Access to experimental medicines for TB: ethical and human rights considerations.

The revised edition of the WHO's Ethics Guidance for the Implementation of the TB Strategy has added a new chapter on compassionate use (CU) and expanded access (EA) to TB drugs. CU and EA programmes authorise access to drugs that have not yet received marketing approval outside of clinical trials. They are aimed at allowing researchers access to investigational drugs in the absence of complete evidence of efficacy and safety to patients with multidrug-resistant (MDR) or rifampicin-resistant TB (RR-TB) when no other treatment options are available. In doing so, the guidance acknowledged the urgent necessity to offer these patients all possible treatments in respect of considerations of justice, human rights, human dignity, autonomy of the individual and protection of the community. Regulators are in general willing to accept a higher level of uncertainty in the risk-benefit assessment of medicines for life-threatening diseases when there is an unmet medical need. This attests to a paradigm change, which this article argues should also apply to allow for effective access to experimental TB medicines. Furthermore, in this article, we analyse the challenges connected to the establishment of a secure and effective regime of access to experimental drugs in the context of MDR/RR-TB as well as the ethical principles and human rights arguments in favour of the development of such programmes.

Decidual cell regulation of trophoblast is altered in pregnancies at risk of pre-eclampsia.

Successful implantation and placentation are dependent on the interaction between decidual stromal cells (DSC) and extravillous trophoblast (EVT) cells. The extent of trophoblast invasion relies on communication between the placenta and maternal decidua. The cyclical process of decidualisation induces a transformation of endometrial fibroblasts to secretory DSC; these secreted products have many functions including the control of trophoblast invasion. Inadequate trophoblast invasion and remodelling of the uterine vessels (the spiral arteries) are associated with pregnancy disorders such as pre-eclampsia. Uterine artery Doppler resistance index (RI) in the first trimester of pregnancy can be used as a proxy measure of remodelling. DSC were isolated from pregnancies with normal (normal RI) or impaired (high RI) spiral artery remodelling. Following isolation, DSC were re-decidualised using cAMP and MPA and secretion of the decidualisation markers IGFBP-1 and prolactin assessed. We examined the impact of DSC-secreted factors on trophoblast cell function, using the EVT cell line SGHPL-4. We demonstrated that DSC exposed to decidual factors were able to re-decidualise in vitro and that the chemoattraction of trophoblasts by DSC is impaired in pregnancies with high RI. This study provides new insights into the role that DSC play in regulating EVT functions during the first trimester of pregnancy. This is the first study to demonstrate that DSC from pregnancies with impaired vascular remodelling in the first trimester secrete factors that inhibit the directional movement of trophoblast cells. This finding may be important in understanding aberrant trophoblast invasion in pregnancies where vascular remodelling is impaired.

Use of Population-based Data to Demonstrate How Waitlist-based Metrics Overestimate Geographic Disparities in Access to Liver Transplant Care.

Liver allocation policies are evaluated by how they impact waitlisted patients, without considering broader outcomes for all patients with end-stage liver disease (ESLD) not on the waitlist. We conducted a retrospective cohort study using two nationally representative databases: HealthCore (2006-2014) and five-state Medicaid (California, Florida, New York, Ohio and Pennsylvania; 2002-2009). United Network for Organ Sharing (UNOS) linkages enabled ascertainment of waitlist- and transplant-related outcomes. We included patients aged 18-75 with ESLD (decompensated cirrhosis or hepatocellular carcinoma) using validated International Classification of Diseases, Ninth Revision (ICD-9)-based algorithms. Among 16 824 ESLD HealthCore patients, 3-year incidences of waitlisting and transplantation were 15.8% (95% confidence interval [CI] : 15.0-16.6%) and 8.1% (7.5-8.8%), respectively. Among 67 706 ESLD Medicaid patients, 3-year incidences of waitlisting and transplantation were 10.0% (9.7-10.4%) and 6.7% (6.5-7.0%), respectively. In HealthCore, the absolute ranges in states' waitlist mortality and transplant rates were larger than corresponding ranges among all ESLD patients (waitlist mortality: 13.6-38.5%, ESLD 3-year mortality: 48.9-62.0%; waitlist transplant rates: 36.3-72.7%, ESLD transplant rates: 4.8-13.4%). States' waitlist mortality and ESLD population mortality were not positively correlated: ρ = -0.06, p-value = 0.83 (HealthCore); ρ = -0.87, p-value = 0.05 (Medicaid). Waitlist and ESLD transplant rates were weakly positively correlated in Medicaid (ρ = 0.36, p-value = 0.55) but were positively correlated in HealthCore (ρ = 0.73, p-value = 0.001). Compared to population-based metrics, waitlist-based metrics overestimate geographic disparities in access to liver transplantation.

