A research agenda to guide progress on childhood obesity prevention in Latin America.

Childhood obesity rates in Latin America are among the highest in the world. This paper examines and evaluates the many efforts underway in the region to reduce and prevent further increases in obesity, identifies and discusses unique research challenges and opportunities in Latin America, and proposes a research agenda in Latin America for the prevention of childhood obesity and concomitant non-communicable diseases. Identified research gaps include biological challenges to healthy growth across the life cycle, diet and physical activity dynamics, community interventions promoting healthy child growth, and rigorous evaluation of national food and activity programs and regulatory actions. Addressing these research gaps is critical to advance the evidence-based policy and practice in childhood obesity tailored to the Latin American context that will be effective in addressing obesity.

Prevention of childhood obesity and food policies in Latin America: from research to practice.

BACKGROUND: Addressing childhood obesity in Latin America requires a package of multisectoral, evidence-based policies that enable environments conducive to healthy lifestyles. OBJECTIVE: Identify and examine key elements to translating research into effective obesity policies in Latin America. METHODS: We examined obesity prevention policies through case studies developed with an expert in the specific policy. Policies were selected based on their level of implementation, visibility and potential impact to reduce childhood obesity. They include: (i) excise taxes on sugar sweetened beverages and energy-dense foods; (ii) front-of-package food label legislation; (iii) trans fatty acids removal from processed foods; and (iv) Ciclovías recreativas or 'open streets'. Case studies were coded to identify components that explained successful implementation and sustainability using the Complex Adaptive Health Systems framework. RESULTS: The analysis identified key elements for effective and sustainable policy, including evidence justifying policy; evidence-based advocacy by civil society; political will; and legislation and skillful negotiations across government, academia, the private sector and civil society. Scientific evidence and evaluation played an important role in achieving tipping points for policies' launch and sustain effective implementation. CONCLUSIONS: Well-coordinated, intersectoral partnerships are needed to successfully implement evidence-based anti-obesity policies. Prospective policy research may be useful for advancing knowledge translation.

Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunconjugate in patients with non-small cell lung carcinoma.

A Phase Ia clinical trial was undertaken to evaluate and compare murine monoclonal antibody KS1/4 and KS1/4-methotrexate immunoconjugate in patients with Stage IIIB or IV non-small cell carcinoma of the lung. Six patients received KS1/4 alone and five patients received KS1/4-methotrexate conjugate. The maximal total dose received per patient in both groups was 1661 mg. Mild to moderate side effects in both groups included fever, chills, anorexia, nausea, vomiting, diarrhea, anemia, and brief transaminasemia. One patient who received antibody alone had an apparent acute immune complex-mediated reaction. Ten of 11 patients had a human anti-mouse response. Posttreatment carcinoma biopsies revealed binding of monoclonal antibody KS1/4 and deposition of C3d and C4c complement fragments. Monoclonal antibody binding and complement deposition correlated with increasing doses of infused antibody. There was one possible clinical response.

Progesterone inhibits gallbladder motility through multiple signaling pathways.

Progesterone (P) has an inhibitory effect on the contractility of gastrointestinal smooth muscle, including the gallbladder. Since P levels are elevated during pregnancy, a biliary stasis may develop during pregnancy that is characterized by an increase in the fasting and residual volumes and by a decrease in emptying capacity. This study investigates the effect of P and two metabolites on contraction in guinea pig gallbladder strips. P induced a concentration-dependent relaxation in guinea pig gallbladder strips precontracted with cholecystokinin octapeptide (CCK). Pretreatment of gallbladder strips with P (50 microM) also reduced the amount of CCK-induced tension. Nifedipine (1 microM) produced a similar effect. Pretreatment of the strips with PKA inhibitor 14--22 amide myristolated (180 nM) or the PKG inhibitor KT5823 (1.2 microM) either separately or in combination significantly reduced the amount of P-induced relaxation. Rp-cAMPs (0.1mM) or H-89 (10 microM) separately or in combination significantly reduced the P-effect; however, the combination of agents produced the largest reduction. Genistein (1 microM), an inhibitor of protein tyrosine kinases, significantly (p<0.01) reduced the amount of P-induced relaxation. The use of strontium in the Kreb's solution as a substitute for Ca(2+) significantly (p<0.01) reduced the amount of CCK-induced tension. Pretreatment of the strips with 2-APB (26 microM), an inhibitor of IP(3,) induced Ca(2+) release, produced a significant (p<0.01) reduction in P-induced relaxation. We conclude that P inhibits gallbladder motility rapidly by nongenomic actions of the hormone. Several pathways that include tyrosine kinase and PKA/cAMP activity may mediate this effect.

