Towards high-quality peri-operative care: a global perspective.

Article 25 of the United Nations' Universal Declaration of Human Rights enshrines the right to health and well-being for every individual. However, universal access to high-quality healthcare remains the purview of a handful of wealthy nations. This is no more apparent than in peri-operative care, where an estimated five billion individuals lack access to safe, affordable and timely surgical care. Delivery of surgery and anaesthesia in low-resource environments presents unique challenges that, when unaddressed, result in limited access to low-quality care. Current peri-operative research and clinical guidance often fail to acknowledge these system-level deficits and therefore have limited applicability in low-resource settings. In this manuscript, the authors priority-set the need for equitable access to high-quality peri-operative care and analyse the system-level contributors to excess peri-operative mortality rates, a key marker of quality of care. To provide examples of how research and investment may close the equity gap, a modified Delphi method was adopted to curate and appraise interventions which may, with subsequent research and evaluation, begin to address the barriers to high-quality peri-operative care in low- and middle-income countries.

Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene.

Myotonic dystrophy, or dystrophia myotonica (DM), is a highly variable multisystem disease in which the classic adult-onset form displays progressive muscle wasting, cataracts, heart block, gonadal atrophy, insulin resistance and neuropsychiatric impairment. Its genetic basis is an expansion of CTG trinucleotide repeats in the DMPK protein kinase gene. Among the triplet repeat expansion disorders, DM is distinguished by the extended length of the repeat tract (5-13 kb in postmortem tissue) and its location in the 3' untranslated region of the gene that contains it. The pathophysiological mechanism for multisystem degeneration in DM is not understood. In contrast to the profound muscle wasting that characterizes advanced DM, only minor histopathological abnormalities have occurred in DMPK knockout mice or in mice that overexpress a human DMPK transgene, making it unlikely that changes in DMPK activity provide a unitary explanation for the disease. A DNAse hypersensitive site that maps 0.7 kb downstream (centromeric) from the CTG repeats is eliminated on DM chromosomes. This finding indicates that the repeat expansion may alter the adjacent chromatin structure and raises the possibility that it may also affect the expression of flanking genes. An interesting candidate flanking gene is DMAHP, a recently discovered homeodomain-encoding gene. We show here that DMAHP expression in myoblasts, muscle and myocardium is reduced by the DM mutation is cis, and the magnitude of this effect depends on the extent of CTG repeat expansion. These observations support the hypothesis that DMAHP participates in the pathophysiology of DM.

Spring phytoplankton production in the Western ross sea.

Coastal zone color scanner (CZCS) imagery of the western Ross Sea revealed the Presence of an intense phytoplankton bloom covering >106,000 square kilometers in early December 1978. This bloom developed inside the Ross Sea polynya, within 2 weeks of initial polynya formation in late November. Primary productivity calculated from December imagery (3.9 grams of carbon per square meter per day) was up to four times the values measured during in situ studies in mid-January to February 1979. Inclusion of this early season production yields a spring-to-summer estimate of 141 to 171 grams of carbon per square meter, three to four times the values previously reported for the western Ross Sea.

Distributions of phytoplankton blooms in the southern ocean.

A regional pigment retrieval algorithm for the Nimbus-7 Coastal Zone Color Scanner (CZCS) has been tested for the Southern Ocean. The pigment concentrations estimated with this algorithm agree to within 5 percent with in situ values and are more than twice as high as those previously reported. The CZCS data also revealed an asymmetric distribution of enhanced pigments in the waters surrounding Antarctica; in contrast, most surface geophysical properties are symmetrically distributed. The asymmetry is coherent with circumpolar current patterns and the availability of silicic acid in surface waters. Intense blooms (>1 milligram of pigment per cubic meter) that occur downcurrent from continental masses result from dissolved trace elements such as iron derived from shelf sediments and glacial melt.

Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3' untranslated region of the DMPK gene. The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.

Biospheric primary production during an ENSO transition.

The Sea-viewing Wide Field-of-view Sensor (SeaWiFS) provides global monthly measurements of both oceanic phytoplankton chlorophyll biomass and light harvesting by land plants. These measurements allowed the comparison of simultaneous ocean and land net primary production (NPP) responses to a major El Niño to La Niña transition. Between September 1997 and August 2000, biospheric NPP varied by 6 petagrams of carbon per year (from 111 to 117 petagrams of carbon per year). Increases in ocean NPP were pronounced in tropical regions where El Niño-Southern Oscillation (ENSO) impacts on upwelling and nutrient availability were greatest. Globally, land NPP did not exhibit a clear ENSO response, although regional changes were substantial.

Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.

Analysis of Stable Isotope Assisted Metabolomics Data Acquired by High Resolution Mass Spectrometry.

Stable isotope assisted metabolomics (SIAM) uses stable isotope tracers to support studies of biochemical mechanisms. We report a suite of data analysis algorithms for automatic analysis of SIAM data acquired on a high resolution mass spectrometer. To increase the accuracy of isotopologue assignment, metabolites detected in the unlabeled samples were used as reference metabolites to generate possible isotopologue candidates for analysis of peaks detected in the labeled samples. An iterative linear regression model was developed to deconvolute the overlapping isotopic peaks of isotopologues present in a full MS spectrum, where the threshold for the weight factor was determined by a simulation study assuming different levels of Gaussian white noise contamination. A normalization method enabling isotope ratio-based normalization was implemented to study the difference of isotopologue abundance distribution between sample groups. The developed method can analyze SIAM data acquired by direct infusion MS and LC-MS, and can handle metabolite tracers containing different tracer elements. Analysis of SIAM data acquired from mixtures of known compounds showed that the developed algorithms accurately identify metabolites and quantify stable isotope enrichment. Application of SIAM data acquired from a biological study further demonstrated the effectiveness and accuracy of the developed method for analysis of complex samples.

Akt inhibition upregulates FasL, downregulates c-FLIPs and induces caspase-8-dependent cell death in Jurkat T lymphocytes.

In T lymphocytes, the role of Akt in regulating Fas/Fas ligand (FasL)-mediated apoptotic signaling and death is not clearly understood. In this study, we observed that inhibition of Akt causes enhanced expression of FasL mRNA and protein and increased death-inducing signaling complex (DISC) formation with Fas-associated death domain (FADD) and procaspase-8 recruitment. Also, caspase-8 was activated at the DISC with accompanying decrease in c-FLIPs expression. FasL neutralizing antibody significantly decreased apoptotic death in the Akt-inhibited T cells. Additionally, Akt inhibition-induced Fas signaling was observed to link to the mitochondrial pathway via Bid cleavage. Further, inhibition of caspase-8 activity effectively blocked the loss of mitochondrial membrane potential and DNA fragmentation, suggesting that DISC formation and subsequent caspase-8 activation are critical initiating events in Akt inhibition-induced apoptotic death in T lymphocytes. These data demonstrate yet another important survival function governed by Akt kinase in T lymphocytes, which involves the regulation of FasL expression and consequent apoptotic signaling.

Hyperphosphorylation of p53 induced by okadaic acid attenuates its transcriptional activation function.

The tumor suppressor and transcriptional factor p53 is a phosphorylated protein. Its phosphorylation states are regulated by several protein kinases and phosphatases. In this study, the wild-type p53 was transfected and expressed in chronic myelogenous leukemia K-562 cells. Incubation of the transfected cells with okadaic acid, an inhibitor of serine phosphatases 2A and 1, induced hyperphosphorylation of p53 protein. The treatment also increased the steady state level of p53 protein in the cells. However, the hyperphosphorylated p53 protein was less active in promoting transcription mediated by two p53-binding DNA elements, the ribosomal gene cluster and the p53 consensus DNA-binding sequence. Nevertheless, the decreased transcription activation was not due to decreased binding of p53 to these elements, as analyzed by mobility shift DNA-binding assays. In addition, the treatment did not induce a conformational change in p53, as assayed by two conformation-specific anti-p53 monoclonal antibodies, PAb240 and PAb1620. These results suggest that the phosphorylation induced by okadaic acid may selectively modulate the transcription activation function of p53. Consequently, phosphorylation may represent a mechanism of p53 inactivation in tumor cells that harbor the wild-type p53.

p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation.