Inhibition of DDAH1, but not DDAH2, results in apoptosis of a human trophoblast cell line in response to TRAIL.

STUDY QUESTION: Does inhibition of dimethylarginine dimethylaminohydrolase (DDAH) increase the sensitivity of trophoblasts to TRAIL-induced apoptosis? SUMMARY ANSWER: Inhibition of DDAH1, but not DDAH2, increases the sensitivity of trophoblasts to TRAIL-induced apoptosis. WHAT IS KNOWN ALREADY: Successful human pregnancy is dependent on adequate trophoblast invasion and remodelling of the maternal spiral arteries. Increased trophoblast apoptosis is seen in pregnancies complicated by pre-eclampsia. The mechanism underlying this increase is unknown. We have previously shown that nitric oxide (NO) is involved in regulating trophoblast motility and invasion, and have also demonstrated an important role for NO in regulating trophoblast sensitivity to apoptotic stimuli. DDAH is an enzyme that metabolizes asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, previously shown to be elevated in the plasma of pre-eclamptic mothers. STUDY DESIGN, SIZE, DURATION: This study used the human extravillous trophoblast-derived cell line SGHPL-4 cells. All experiments were performed at least three times. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effect of DDAH on trophoblast apoptosis was examined using siRNA and time-lapse microscopy. Changes in the expression of DDAH were followed by PCR and western blot analysis. Receptor expression was followed by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibiting the expression of DDAH1, but not DDAH2, resulted in a significant increase in the sensitivity of the EVT cell line SGHPL-4 to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis (P < 0.01). This response could be mimicked by the addition of Asymmetric Dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis and the substrate for both isoforms of DDAH. We further showed that this increased sensitivity to apoptosis is accompanied by a significant increase in the expression of TRAIL receptor 2 (TR2; P < 0.05) but not TRAIL receptor 1 (TR1). LIMITATIONS, REASONS FOR CAUTION: This study was performed only in vitro using a well characterized trophoblast cell line, SGHPL-4, derived from first trimester extravillous trophoblasts. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insight into the role of the DDAH/ADMA pathway in the regulation of trophoblast function. Both dysregulation of DDAH and the accumulation of ADMA have been associated with the development of pre-eclampsia. This is the first study to implicate the DDAH/ADMA pathway as a mechanism that might underlie the poor trophoblast invasion seen in this common pregnancy disorder. STUDY FUNDING/COMPETING INTERESTS: B.A.L. was supported by a grant from Action Medical Research UK (SP4577). A.E.W. was supported by a grant from the Wellcome Trust (091550). There are no competing interests and the authors have no conflict interest to declare.

Increased angiogenic factor secretion by decidual natural killer cells from pregnancies with high uterine artery resistance alters trophoblast function.

STUDY QUESTION: Are the concentrations of factors secreted by decidual natural killer (dNK) cells from pregnancies at high risk of poor spiral artery remodelling different to those secreted from pregnancies at low risk? SUMMARY ANSWER: Expression levels of PLGF, sIL-2R, endostatin and angiogenin were significantly increased by dNK cells from high-risk pregnancies, and angiogenin and endostatin were found to alter trophoblast function. WHAT IS KNOWN ALREADY: During early pregnancy, maternal uterine spiral arteries are remodelled from small diameter, low-flow, high-resistance vessels into larger diameter, higher flow vessels, with low-resistance. This change is essential for the developing fetus to obtain sufficient oxygen and nutrients. dNK cells have been implicated in this process. STUDY DESIGN, SIZE, DURATION: dNK cells were isolated from first trimester terminations of pregnancies (obtained with local ethical approval) screened for normal- or high-resistance index, indicative of cases least (<1%) and most (>21%) likely to have developed pre-eclampsia had the pregnancy not been terminated (n = 18 each group). Secreted factors and the effects of these on the trophoblast cell line, SGHPL-4, were assessed in vitro. PARTICIPANTS/MATERIALS, SETTING, METHODS: A multiplex assay was used to assess dNK cell-secreted factors. SGHPL-4 cell functions were assessed using time-lapse microscopy, 3D invasion assays, endothelial-like tube formation ability and western blot analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The expression levels of PLGF (P < 0.01), sIL-2R (P < 0.01), endostatin (P < 0.05) and angiogenin (P < 0.05) were significantly increased by dNK cells from high-risk pregnancies. Endostatin significantly decreased SGHPL-4 invasion (P < 0.05), SGHPL-4 tube formation (P < 0.05) and SGHPL-4 Akt(ser473) phosphorylation (P < 0.05). Angiogenin significantly decreased SGHPL-4 invasion (P < 0.05), but increased SGHPL-4 tube formation (P < 0.01) and decreased SGHPL-4 Akt(ser473) phosphorylation (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The culture of dNK cells and protein concentrations in vitro may not fully represent the in vivo situation. Although SGHPL-4 cells are extravillous trophoblast derived, further studies would be needed to confirm the roles of angiogenin and endostatin in vivo. WIDER IMPLICATIONS OF THE FINDINGS: The altered expression of secreted factors of dNK cells may contribute to pregnancy disorders associated with poor spiral artery remodelling. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Wellcome Trust (project reference 091550). R.F. was a recipient of a PhD studentship from the Division of Biomedical Sciences, St. George's, University of London. The authors have no conflict of interests.