Coordinate activation of endogenous p38alpha, beta, gamma, and delta by inflammatory stimuli.

The p38 family of mitogen-activated protein kinases is believed to mediate a variety of leukocyte responses to pro-inflammatory stimuli. There are four members of the p38 family, and although activation of the different members has been studied in transiently transfected cells much less is known about activation of the endogenous p38s, particularly in myeloid lineage cells. To investigate activation of endogenous p38s, we have made monoclonal antibodies specific for each p38 and have used these antibodies to study p38 activation by pro-inflammatory stimuli in several human monocytic cell lines. Without stimulation endogenous p38alpha kinase activity was readily detectable, whereas that of p38beta, gamma, and delta was barely measurable. In response to inflammatory stimuli, we observed a time- and dose-dependent activation of all four p38s. The kinetics of activation of each of the p38s were similar for each stimulus used, suggesting a common upstream activation pathway. Simultaneous activation of the p38s suggests that all four may be important in inflammation.

Phagocytosis of gram-negative bacteria by a unique CD14-dependent mechanism.

THP-1-derived cell lines were stably transfected with constructs encoding glycophosphatidylinositol (GPI)-anchored or transmembrane forms of human CD14. CD14 expression was associated with enhanced phagocytosis of serum (heat-inactivated)-opsonized Escherichia coli (opEc). Both the GPI-anchored and transmembrane forms of CD14 supported phagocytosis of opEc equally well. Lipopolysaccharide-binding protein (LBP) played a role in CD14-dependent phagocytosis as evidenced by inhibition of CD14-dependent phagocytosis of opEc with anti-LBP monoclonal antibody (mAb) and by enhanced phagocytosis of E. coli opsonized with purified LBP. CD14-dependent phagocytosis was inhibited by a phosphatidylinositol (PI) 3-kinase inhibitor (wortmannin) and a protein tyrosine kinase inhibitor (tyrphostin 23) but not a protein kinase C inhibitor (bisindolyl-maleimide) or a divalent cation chelator (ethylenediaminetetraacetate). Anti-LBP mAb 18G4 and anti-CD14 mAb 18E12 were used to differentiate between the pathways involved in CD14-dependent phagocytosis and CD14-dependent cell activation. F(ab')2 fragments of 18G4, a mAb to LBP that does not block cell activation, inhibited ingestion of opEc by THP1-wtCD14 cells. 18E12 (an anti-CD14 mAb that does not block LPS binding to CD14 but does inhibit CD14-dependent cell activation) did not inhibit phagocytosis of LBP-opEc by THP1-wtCD14 cells. Furthermore, CD14-dependent phagocytosis was not inhibited by anti-CD18 (CR3 and CR4 beta-chain) or anti-Fcgamma receptor mAb.

Activation of phospholipase D in FRTL-5 thyroid cells by forskolin and dibutyryl-cyclic adenosine monophosphate.