The p53 tumor suppressor gene plays a role in controlling a G1 phase checkpoint. The WAF1/CIP1 gene with encodes p21WAF1/CIP1 protein, an inhibitor of cyclin-dependent kinases, is a downstream mediator of p53 function. We examined expression of the WAF1/CIP1 gene and its relationship to growth arrest and differentiation in p53-null human leukemic cell lines. We show that p53-independent induction of WAF1/CIP1 occurs in human leukemia cells treated with 12-O-tetradecanoylphorbol-13-acetate, okadaic acid, or IFN-gamma but not with retinoic acid, vitamin D3, or DMSO. Furthermore, WAF1/CIP1 induction correlates with growth arrest associated with monocyte-macrophage differentiation. The present studies support the idea that WAF1/CIP1 gene expression can be regulated through multiple mechanisms, suggesting that strategies may be designed to restore the G1 checkpoint controls in p53-null cells by targeting these p53-independent mechanisms of WAF1/CIP1 induction.

ORMOCHALCs: organically modified chalcogenide polymers for infrared optics.

A novel method combining elemental sulfur and selenium was developed, yielding crystalline sulfur-selenium compounds. The compounds were melted, and an organic comonomer added. Once the organic comonomer was consumed, the viscous compound was vitrified and allowed to cool yielding organic-inorganic hybrid polymers that are termed Organically Modified Chalcogenide (ORMOCHALC) polymers.

Alternations in lipid membrane fluidity and the physical state of cell-surface sialic acid in zinc-deficient rat erythrocyte ghosts.

Erythrocyte ghosts, prepared from the blood of rats fed zinc-deficient diets, were evaluated for membrane fluidity and surface sialic acid properties using spin-labeled probes and electron spin resonance (ESR) spectroscopy. These physical parameters of the erythrocyte ghosts from the zinc-deficient group were compared to those for erythrocyte ghosts obtained from ad libitum and pair fed controls consuming zinc-adequate diets. As the animals became progressively zinc deficient, the erythrocyte ghost membranes became more fluid than those from the control groups. In addition, the apparent rotational correlation time of Tempamine spin probes on surface sialic acid residues was smaller for the zinc deficient group, indicative of an increased rotational mobility of the spin label. These results suggest that zinc deficiency can have pronounced effects on the physical state of membrane bilayer lipids and cell surface carbohydrates and supports the view that many of the pathological signs of zinc deficiency are due to a general membrane defect.

Effect of sorbitol on psychomotor function: its use in alcoholic cirrhosis.

Sorbitol solution has been used to a control substance of evaluating the efficacy of lactulose therapy for hepatic encephalopathy (HE). However, recent in vitro studies suggested that sorbitol may be an inert placebo and may have therapeutic relevance. We evaluated in vivo metabolism of sorbitol in healthy volunteers and alcoholic cirrhotic patients and found that sorbitol was metabolized by gut bacteria in a similar manner to lactulose. We next evaluated the effect of sorbitol treatment on five psychomotor performances tests in cirrhotic patients. Patients receiving sorbitol demonstrated improvement in all psychomotor tests, whereas similar patients not receiving sorbitol showed no improvement. We conclude the following: sorbitol is metabolized by gut bacteria in man, sorbitol therapy improved psychomotor performance in cirrhotic patients, and previous studies using sorbitol as a control underestimated the beneficial effects of lactulose.

Psychomotor performance defects in cirrhotic patients without overt encephalopathy.

Psychometric tests were administered to 36 alcoholic patients with cirrhosis without overt portal systemic encephalopathy and to 32 alcoholics without liver diseases. Verbal ability was preserved in both groups. The cirrhotic patients scored worse than the alcoholics without liver disease on most of the tests of psychomotor performance. Based on the three most discriminative tests, 50% of the cirrhotic patients had one or more scores that were more abnormal than those of any member of the alcoholic group. Significant correlations were found between the severity of liver disease and most tests of performance in the cirrhotic group, due primarily to the influence of serum albumin as a component of the severity index. We conclude that psychomotor tests are sensitive tools for the detection of latent encephalopathy, and that nutritional status probably plays a role in determining test performance.

Effect of influenza vaccine on warfarin anticoagulation.

Recent studies have indicated that viral infections, influenza vaccination, or drugs that increase interferon synthesis all decrease hepatic drug metabolism. We report a case in which influenza vaccination was temporally related to an increased anticoagulant effect of warfarin. A prospective study evaluating the effect of influenza vaccination on the prothrombin time of eight patients anticoagulated over the long term showed that there was prolongation of prothrombin time of 40%. In a second study, the effect of influenza vaccination on warfarin t1/2 was determined in healthy subjects. No significant effect on warfarin metabolism was observed after vaccination. We conclude that influenza vaccination is associated with increased anticoagulant response in some patients receiving anticoagulants over a long term. This effect appears to be related to some step in the coagulation pathway and not to decreased warfarin metabolism and a subsequent rise in serum concentration.

