Leaving no one behind? Social inclusion of health insurance in low- and middle-income countries: a systematic review.

BACKGROUND: One way to achieve universal health coverage (UHC) in low- and middle-income countries (LMIC) is the implementation of health insurance schemes. A robust and up to date overview of empirical evidence assessing and substantiating health equity impact of health insurance schemes among specific vulnerable populations in LMICs beyond the more common parameters, such as income level, is lacking. We fill this gap by conducting a systematic review of how social inclusion affects access to equitable health financing arrangements in LMIC. METHODS: We searched 11 databases to identify peer-reviewed studies published in English between January 1995 and January 2018 that addressed the enrolment and impact of health insurance in LMIC for the following vulnerable groups: female-headed households, children with special needs, older adults, youth, ethnic minorities, migrants, and those with a disability or chronic illness. We assessed health insurance enrolment patterns of these population groups and its impact on health care utilization, financial protection, health outcomes and quality of care. RESULTS: The comprehensive database search resulted in 44 studies, in which chronically ill were mostly reported (67%), followed by older adults (33%). Scarce and inconsistent evidence is available for individuals with disabilities, female-headed households, ethnic minorities and displaced populations, and no studies were yielded reporting on youth or children with special needs. Enrolment rates seemed higher among chronically ill and mixed or insufficient results are observed for the other groups. Most studies reporting on health care utilization found an increase in health care utilization for insured individuals with a disability or chronic illness and older adults. In general, health insurance schemes seemed to prevent catastrophic health expenditures to a certain extent. However, reimbursements rates were very low and vulnerable individuals had increased out of pocket payments. CONCLUSION: Despite a sizeable literature published on health insurance, there is a dearth of good quality evidence, especially on equity and the inclusion of specific vulnerable groups in LMIC. Evidence should be strengthened within health care reform to achieve UHC, by redefining and assessing vulnerability as a multidimensional process and the investigation of mechanisms that are more context specific.

Mice lacking functional CD95-ligand display reduced proliferation of the intestinal epithelium without gross homeostatic alterations.

Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration. CD95L is highly expressed in Paneth cells of the small intestine which are in close contact with intestinal stem cells. This suggests a potential role for CD95L in controlling stem cell function and, possibly, intestinal homeostasis. We analyzed the intestines of mice deficient for functional CD95L (gld) for potential alterations in the diversity of stem-cell-lineages and parameters of intestinal homeostasis. Stem cell diversity was assessed by analyzing methylation patterns of the non-transcribed mMYOD gene. Proliferation was analyzed by BrdU labeling and differentiation was assessed by immunohistochemistry. Of all parameters analyzed, only epithelial cell proliferation was significantly reduced in the small intestines of gld-mice, but not in their colons which lack CD95L expression. We conclude that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis.

Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells.

OBJECTIVE: To assess the contribution of hypoxia and bone marrow-derived cells to aggressive outgrowth of micrometastases after liver surgery. BACKGROUND: Liver surgery generates a microenvironment that fosters aggressive tumor recurrence. These areas are characterized by chronic hypoxia and influx of bone marrow-derived cells. METHODS: The contribution of hematopoietic cell types was studied in mice lacking specific components of the immune system and in irradiated mice lacking all bone marrow-derived cells. Tumor cells were derived from colorectal cancer patients and from a metastatic tumor cell line. Hypoxia-induced changes in stem cell and differentiation marker expression, clone-forming potential, and metastatic capacity were assessed. The effect of vascular clamping on cancer stem cell (CSC) characteristics was performed in mice bearing patient-derived liver metastases. RESULTS: Immune cells and bone marrow-derived cells were not required for aggressive outgrowth of micrometastases in livers treated with surgery. Rather, hypoxia was sufficient to promote invasion and accelerate metastatic outgrowth. This was associated with a rapid loss of differentiation markers and increased expression of CSC markers and clone-forming capacity. Likewise, metastases residing in ischemia-reperfusion-injured liver lobes acquired CSC characteristics. Despite their renowned general resistance to chemotherapy, clone-forming CSCs were readily killed by the hypoxia-activated prodrug tirapazamine. CONCLUSIONS: Surgery-generated hypoxia in the liver causes rapid dedifferentiation of tumor cells into immature CSCs with high clone- and metastasis-forming capacity. The results help explain the phenomenon of aggressive local tumor recurrence after liver surgery and offer a potential strategy to kill aggressive CSCs by hypoxia-activated prodrugs.