IFPA Meeting 2013 Workshop Report III: maternal placental immunological interactions, novel determinants of trophoblast cell fate, dual ex vivo perfusion of the human placenta.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At IFPA meeting 2013 there were twelve themed workshops, three of which are summarized in this report. These workshops related to various aspects of placental biology but collectively covered areas of placental function, cell turnover and immunology: 1) immunology; 2) novel determinants of placental cell fate; 3) dual perfusion of human placental tissue.

IFPA Meeting 2011 workshop report II: Angiogenic signaling and regulation of fetal endothelial function; placental and fetal circulation and growth; spiral artery remodeling.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2011 there were twelve themed workshops, three of which are summarized in this report. These workshops related to vascular systems and circulation in the mother, placenta and fetus, and were divided in to 1) angiogenic signaling and regulation of fetal endothelial function; 2) placental and fetal circulation and growth; 3) spiral artery remodeling.

Amygdaloid kindling is anxiogenic but fails to alter object recognition or spatial working memory in rats.

Kindling in rats produces enduring behavioral changes that parallel the psychobehavioral disturbances frequently accompanying temporal lobe epilepsy. Some evidence suggests that the site of kindling is an important determinant of the type of behavioral changes observed following kindling, although this variable has not been systematically investigated. In the present experiments, the effects of amygdaloid kindling were assessed on a battery of behavioral tests we used previously to assess the effects of kindling in dorsal hippocampus or perirhinal cortex. Three generalized seizures were kindled with stimulation in or near the basolateral amygdala. One week later, rats were tested successively on measures of anxiety, activity, object recognition memory, and spatial working memory over a period of 3 weeks. Amygdaloid kindling produced increased anxiety, but spared all other behaviors assessed. This pattern of results is partially distinct from the previously described effects of perirhinal cortical kindling, which increases anxiety but also impairs object recognition memory, and is completely distinct from dorsal hippocampal kindling, which selectively increases activity and impairs spatial working memory. The observations suggest that kindling of distinct highly interconnected temporal lobe sites produces distinct patterns of behavioral comorbidity. The underlying mechanisms are thus most likely localized to intrinsic circuits at the site of seizure origination.

Anterior perirhinal cortex kindling produces long-lasting effects on anxiety and object recognition memory.

Temporal lobe epilepsy (TLE) is frequently accompanied by memory impairments and, although their bases are unknown, most research has focused on the hippocampus. The present study investigated the importance of another medial temporal lobe structure, the perirhinal cortex (Prh), in changes in memory in TLE using kindling as a model. Rats were kindled twice daily with anterior Prh stimulation until three fully generalized seizures were evoked. Beginning 7 days later and on successive days, rats were tested in an elevated plus maze, a large circular open field, an open field object exploration task and a delayed-match-to-place task in a water maze in order to assess anxiety-related and exploratory behaviour, object recognition memory and spatial cognition. Kindling increased anxiety-related behaviour in both the elevated plus and open field mazes and disrupted spontaneous object recognition but spared all other behaviours tested. These results are consistent with other findings indicating a greater role for the Prh in object memory and emotional behaviour than in spatial memory and contrast with the selective disruption of spatial memory produced by dorsal hippocampal kindling. The site-selectivity of the behavioural disruptions produced by kindling indicates that such effects are probably mediated by changes particular to the site of seizure initiation rather than to changes in the characteristic circuitry activated by limbic seizure generalization. Further investigation of the behavioural effects of Prh kindling may be useful for studying the mechanisms of mnemonic and affective dysfunction associated with TLE and offer insights into bases for variability in such dysfunction across patients.