We demonstrated previously that TSH activates phospholipase D (PLD) via stimulation of protein kinase C (PKC) in Fischer rat thyroid line (FRTL)-5 thyroid cells. To examine the role of the cAMP pathway in the regulation of PLD, we studied the effects of forskolin (0-100 microM; 30 min) and dibutyryl cAMP (dbcAMP; 0-1 mM; 30 min) on PLD activation. FRTL-5 thyroid cells were labeled mainly in phosphatidylcholine with [3H]myristate followed by incubation with 200 mM ethanol before the addition of agonist. PLD was assessed by the measurement of [3H]phosphatidylethanol. Forskolin (100 nM to 100 microM) and dbcAMP (100 pM to 100 microM) increased PLD activity significantly. Maximal responses to forskolin and dbcAMP exceed the PLD responses produced by 100 microU/ml of TSH. To determine whether the effects of forskolin and dbcAMP on PLD occurred as a consequence of PKC activation, FRTL-5 thyroid cells were preincubated for 10 min with the PKC inhibitors, chelerythrine (1 microM) or calphostin C (1 microM), or they were pretreated for 24 h with phorbol myristate acetate (100 nM) to down-regulate PKC. Unlike TSH-mediated PLD activation, these treatments had no effect on PLD activation by cAMP agonists. Forskolin (10 microM; 30 min) had no effect on the subcellular distribution of PKC alpha-, epsilon-, or zeta-isoforms, confirming the lack of involvement of PKC. The protein kinase A (PKA) inhibitors, H-89 (10 microM; 30 min) and dideoxyadenosine (5 nM; 10 min) significantly decreased the forskolin- and dbcAMP-mediated PLD activation without any effect on the phorbol ester-mediated PLD response. Following pretreatment with H-89 or dideoxyadenosine, the TSH-mediated PLD response was also significantly reduced. These studies indicate that forskolin and dbcAMP stimulate PLD in FRTL-5 thyroid cells directly via PKA without involvement of PKC. Studies of cells in the presence and absence of ethanol revealed approximately 60% of the phosphatidate plus diacylglycerol produced via TSH occurs via PLD activation. Although TSH-mediated inositol phosphate generation occurred with similar concentrations of TSH that led to PLD activation, 10-fold higher TSH concentrations were required to increase intracellular Ca2+. These results and the lack of a rapid Ca2+ transient following physiological TSH concentrations suggest that alternatives to conventional hydrolysis of phosphatidylinositol 4,5-bisphosphate may initiate PKC activation. Thus, the two major signal transduction systems in the FRTL-5 thyroid cell (PKA and PKC) appear to converge on PLD activation. Stimulation of both of these pathways by TSH may be required for optimal physiological activation of PLD.

Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin.

Sunlight has long been recognized as a major provider of vitamin D for humans; radiation in the UVB (290-315 nm) portion of the solar spectrum photolyzes 7-dehydrocholesterol in the skin to previtamin D3, which, in turn, is converted by a thermal process to vitamin D3. Latitude and season affect both the quantity and quality of solar radiation reaching the earth's surface, especially in the UVB region of the spectrum, but little is known about how these influence the ability of sunlight to synthesize vitamin D3 in skin. A model has been developed to evaluate the effect of seasonal and latitudinal changes on the potential of sunlight to initiate cutaneous production of vitamin D3. Human skin or [3 alpha-3H]7-dehydrocholesterol exposed to sunlight on cloudless days in Boston (42.2 degrees N) from November through February produced no previtamin D3. In Edmonton (52 degrees N) this ineffective winter period extended from October through March. Further south (34 degrees N and 18 degrees N), sunlight effectively photoconverted 7-dehydrocholesterol to previtamin D3 in the middle of winter. These results quantify the dramatic influence of changes in solar UVB radiation on cutaneous vitamin D3 synthesis and indicate the latitudinal increase in the length of the "vitamin D winter" during which dietary supplementation of the vitamin may be advisable.

Oculosympathetic spasm with cervical spinal cord injury.

A 23-year-old man, involved in a motor-vehicle accident, became quadraparetic due to cervical spinal cord injury at the C-4 to C-6 level. Five months later he was noted to have bilateral, asymmetric pupillary mydriasis precipitated by elevation and stretch of an arm or leg. Pharmacologic pupillary testing and ciliospinal reflex responses suggested that the oculosympathetic pathways were intact. Computed tomographic myelography using metrizamide disclosed a posttraumatic syringomyelic cyst at C-4. This pupillary phenomenon has been termed oculosympathetic spasm, and we reviewed four previous reports. While the cause of oculosympathetic spasm remains speculative, it may represent a localized form of autonomic hyperreflexia.

Dorsal midbrain syndrome in multiple sclerosis.

Complaining only of vertical diplopia, a 34-year-old woman had pupillary light-near dissociation, upward gaze paresis, convergence-retraction nystagmus, and skew deviation. Cranial computerized tomography excluded a space-occupying lesion. Additional history and examination established the diagnosis of clinically definite multiple sclerosis. Dorsal midbrain syndrome due to multiple sclerosis rare.

Antineuronal (anti-Ri) antibodies in a patient with steroid-responsive opsoclonus-myoclonus.