CD95 signaling in colorectal cancer.

CD95 and its ligand (CD95L) are widely expressed in colorectal tumors, but their role in shaping tumor behavior is unclear. CD95 activation on tumor cells can lead to apoptosis, while CD95L attracts neutrophils, suggesting a function in tumor suppression. However, CD95 can also promote tumorigenesis, at least in part by activating non-apoptotic signaling pathways that stimulate tumor cell proliferation, invasion and survival. In addition, CD95 signaling in stromal cells and tumor-infiltrating inflammatory cells has to be taken into account when addressing the function of CD95 and its ligand in colorectal tumor biology. We present a model in which the tumor-suppressing and tumor-promoting activities of CD95/CD95L together determine colorectal tumor behavior. We also discuss how these multiple activities are changing our view of CD95 and CD95L as potential therapeutic targets in the treatment of colorectal cancer. We conclude that locking CD95 in apoptosis-mode may be a more promising anti-cancer strategy than simply inhibiting or stimulating CD95.

The death receptor CD95 activates the cofilin pathway to stimulate tumour cell invasion.

The death receptor CD95 promotes apoptosis through well-defined signalling pathways. In colorectal cancer cells, CD95 primarily stimulates migration and invasion through pathways that are incompletely understood. Here, we identify a new CD95-activated tyrosine kinase pathway that is essential for CD95-stimulated tumour cell invasion. We show that CD95 promotes Tyr 783 phosphorylation of phospholipase C-γ1 through the platelet-derived growth factor receptor-ß, resulting in ligand-stimulated phosphatidylinositol (4,5)-bisphosphate (PIP(2)) hydrolysis. PIP(2) hydrolysis liberates the actin-severing protein cofilin from the plasma membrane to initiate cortical actin remodelling. Cofilin activation is required for CD95-stimulated formation of membrane protrusions and increased tumour cell invasion.

Malignant cells facilitate lung metastasis by bringing their own soil.

Metastatic cancer cells (seeds) preferentially grow in the secondary sites with a permissive microenvironment (soil). We show that the metastatic cells can bring their own soil--stromal components including activated fibroblasts--from the primary site to the lungs. By analyzing the efferent blood from tumors, we found that viability of circulating metastatic cancer cells is higher if they are incorporated in heterotypic tumor-stroma cell fragments. Moreover, we show that these cotraveling stromal cells provide an early growth advantage to the accompanying metastatic cancer cells in the lungs. Consistent with this hypothesis, we demonstrate that partial depletion of the carcinoma-associated fibroblasts, which spontaneously spread to the lung tissue along with metastatic cancer cells, significantly decreases the number of metastases and extends survival after primary tumor resection. Finally, we show that the brain metastases from lung carcinoma and other carcinomas in patients contain carcinoma-associated fibroblasts, in contrast to primary brain tumors or normal brain tissue. Demonstration of the direct involvement of primary tumor stroma in metastasis has important conceptual and clinical implications for the colonization step in tumor progression.

Differentiated human colorectal cancer cells protect tumor-initiating cells from irinotecan.

BACKGROUND & AIMS: Stem cells of normal tissues have resistance mechanisms that allow them to survive genotoxic insults. The stem cell-like cells of tumors are defined by their tumor-initiating capacity and may have retained these resistance mechanisms, making them resistant to chemotherapy. We studied the relationship between resistance to the topoisomerase I inhibitor irinotecan and tumor-initiating potential in human colonosphere cultures and in mice with colorectal xenograft tumors. METHODS: Colonosphere cultures were established from human colorectal tumor specimens obtained from patients who underwent colon or liver resection for primary or metastatic adenocarcinoma. Stem cell and differentiation markers were analyzed by immunoblotting and fluorescence-activated cell sorting. Clone- and tumor-initiating capacities were assessed by single-cell cloning and in immune-deficient mice. Sensitivity to irinotecan was assessed in vitro and in tumor-bearing mice. The relationship between drug resistance and tumor-initiating capacity was tested by fluorescence-activated cell sorting of colonosphere cells, based on expression of ABCB1 and aldehyde dehydrogenase (ALDH) activity. RESULTS: Colonosphere cultures had a high capacity to initiate tumors in mice and were resistant to irinotecan. Inhibition of the drug-efflux pump ABCB1 by PSC-833 allowed irinotecan to eradicate tumor-initiating cells. However, ABCB1 was expressed only by a subpopulation of differentiated tumor cells that did not form clones or tumors. Conversely, tumor-initiating cells were ABCB1-negative and were identified by high ALDH activity. Tumorigenic ALDHhigh/ABCB1negative cells generated nontumorigenic ALDHlow/ABCB1positive daughter cells in vitro and in tumor xenografts. PSC-833 increased the antitumor efficacy of irinotecan in mice. CONCLUSIONS: The resistance of colorectal tumors to irinotecan requires the cooperative action of tumor-initiating ALDHhigh/ABCB1negative cells and their differentiated, drug-expelling, ALDHlow/ABCB1positive daughter cells.

Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells.

BACKGROUND & AIMS: Death receptors expressed on tumor cells can prevent metastasis formation by inducing apoptosis, but they also can promote migration and invasion. The determinants of death receptor signaling output are poorly defined. Here we investigated the role of oncogenic K-Ras in determining death receptor function and metastatic potential. METHODS: Isogenic human and mouse colorectal cancer cell lines differing only in the presence or absence of the K-Ras oncogene were tested in apoptosis and invasion assays using CD95 ligand and tumor necrois factor-related apoptosis-inducing ligand (TRAIL) as stimuli. Metastatic potential was assessed by intrasplenic injections of green fluorescent protein- or luciferase-expressing tumor cells, followed by intravital fluorescence microscopy or bioluminescence imaging, and confocal microscopy and immunohistochemistry. Ras-effector pathway control of CD95 output was assessed by an RNA-interference and inhibitor-based approach. RESULTS: CD95 ligand and TRAIL stimulated invasion of colorectal tumor cells and liver metastases in a K-Ras-dependent fashion. Loss of mutant K-Ras switched CD95 and TRAIL receptors back into apoptosis mode and abrogated metastatic potential. Raf1 was essential for the switch in CD95 function, for tumor cell survival in the liver, and for K-Ras-driven formation of liver metastases. K-Ras and Raf1 suppressed Rho kinase (ROCK)/LIM kinase-mediated phosphorylation of the actin-severing protein cofilin. Overexpression of ROCK or LIM kinase allowed CD95L to induce apoptosis in K-Ras-proficient cells and prevented metastasis formation, whereas their suppression protected K-Ras-deficient cells against apoptosis. CONCLUSIONS: Oncogenic K-Ras and its effector Raf1 convert death receptors into invasion-inducing receptors by suppressing the ROCK/LIM kinase pathway, and this is essential for K-Ras/Raf1-driven metastasis formation.

A role for CD95 signaling in ischemia/reperfusion-induced invasion and outgrowth of colorectal micrometastases in mouse liver.

BACKGROUND: Ischemia/reperfusion (I/R) injury in the liver is associated with accelerated outgrowth of micrometastases. The aim of the study was to test the role of CD95 signaling in accelerated outgrowth of colorectal liver metastases following I/R. METHODS: Mice underwent vascular clamping 5 days after induction of colorectal liver metastases. Invasion and outgrowth of micrometastases following I/R were analyzed by post-mortem confocal microscopy (36 hr post-I/R) and by morphometric assessment of tumor load (5 days post-I/R), respectively. Tumor cell CD95 was suppressed by lentiviral RNA interference. The contribution of host CD95L was assessed by using gld-mice lacking functional CD95L. RESULTS: CD95-knockdown in tumor cells strongly reduced perinecrotic invasion (tumor diameter from ∼830 to ∼470 µm) and largely prevented outgrowth acceleration of perinecrotic liver metastases following I/R (from ∼8- to ∼4.5-fold). In gld-mice, the relative hepatic area with necrosis was markedly reduced. Perinecrotic tumor cell clusters still displayed an invasive phenotype (tumor diameter of ∼980 µm). However, I/R-induced acceleration of tumor outgrowth was reduced in gld-mice from ∼8- to ∼5-fold. CONCLUSIONS: I/R induces invasion and accelerated outgrowth of preestablished metastases in a CD95-dependent manner. Activation of the CD95 system following I/R not only contributes to liver injury, but may also promote aggressive tumor recurrence.

CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation.

BACKGROUND & AIMS: Recently, we have shown that micro-metastases, in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA), display strongly accelerated outgrowth. CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apoptosis-resistant tumor cells. Therefore, we tested whether CD95 signaling plays a role in accelerated outgrowth of colorectal liver metastases following RFA. METHODS: Hypoxia-induced invasion was assessed in three-dimensional EGFP-expressing C26 tumor cell cultures by confocal microscopy. CD95 localization was tested by immunofluorescence. Invasion and outgrowth of liver metastases following RFA were analyzed by post-mortem confocal microscopy and by morphometric assessment of tumor load. Neutralization of CD95L was performed by using antibody MFL4. CD95 was suppressed by lentiviral RNA interference. The role of host CD95L was assessed using gld mice. RESULTS: Micro-metastases in the hypoxic transition zone following RFA displayed a highly invasive phenotype and increased expression of CD95 and CD95L. Hypoxia-induced tumor cell invasion in vitro increased the expression of CD95 and CD95L and induced translocation of CD95 to the invasive front. In vitro invasion, metastasis invasion, and accelerated tumor growth in the transition zone were strongly suppressed by neutralizing CD95L or by suppressing tumor cell CD95. In contrast, metastasis invasion and outgrowth were unaffected in gld mice. CONCLUSIONS: Hypoxia causes autocrine activation of CD95 on colorectal tumor cells, thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA. Further pre-clinical work is needed to assess the role of CD95L neutralization, either alone or in combination with chemotherapy, in limiting aggressive recurrence of liver metastases following RFA.

Crystal structure of the cytosolic C2A-C2B domains of synaptotagmin III. Implications for Ca(+2)-independent snare complex interaction.

Synaptotagmins are synaptic vesicle-associated, phospholipid-binding proteins most commonly associated with Ca(+2)-dependent exocytotic and Ca(+2)- independent endocytotic events. Synaptotagmin III is a 63.2-kD member of the synaptotagmin homology group; one of its characteristic properties is the ability to bind divalent cations and accessory proteins promiscuously. In the cytosolic portion of this protein, a flexible seven-amino acid linker joins two homologous C2 domains. The C2A domain binds to phospholipid membranes and other accessory proteins in a divalent cation-dependent fashion. The C2B domain promotes binding to other C2B domains, as well as accessory proteins independent of divalent cations. The 3.2 A crystal structure of synaptotagmin III, residues 295-566, which includes the C2A and C2B domains, exhibits differences in the shape of the Ca(+2)-binding pocket, the electrostatic surface potential, and the stoichiometry of bound divalent cations for the two domains. These observations may explain the disparate binding properties of the two domains. The C2A and the C2B domains do not interact; synaptotagmin, therefore, covalently links two independent C2 domains, each with potentially different binding partners. A model of synaptotagmin's involvement in Ca(+2)-dependent regulation of membrane fusion through its interaction with the SNARE complex is presented.

Demonstration of positionally disordered water within a protein hydrophobic cavity by NMR.

The presence and location of water of hydration (that is, bound water) in the solution structure of human interleukin-1 beta (hIL-1 beta) was investigated with water-selective two-dimensional heteronuclear magnetic resonance spectroscopy. It is shown here that in addition to water at the surface of the protein and ordered internal water molecules involved in bridging hydrogen bonds, positionally disordered water is present within a large, naturally occurring hydrophobic cavity located at the center of the molecule. These water molecules of hydration have residency times in the range of 1 to 2 nanoseconds to 100 to 200 microseconds and can be readily detected by nuclear magnetic resonance (NMR). Thus, large hydrophobic cavities in proteins may not be truly empty, as analysis of crystal structures appears to show, but may contain mobile water molecules that are crystallographically invisible but detectable by NMR.

Seasat scatterometer: results of the gulf of alaska workshop.

The Seasat microwave scatterometer was designed to measure, globally and in nearly all weather, wind speed to an accuracy of +/- 2 meters per second and wind direction to +/- 20 degrees in two swaths 500 kilometers wide on either side of the spacecraft. For two operating modes in rain-free conditions, a limited number of comparisons to high-quality surface truth indicates that these specifications may have been met.