The relation between extent of dorsal hippocampal kindling and delayed-match-to-place performance in the Morris water maze.

Dorsal hippocampal kindling impairs subsequent performance on spatial tasks. The relation between this effect and the extent of kindling achieved prior to testing has not been clearly established. Thus, the present study investigated the effects of dorsal hippocampal kindling on performance of a delayed-match-to-place (DMTP) task in the Morris water maze by assessing performance after each of series of different points in the kindling process including 1, 6, 11, and 16 afterdischarges, 1 stage 1 seizure, and 1 stage 5 seizure. We found that kindling produced a deficit that was apparent very early into kindling in terms of both direct swim (by 1 AD) and escape distance (by 6 ADs) measures but that did not clearly change in severity with further kindling. These results illustrate that kindling of even a few localized hippocampal seizures can disrupt spatial cognition and suggest that the mechanisms mediating memory disruption either do not change substantially as kindling progresses or that compensatory processes are engaged across training that mitigate any further kindling-related deteriorations in performance.

Transfer of risk: "right to sue" legislation and managed care organization stock performance.

We examined whether Congress's consideration of legislation that gave consumers the right to sue managed care organizations impacted the performance of these companies' stocks relative to that of the market. For each company examined, the total return related to such legislation was negative and substantially lower than that expected from the market model; losses in market value were from 17 percent to 48 percent for individual companies and 22 percent for a capitalization-weighted portfolio. The study suggests that equity markets responded to the proposed legislation quickly and that the impact of proposed legislation is felt through loss of market value and increased corporate risk.

Dorsal hippocampal kindling produces a selective and enduring disruption of hippocampally mediated behavior.

Kindling produces enduring neural changes that are subsequently manifest in enhanced susceptibility to seizure-evoking stimuli and alterations in some types of behavior. The present study investigated the effects of dorsal hippocampal (dHPC) kindling on a variety of behaviors to clarify the nature of previously reported effects on spatial task performance. Rats were kindled twice daily with dHPC stimulation until three fully generalized seizures were evoked. Beginning 7 d later and on successive days, rats were tested in an elevated plus maze, a large circular open field, an open field object exploration task, and a delayed-match-to-place (DMTP) task in a water maze to assess anxiety-related and activity-related behavior (tasks 1 and 2), object recognition memory (task 3), and spatial cognition (task 4). Kindling disrupted performance on the DMTP task in a manner that was not delay dependent and produced a mild enhancement of activity-related behaviors in the open field task but not the elevated plus maze. All other aspects of testing were spared. These findings indicate that dHPC kindling produces enduring and selective effects on behavior that are consistent with a restricted disruption of hippocampally mediated functions. Possible bases for these effects are changes in local NMDA receptor function and/or changes in local inhibition, which might alter the optimal conditions for experience-dependent induction of intrahippocampal plasticity. This preparation may be useful for studying the mechanisms of mnemonic dysfunction associated with temporal lobe epilepsy and may offer unique insights into the mechanisms underlying normal hippocampal function.

Susceptibility to kindling and neuronal connections of the anterior claustrum.

The claustrum has been implicated in the kindling of generalized seizures from limbic sites. We examined the susceptibility of the anterior claustrum itself to kindling and correlated this with an anatomical investigation of its afferent and efferent connections. Electrical stimulation of the anterior claustrum resulted in a pattern of rapid kindling with two distinct phases. Early kindling involved extremely rapid progression to bilaterally generalized seizures of short duration. With repeated daily kindling stimulations, early-phase generalized seizures abruptly became more elaborate and prolonged, resembling limbic-type seizures as triggered from the amygdala. We suggest that the rapid rate of kindling from the anterior claustrum is an indication that the claustrum is functionally close to the mechanisms of seizure generalization. In support of our hypothesis, we found significant afferent, efferent, and often reciprocal connections between the anterior claustrum and areas that have been implicated in the generation of generalized seizures, including frontal and motor cortex, limbic cortex, amygdala, and endopiriform nucleus. Additional connections were found with various other structures, including olfactory areas, nucleus accumbens, midline thalamus, and brainstem nuclei including the substantia nigra and the dorsal raphe nucleus. The anatomical connections of the anterior claustrum are consistent with its very high susceptibility to kindling and support the view that the claustrum is part of a forebrain network of structures participating in the generalization of seizures.