The effect of severe zinc deficiency on serum levels of albumin, transferrin, and prealbumin in man.

Concentrations of three serum transport proteins, albumin, transferrin, and prealbumin, were determined in seven patients with severe zinc deficiency. Zinc deficiency was manifested not only by depressed serum zinc concentrations, but also by skin lesions typical of zinc deficiency that corrected with zinc supplementation only. Concentrations of all three serum proteins were significantly depressed in zinc-deficient patients compared to healthy controls, and levels of all three proteins improved or corrected with a short period of zinc supplementation as the sole form of therapeutic intervention. Prealbumin levels dropped and corrected most rapidly, probably due in part to its short half-life of 2 days. This study demonstrates that zinc plays an important role in protein metabolism in man and is necessary for the maintenance of normal levels of certain transport proteins. These results support the possibility that zinc deficiency may alter tissue availability of other nutrients such as vitamin A or iron through its effect on transport proteins.

Zinc and T-lymphocyte function in hemodialysis patients.

Thirteen patients maintained on long-term hemodialysis were studied with respect to their serum zinc concentration and T-lymphocyte response to phytohemagglutinin. Six patients demonstrated depression of T-cell mitogen response, while seven patients demonstrated a normal response. The mean serum zinc concentration of the patients with abnormal response was lower than those patients with a normal response (63 +/- 11 versus 75 +/- 14 microgram/di, respectively). There was no significant correlation between an individual's serum zinc concentration and T-cell response (r = 0.16). Five patients whose T-cell responses were depressed were given intravenous zinc chloride during each dialysis run for 6 wk (10 mg intravenous zinc, three times weekly) and were evaluated before and after therapy. All five patients remained anergic to four skin tests antigens. Only one patient (who had the lowest pretreatment serum zinc concentration at 48 micrograms/dl) demonstrated significant improvement in mitogen response after zinc therapy. Although dialysis patients commonly have low serum zinc concentrations and depressed mitogen response, in our patients these two findings were generally unrelated. Additionally, supplemental zinc did not change base-line measurements of T-lymphocyte mitogen response in four of five patients studied.

Impaired handling of orally administered zinc in pancreatic insufficiency.

Five patients with pancreatic insufficiency were evaluated for presence of impaired handling of orally administered zinc. Six hospital employees, eight alcoholic cirrhotics, and four patients with small bowel disease served as healthy or chronically ill controls. Two zinc tolerance tests (ZTT) were performed on each subject, one test using zinc sulfate and the other using zinc dipicolinate, a putative zinc binding ligand. Healthy controls demonstrated normal ZTT curves, with no significant difference between the two forms of zinc. Chronically ill controls had significantly depressed ZTT curves compared to healthy controls with both forms of zinc administered. In contrast, pancreatic insufficiency patients had significantly depressed ZTT curves with zinc sulfate but not with zinc dipicolinate, demonstrating a 40% reduction in the area under the curve with zinc sulfate compared to healthy controls. Our study shows impaired handling of orally administered zinc sulfate but not zinc dipicolinate in patients with pancreatic insufficiency and suggests normal pancreatic function may play a role in zinc metabolism in man.

Serum copper and ceruloplasmin levels and urinary copper excretion in thermal injury.

Conflicting reports regarding copper status in thermal injury patients have been published. We determined serial serum-copper and serum-ceruloplasmin levels and 24-h urinary excretion of copper in 23 patients with second- and third-degree thermal burns. Throughout hospitalization, mean serum-copper concentration was significantly depressed; lowest levels were found in patients with greater than 40% total body surface area burns. Serum ceruloplasmin was also depressed, an unexpected finding because this protein is a positive acute-phase reactant poststress. Mean urinary excretion of copper was elevated, reaching 2.5 times the upper limit of normal 2 wk postburn. Depressed serum-copper levels paralleled the serum-ceruloplasmin levels rather than the increased urinary-copper losses. Further studies are required to determine the mechanism(s) of this altered copper metabolism and whether physiological or biochemical evidence of copper deficiency accompanies the observed hypocupremia.