Prospective Design of Anti-Transferrin Receptor Bispecific Antibodies for Optimal Delivery into the Human Brain.

Anti-transferrin receptor (TfR)-based bispecific antibodies have shown promise for boosting antibody uptake in the brain. Nevertheless, there are limited data on the molecular properties, including affinity required for successful development of TfR-based therapeutics. A complex nonmonotonic relationship exists between affinity of the anti-TfR arm and brain uptake at therapeutically relevant doses. However, the quantitative nature of this relationship and its translatability to humans is heretofore unexplored. Therefore, we developed a mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model for bispecific anti-TfR/BACE1 antibodies that accounts for antibody-TfR interactions at the blood-brain barrier (BBB) as well as the pharmacodynamic (PD) effect of anti-BACE1 arm. The calibrated model correctly predicted the optimal anti-TfR affinity required to maximize brain exposure of therapeutic antibodies in the cynomolgus monkey and was scaled to predict the optimal affinity of anti-TfR bispecifics in humans. Thus, this model provides a framework for testing critical translational predictions for anti-TfR bispecific antibodies, including choice of candidate molecule for clinical development.

Influence of mineral intake and use of oral contraceptives before pregnancy on the mineral content of human colostrum and of more mature milk.

PIP: The effects of mineral intake and long-term oral contraceptive use before pregnancy on the mineral content of milk of healthy lactating women were evaluated in a study of 52 volunteers ages 18-31. Subjects reporting previous oral contraceptive use had significantly lower levels of copper in serum, perhaps reflecting reduced copper stores resulting from prolonged estrogen exposure, but concomitant changes in copper levels in their milk were not noted. Serum calcium and magnesium levels were not significantly affected by prior pill use. Pill use had no significant effect on concentrations of calcium, magnesium, zinc, copper, or iron in colostrum at day 3 or more mature milk at day 14 of lactation, while mean manganese levels were significantly lower at both times for previous oral contraceptive users (but still exceeded manganese levels recommended for infants). Mineral and vitamin supplementation significantly improved the levels of zinc and iron intake, but did not appreciably alter the mineral content of milk. Higher levels of zinc were found in colostrum compared to day 14 milk, while manganese concentrations increased significantly during the 1st 2 weeks of lactation. Calcium, magnesium, iron and copper levels did not change significantly as lactation progressed. Levels of calcium, magnesium, zinc, copper, and manganese in colostrum were significantly positively correlated with the mineral concentration on day 14. No significant diurnal or daily variation was observed in the levels of calcium, magnesium, or zinc content in milk during 2 24-hour periods.^ieng

Strongyloides stercoralis hyperinfection in a patient with the acquired immune deficiency syndrome.

Severe infections with Strongyloides stercoralis occur in immunocompromised patients. Strongyloides hyperinfection syndrome complicated by gram-negative bacteremia and meningitis in a bisexual man with the acquired immune deficiency syndrome (AIDS) is described. Increased awareness of this infection, which may also be sexually transmitted, is recommended when caring for patients with AIDS who are homosexual, or have resided in areas endemic for strongyloidiasis. Multiple stool examinations should be performed routinely for such patients. Examination of sputum for the parasite is recommended if pneumonia is present. Prompt diagnosis and therapy are essential for prevention of fatal dissemination.

PIP: Severe infections with Strongyloides stercoralis occur in immunocompromised patients. Strongyloides hyperinfection syndrome complicated by gram-negative bacteremia and meningitis in a bisexual man with acquired immune deficiency syndrome (AIDS) is described. Increased awareness of this infection, which may also be sexually transmitted, is recommended when caring for patients with AIDS who are homosexual, or have resided in areas endemic for strongyloidiasis. Multiple stool examinations should be performed routinely for such patients. Examination of sputum for the parasite is recommended if pneumonia is present. Prompt diagnosis and therapy is essential for prevention of fatal dissemination.

Osmolality of substances used in the intensive care nursery.

It has been well documented that the administration of hypertonic substances to the newborn may result in a variety of adverse effects, including hepatic, intestinal, and/or neuronal injury. Furthermore, neonates are exposed to a large number of drugs and other substances while in the intensive care nursery setting. As few data are available that document the actual osmolality of many of the substances employed in caring for the sick neonate, the present study measured the osmolality of 64 medications as well as 23 formulas or nutritional supplements used in the intensive care nursery. Osmolality was determined by both vapor pressure and freezing point depression. Results indicate that a large number of medications normally administered by the enteral route possess a markedly elevated osmolality in excess of 2,000 mosm/kg H2O. Although parenterally administered medications normally have a much lower osmolality, several possess significantly elevated levels. It is recommended that measures be taken to minimize the osmolality of substances administered to the critically ill newborn whenever possible.