Thiamine treatment of chronic hepatitis B infection.

OBJECTIVE: Chronic hepatitis B is an international health concern that causes cirrhosis, hepatocellular carcinoma, liver failure, and death. Current treatment options are expensive and associated with side effects; however, indirect evidence suggests a relationship between relative thiamine deficiency and chronic hepatitis B infection. METHODS: The authors present three case studies wherein multiple crossovers of daily thiamine administration were used to evaluate a hypothesized association between thiamine treatment and aminotransferase levels. RESULTS: In each case study, thiamine administration was associated with reduction in aminotransferase levels and the fall of HBV DNA to undetectable levels. Analyses by t test demonstrated a statistically significant reduction in aminotransferase levels in all three cases. CONCLUSIONS: The relationship between thiamine administration and chronic hepatitis B infection warrants further study. If proven effective in reducing liver damage or inducing remission of the hepatitis B virus in larger trials, thiamine will offer obvious advantages over the current treatments for chronic viral hepatitis B infection.

Double-blind, placebo-controlled trial of methylphenidate in older, depressed, medically ill patients.

OBJECTIVE: The authors examined the efficacy of methylphenidate in the treatment of depression in a group of older, medically ill patients. METHOD: Sixteen patients underwent an 8-day double-blind, randomized, placebo-controlled crossover trial; 13 completed the trial. RESULTS: Statistically and clinically significant treatment responses were found. CONCLUSIONS: These results support the use of methylphenidate in older, medically ill patients in whom rapid resolution of depressive symptoms is crucial.

Advance directives and the cost of terminal hospitalization.

BACKGROUND: It has been assumed that patients using advance directives would direct terminal care away from the intensive care unit and choose shorter, less costly, less technological terminal hospital stays. METHODS: This retrospective cohort study examined 336 consecutive patients who died in a university tertiary care medical center: 242 without advance directives, 66 with a previously completed advance directive, 13 admitted for the express purpose of terminal care, and 15 who signed an advance directive during their terminal hospitalization. Total charges (hospital and physician) were calculated for all patients and were adjusted using both physician and hospital diagnosis-related group weights. Patient participation in end-of-life decisions was determined by chart review. RESULTS: The group without advance directives had dramatically higher mean total ($49,900 vs $31,200) terminal hospitalization charges than the group with previously completed advance directives, producing a charge ratio of 1.6. After diagnosis-related group adjustment, the charge ratio was 1.35 (95% confidence interval, 1.07 to 1.72) for physician charge, 1.36 (95% confidence interval, 1.06 to 1.74) for hospital charge, and 1.35 (95% confidence interval, 1.08 to 1.73) for total charge. Multiple regression analysis controlling for age, sex, and cancer diagnosis confirmed these findings. Patients with advance directives were significantly more likely to limit treatment and to participate in end-of-life decisions. CONCLUSION: Patients without advance directives have significantly higher terminal hospitalization charges than those with advance directives. Our investigation suggests that the preferences of patients with advance directives are to limit care and these preferences influence the cost of terminal hospitalization.

A comparison of the educational costs and incomes of physicians and other professionals.

BACKGROUND: Efforts at physician-payment reform in the United States have focused largely on the relative incomes of primary care physicians and specialists, who more often have procedure-based practices. Comparisons of the incomes of physicians and other professional groups have received less attention. METHODS: We used standard financial techniques to determine the return on educational investment over a working lifetime for five groups of professionals: primary care physicians, specialist physicians, dentists, attorneys, and graduates of business schools. RESULTS: In current dollars, the difference in the average future hourly income between a given professional and a high-school graduate of the same age, after educational expenses are subtracted (average hours-adjusted net present value of the educational investment) was greatest for specialist physicians and attorneys; dentists and businesspeople had intermediate values; and primary care physicians had the lowest value. The annual yield on the educational investment over a working life (hours-adjusted internal rate of return) was 15.9 percent for primary care physicians, as compared with 29.0 percent for businesspeople, 25.4 percent for attorneys, 20.9 percent for specialist physicians, and 20.7 percent for dentists. A sensitivity analysis showed that primary care physicians did less well in terms of the return on investment than the other groups even when we varied the assumptions in our model widely and that specialist physicians did less well than attorneys working in law firms and dental specialists. CONCLUSIONS: Students can expect a poorer financial return on their educational investment when they choose a career in primary care medicine than when they choose a procedure-based medical or surgical specialty, business, the law, or dentistry.