Volume growth of abdominal aortic aneurysms correlates with baseline volume and increasing finite element analysis-derived rupture risk.
The diagnosis and management of abdominal aortic aneurysms (AAAs) currently relies on the aortic maximal diameter, which grows in an unpredictable manner. Infrarenal aortic volume has recently become clinically feasible to measure, and an estimate of biomechanical rupture risk derived from finite element analysis, the peak wall rupture index (PWRI), has been shown to predict AAA rupture. Our objective was to ascertain how well volume growth correlates with baseline volume and increasing PWRI, compared with the maximal diameter. We retrospectively identified 41 AAA patients (nine women, 32 men) at our institution who had undergone two computed tomography angiographies with an interval of 8 to 17 months. Digital three-dimensional reproductions of the aneurysms were segmented from the 82 computed tomography angiographies. AAA diameter, volume, and PWRI were measured and calculated with finite element analysis software. Growth rates of diameter and volume were related to baseline diameter and volume as well as to change rates of PWRI. Significant growth was defined as growth exceeding our interobserver 95% limits of agreement. Diameter growth rate did not correlate with baseline diameter (r = 0.15, 95% confidence interval [CI], -0.17 to 0.45), but volume growth rate correlated with baseline volume (r = 0.56; 95% CI, 0.30-0.75). The correlation between baseline volume and volume growth rate was stronger than the correlation between baseline diameter and diameter growth rate (95% CI, 0.086-0.71). Increasing PWRI correlated with volume growth rate (r = 0.70; 95% CI, 0.40-0.87) but not with diameter growth rate (r = 0.044; 95% CI, -0.44 to 0.51), and the difference between the correlation coefficients was significant (95% CI, 0.11-1.16). Volume better predicts aneurysm growth rate and correlates stronger with increasing estimated biomechanical rupture risk compared with diameter. Our results support the notion of monitoring all three dimensions of an AAA.


The use of ventriculoperitoneal shunts for uncontrollable intracranial hypertension in patients with HIV-associated cryptococcal meningitis with or without hydrocephalus.
Extremely elevated intracranial pressure (ICP) in patients with HIV and cryptococcal meningitis is a poor prognostic predictor of death during initial therapy. The risks associated with implanting a cerebrospinal fluid (CSF) shunt into immunocompromised patients with ongoing CSF infection have historically discouraged surgeons from implanting CSF shunts in patients with HIV and cryptococcal meningitis. An unanswered question is whether ventriculoperitoneal (VP) shunts can effectively provide long-term treatment for patients with intracranial hypertension and HIV-associated cryptococcal meningitis in China. Outcomes for 9 patients with HIV-associated cryptococcal meningitis who were given VP shunts for increased ICP were retrospectively analyzed. Each patient's age, sex, clinical manifestations, CD4+ lymphocyte count, HIV viral load, neurological status, CSF features, image findings, anad other opportunistic infections were recorded for analysis. All patients had signs and symptoms of increased ICP, including headaches, nausea, and vomiting. Seven patients (77.78%) had visual loss due to persistent papilledema. The median time from diagnosis of cryptococcal meningitis to VP shunting in the 9 patients was 5 months (range 0.5-12.5 months). Seven patients (77.78%) had good outcomes, with recovery from 1 month to 48 months. Two patients had poor outcomes; one died six months after shunting due to severe adverse reactions to antiretroviral drugs, and the other died two weeks after surgery. Patients with intracranial hypertension and HIV-associated cryptococcal meningitis who cannot tolerate cessation of external lumbar CSF drainage or frequent lumbar punctures may be eligible for VP shunt placement, despite severe immunosuppression and persistent CSF cryptococcal infection.