A 45-year-old woman developed opsoclonus, myoclonus, and severe truncal and gait ataxia. Serum and CSF contained IgG antibodies that appear to be identical to "anti-Ri" antibodies associated with paraneoplastic opsoclonus and ataxia. The patient had a fluctuating course with exacerbations that responded well to corticosteroids and later to cyclophosphamide. Her anti-Ri antibody titer has declined significantly but still remains high. After more than 3 years of follow-up, no neoplasm has been detected.

Ocular stroke and carotid artery dissection.

Carotid artery dissection frequently causes transient ipsilateral visual impairment. We present 2 cases of permanent ocular vaso-occlusion sequelae consequent to dissection of the ipsilateral internal carotid, definite in one and probable in the other. In both, the ocular strokes led to the recognition of the underlying carotid vasculopathy.

Aneurysmal compression of the anterior visual pathways.

Ten patients with aneurysmal compression of the anterior visual pathways had visual loss, unilateral in 4 and bilateral in 6. There was no typical clinical presentation. Visual loss was acute or gradual, acuity sometimes fluctuated, and visual field testing was highly variable. The aneurysms were supraclinoid (four patients), carotid-ophthalmic (two), anterior communicating-anterior cerebral (three), and intracavernous carotid (one). Nine patients had successful clipping of their aneurysm, and in one, ipsilateral common carotid ligation was performed. Postoperatively, visual acuity was improved in six cases, unchanged in three, and worse in one.

Internuclear ophthalmoplegia: recovery and plasticity.

We studied refixational eye movements of a patient during the gradual resolution of an internuclear ophthalmoplegia (secondary to head trauma) in an attempt to determine the relative contributions of both medial longitudinal fasciculus (MLF) recovery and secondary central plastic changes. Adduction-refixational eye movements in the affected eye consisted of an initial fast (saccadic) portion followed by a slow drift toward the new intended eye position. The fast and slow components of the movements reflected, respectively, the pulse and step increases in neural innervation. Shortly after the traumatic insult, the affected eye exhibited low adduction gain (pulse gain 0.34; step gain 0.37) and slow saccades with peak velocities of 55% and durations of 278%, normalized for achieved, rather than intended, amplitudes. Several months later the pulse and step gains, peak velocities, and durations of the saccades improved to 0.81, 0.92, 87%, and 145%, respectively. The increased gains and faster velocity were accomplished by increases in the firing frequency of the pulse and step, reflecting recovery of MLF axons, rather than saccadic system plasticity, which would have resulted in increased duration of the saccadic pulse.

Congenitally corrected transposition of the great vessels: localization of the site of complete atrioventricular block using his bundle electrograms.

Complete atrioventricular block proximal to the bundle of His in a patient with congenitally corrected transposition of the great vessels was documented using His bundle electrograms. The spontaneous rhythnm probably originated from the bundle of His and was responsive to carotid sinus massage, atropine and isometric and treadmill exercise. These electrophysiologic observations are consistent with recent anatomic studies of congenitally corrected transposition of the great vessels.

A survey screen for prediction of apnea.

Questionnaire data from patients presenting at three sleep disorders centers were used to develop and assess a screening tool for sleep apnea based on the reporting of the frequency of various symptoms of sleep apnea and other sleep disorders plus age, body mass index (BMI) and gender. Patients were not specifically referred for suspicion of sleep apnea. Separate factor analyses of survey responses from 658, 193 and 77 respondents from the first, second and third sites, respectively, each yielded four orthogonal factors, one of which accounted for all the questions concerned with the frequency of disordered breathing during sleep. The survey was shown to be reliable in a subset of patients from one of the sites (test-retest correlation = 0.92). Survey data were then compared to a clinical measure of sleep apnea (respiratory disturbance index) obtained from polysomnography. A multivariable apnea risk index including survey responses, age, gender and BMI was estimated using multiple logistic regression in a total sample of 427 respondents from two of the sites. Predictive ability was assessed using receiver operating characteristic (ROC) curves. The area under the ROC curve was 0.79 (p < 0.0001). For BMI alone, it was 0.73, and for an index measuring the self-report of the frequency of apnea symptoms, it was 0.70. The multivariable apnea risk index has potential utility in clinical settings.

Night-to-night variability in CPAP use over the first three months of treatment.

