence of the LLIN. Nor did it show any selective neutrality or disadvantage to kdr in the presence of the combination treatment. Initial genotyping of 100 adult An. gambiae, which emerged from larvae collected at the field site (Akron), showed a kdr frequency of 0.91, a value consistent with the samples collected from the huts. This high frequency of kdr and the relatively small samples analysed made it impossible for the current study to demonstrate any differential selection of kdr between the LLIN and combination treatments.The results for the molecular studies are presented in Table A combination of IRS and LLINs can only be justified economically if it provides greater levels of protection or greater transmission control than is achievable by the single interventions. The present comparisons show that the combining of chlorfenapyr IRS and pyrethroid LLINs in the same hut provides personal protection (mostly attributable to the LLIN component) and transmission control potential  over and above what the individual components are able to achieve. With the massive injection of international aid by the Global Fund and President's Malaria Initiative for universal coverage of LLINs and IRS transmission control, the roll-out of such a combination intervention appears well justified on the basis of the present suggestive small scale study.kdr or metabolic mechanisms is springing up in countries across sub-Saharan Africa [The spectre of resistance haunts our capacity to control malaria in the future. Pyrethroid resistance due to n Africa . While cn Africa ,8. ConfrAn. gambiae and Cx. quinquefasciatus when applied as IRS [Previously it was shown that chlorfenapyr is capable of controlling pyrethroid-resistant d as IRS . The mosd as IRS . Taken tThese findings stand in contrast to the experimental hut studies in Burkina Faso in which a combination of pyrethroid-treated wall linings and ITN failed to induce any increase in mortality of malaria vectors over that of ITN alone . This diThe relatively high mortality of mosquitoes in chlorfenapyr IRS-treated huts confirms the potential of the pyrole insecticide as an alternative IRS treatment . Hut triCx. quinquefasciatus, the nuisance mosquito in urban West Africa and filariasis vector in East Africa, is strongly resistant to pyrethroids and consistently records low mortality rates (less than 15%) in the presence of LLINs in experimental huts studies [Cx. quinquefasciatus increased to 51% when the LLINs were combined with chlorfenapyr IRS. The fact that the combination killed up to three times more Cx. quinquefasciatus mosquitoes than LLINs alone enhances the acceptability and compliance of this combined strategy for malaria control in peri-urban settings. studies . This is studies . In the Combining chlorfenapyr IRS and LLINs has an additive effect on the mortality of pyrethroid-resistant mosquitoes. In areas of high pyrethroid resistance or high transmission intensity, control programmes with sufficient resources should consider implementing a combination intervention of LLIN plus non pyrethroid-based IRS. Chlorfenapyr IRS is shown to be an ideal supplement to pyrethroid LLIN for improving the control of pyrethroid-resistant mosquitoes.The authors declare that they have no competing interests.CN: Project supervision, data entry, data analysis and interpretation, drafted the manuscript. RN: Project design and supervision, data interpretation, manuscript revision. PB, AO, EV: Conducted the field trials, molecular analyses, bioassay testing. AA: Co-supervision, data processing, manuscript revision. MA: Co-design of the project, manuscript review and revision. MR: Project design, coordination with IVCC and BASF, interpretation of the results, revision of the manuscript. All authors read and approved the final manuscript.