Lack of improved growth outcome related to nonnutritive sucking in very low birth weight premature infants fed a controlled nutrient intake: a randomized prospective study.

The effect of nonnutritive sucking during gavage feeding on nutritional outcome and gastrointestinal transit time was evaluated in 18 premature appropriate for gestational age infants whose birth weights were less than or equal to 1,400 g and gestational ages were less than or equal to 30 weeks. Infants were randomized to a treatment (nonnutritive sucking infants received a pacifier for 30 minutes with each feeding, 12 times per day until they reached a weight of 1,500 g, eight times per day thereafter) or control (no pacifier) group. The nine nonnutritive sucking (five girls, four boys) and nine control (five girls, four boys) infants were treated for 14 days. Infants were without medical complications and were fed a single premature formula by intermittent gastric gavage at exactly 120 kcal/kg/d throughout the study period. Weight gain, linear growth, subscapular and triceps skinfold, and arm circumference accretions were assessed weekly. Serum proteins (albumin, prealbumin, retinol-binding protein, and transferrin) were measured weekly. Gastrointestinal transit times were measured weekly using carmine red markers. In contrast to previous studies, these data indicate no apparent effect of nonnutritive sucking on growth outcome, serum proteins, or gastrointestinal transit time in growing, very low birth weight infants when nutrient intake was controlled. In a subgroup of eight boys (four nonnutritive sucking, four control), energy and fat excretions were determined from 72-hour fecal collections and energy expenditure was estimated from six-hour cumulative heart rate measurements. Neither excretion of fat and calories nor estimated energy expenditure was affected significantly by nonnutritive sucking in this subgroup of baby boys. Fat excretion correlated well (r = .987) with energy excretion.

Impact of a coordinated tuberculosis Team in an inner-city hospital in New York City.

OBJECTIVE: To evaluate the impact of a coordinated approach for the isolation, diagnosis, and treatment of patients with tuberculosis. DESIGN: Retrospective cohort study. SETTING: Bronx-Lebanon Hospital Center, an inner-city hospital in the South Bronx, New York City. PATIENTS: Patients with smear-positive, culture-confirmed pulmonary tuberculosis. INTERVENTIONS: Institution of a coordinated tuberculosis team. RESULTS: Admissions of 46 patients before and 39 patients after the formation of a tuberculosis team were reviewed. Before institution of the tuberculosis team, 35% of patients were isolated within 24 hours of presentation, 41% never were isolated, and the mean number of days patients were not isolated was 19. After implementation of the tuberculosis team, 59% of patients were isolated within 24 hours, only 5% were never isolated, and the mean number of days patients were not isolated was 3.5. These differences were statistically significant. There also was a corresponding decrease in length of hospitalization. In addition, there were noticeable improvements in patient and staff morale and attitudes. CONCLUSIONS: The tuberculosis team likely has decreased the risk of nosocomial tuberculosis transmission by increasing the proportion of infectious tuberculosis patients admitted into AFB isolation and by reducing (by 780) the number of days out of isolation while smear positive. There also were concomitant financial savings.

Stabilization of helical peptides by mixed spaced salt bridges.

Whether or not surface salt bridges have a strong stabilizing effect on the native structure in proteins remains uncertain. Previous studies of model peptides have shown that salt bridges spaced at i,i +4 along the chain are more stabilizing than those spaced at i,i +3, with a preference for the order acid-base rather than base-acid from N to C terminus. An analysis of the effect of spacing the ion pairs in short helical peptides is presented, in which acidic and basic side chains spaced two or three residues apart alternate along the chain. The mixed spacing proves to be stabilizing relative to pure spacings. A control peptide in which salt bridges were spaced uniformly three residues apart proved to form a beta-sheet structure rather than alpha-helix. This is due to formation of a silk-like apolar face consisting of alanine side chains; the mesoscopic structure formed by these sheets can be imaged by scanning microscopy.