The purpose of this study was to examine the relationship between night-to-night variability and nightly duration of continuous positive airway pressure (CPAP) therapy over the first 9 weeks of treatment and to determine when patients begin to establish a nonadherent pattern of use. Data were analyzed from a study of daily CPAP use covertly monitored in 32 diagnosed patients with obstructive sleep apnea (OSA) using a microprocessor monitor encased in a CPAP machine. Patterns of CPAP use were bimodal, based on the frequency of nightly use. Approximately half the subjects were consistent users of CPAP, applying it > 90% of the nights for an average of 6.22 +/- 1.21 hours per night, while the other half comprised intermittent users who had a wide range of daily use averaging 3.45 +/- 1.94 hours per night on the nights CPAP was used. The percent of days skipped was significantly correlated with decreased nightly duration (rho = -0.73, p < 0.0001). Analysis of the night-to-night pattern of use revealed that the two groups differed significantly in the nightly duration of CPAP use by the fourth day of treatment (p = 0.001). Exploration of factors that potentially differentiate the two groups revealed no reliable predictors. However, intermittent users continued to report significantly greater OSA symptoms (snoring, snorting, and apnea) posttreatment, suggesting that they continued to experience sleep disordered breathing.

Endotoxin tolerance is induced in Chinese hamster ovary cell lines expressing human CD14.

Changes in patterns of gene induction by myeloid lineage cells following multiple exposures to endotoxin (lipopolysaccharide; LPS) is a feature of LPS tolerance. To further understand the mechanism of this phenomenon we describe studies using stably transfected Chinese hamster ovary cell lines that express human CD14 (CHO-hCD14). Using NF-kappa B activation as a measure of LPS-induced cell activation we show that a single treatment with LPS renders CHO-hCD14 cells tolerant to subsequent challenge with LPS, but not with other stimuli such as tumor necrosis factor. Tolerance may result from the induction of gene(s) that control LPS-induced signaling pathways and here we suggest that such genes may be found in the group of immediate, early response genes characterized by the protein phosphatase 3CH134. The CHO-hCD14 cell lines provide a novel model system to further explore the mechanism of endotoxin tolerance.

One negative polysomnogram does not exclude obstructive sleep apnea.

Night-to-night variability of apneas on overnight polymnography exists in patients with documented obstructive sleep apnea (OSA). In this study, we evaluated the possibility that this variability may be severe enough to miss the diagnosis of OSA in patients clinically at risk for the disease. We prospectively studied 11 patients who were deemed on clinical grounds to have probable OSA, but had a negative result on overnight polysomnography. Six of the 11 patients were found to have a positive second study with a significant rise in the apnea/hypopnea index (AHI) from 3.1 +/- 1.0 to 19.8 +/- 4.7 (mean +/- SEM, p < 0.01). The cause of the negative first study in these patients is unclear, but it does not seem related to risk factor pattern, sleep architecture, or test interval. The change in AHI was not found to be rapid eye movement (REM)-dependent. This study demonstrates that a negative first-night study is insufficient to exclude OSA in patients with one or more clinical markers of the disease.

Tuberculous pleural effusions.

While a number of recent reports have documented the changing clinical and radiographic spectrum of parenchymal tuberculosis, relatively little attention has been paid to changes in the patterns of pleural tuberculosis. We therefore reviewed the clinical, laboratory, and radiographic characteristics of 26 adult patients with tuberculous pleural effusions. We found that pleural tuberculosis has become a disease of older adults (median age, 56 years) and that 19 percent (5/26) of the cases were due to postprimary (reactivation) disease. This shift in age led to problems in diagnosis, since many of these older patients had underlying or coexisting disease that could have caused a pleural effusion. Both specimens of pleural fluid and pleural biopsy were useful in establishing the diagnosis. Examination of sputum was less helpful. All patients who were not anergic had positive cutaneous reactions to first-strength purified protein derivative of tuberculin. Lymphocytosis of the pleural fluid was not a uniform finding; only 62 percent of our patients had greater than 50 percent lymphocytes on their initial examinations of pleural fluid, and four patients had greater than 90 percent polymorphonuclear cells. All of the effusions were exudates, and four had glucose levels in the pleural fluid that were less than 30 mg/dl. Pleural tuberculosis is an important diagnostic consideration in adult or elderly patients with exudative pleural effusions.