A role for calcium in the breakdown of inositol phospholipids in intact and digitonin-permeabilized pancreatic islets.
Glucose (20 mM) and 4-methyl-2-oxopentanoate (10 mM) both caused a pronounced stimulation of insulin release and of [3H]inositol phosphate production in rat pancreatic islets prelabelled with myo-[3H]inositol. Secretory responses to these nutrients were markedly impaired by lowering the Ca2+ concentration of the incubation medium to 10(-4)M or less, whereas stimulated inositol phosphate production was sensitive to Ca2+ within the range 10(-6)-10(-4)M. Inositol phosphate formation in response to carbamoylcholine was also found to be dependent on the presence of 10(-5)M-Ca2+ or above. Raising the concentration of K+ in the medium resulted in a progressive, Ca2+-dependent stimulation of inositol phosphate production in islets, although no significant stimulation of insulin release was observed. In islets prelabelled with myo[3H]inositol, then permeabilized by exposure to digitonin, [3H]inositol phosphate production could be triggered by raising the Ca2+ concentration from 10(-7) to 10(-5)M. This effect was dependent on the concentration of ATP and the presence of Li+, and involved detectable increases in the levels of InsP3 and InsP2 as well as InsP. A potentiation of inositol phosphate production by carbamoylcholine was observed in permeabilized islets at lower Ca2+ concentrations, although nutrient stimuli were ineffective. No significant effects were observed with guanine nucleotides or with neomycin, although NADH produced a modest increase and adriamycin a small inhibition of inositol phosphate production in permeabilized islets. These results strongly suggest that Ca2+ ions play an important role in the stimulation of inositol lipid metabolism in islets in response to nutrient secretagogues, and that inositide breakdown may actually be triggered by Ca2+ entry into the islet cells.


Anaplastic meningioma with extremely rapid recurrence.
A 62-year-old woman presented with an uncommon case of anaplastic meningioma manifesting as recent memory disturbance. Magnetic resonance imaging revealed a mass located in the right temporal lobe. She became unconscious because of uncal herniation and underwent urgent surgery. The tumor was completely resected, except for a lesion tightly attached to arteries. Histological examination indicated the presence of anaplastic meningioma with an extremely high MIB-1 labeling index (70%). After 43 days, the patient developed local recurrence and dissemination in the left temporal lobe. The exceptionally high MIB-1 labeling index corresponded with a short tumor doubling time (8.2 days). Whole-brain irradiation and linear accelerator surgery for disseminated lesions were performed, and the tumor growth halted. Although meningiomas rarely show malignant behavior, corresponding to World Health Organization grade III, it is necessary to consider malignant behavior when treating meningiomas.


Genetic Modifiers for Neuromuscular Diseases.
Neuromuscular diseases, which encompass disorders that affect muscle and its innervation, are highly heritable. Genetic diagnosis now frequently pinpoints the primary mutation responsible for a given neuromuscular disease. However, the results from genetic testing indicate that neuromuscular disease phenotypes may vary widely, even in individuals with the same primary disease-causing mutation. Clinical variability arises from both genetic and environmental factors. Genetic modifiers can now be identified using candidate gene as well as genomic approaches. The presence of genetic modifiers for neuromuscular disease helps define the clinical outcome and also highlights pathways of potential therapeutic utility. Herein, we will focus on single gene neuromuscular disorders, including muscular dystrophy, spinal muscular atrophy, and amyotrophic lateral sclerosis, and the methods that have been used to identify modifier genes. Animal models have been an invaluable resource for modifier gene discovery and subsequent mechanistic studies. Some modifiers, identified using animal models, have successfully translated to the human counterpart. Furthermore, in a few instances, modifier gene discovery has repetitively uncovered the same pathway, such as TGFβ signaling in muscular dystrophy, further emphasizing the relevance of that pathway. Knowledge of genetic factors that influence disease can have direct clinical applications for prognosis and predicted outcome.


[Thoracoabscessotomy in combined treatment of lung gangrene].
Patients with gangrene and gangrenous abscess of the lung belong to the most severe group of patients with purulent lung diseases. Conservative treatment is not effective, lethality after lung resection or pneumonectomy ranges from 20 to 70%, therefore the study of less traumatic but life-saving operations is topical. From 1996 to 1998, 296 patients with purulent destructive processes in the lung were hospitalized, 34 of them had gangrene or gangrenous abscess of the lung with significant intoxication. Thoracoabscessostomy by original method with consecutive necrectomies, sanitation of purulent cavity was performed in 27 patients. After operation 2 patients died, 25 patients were discharged with clinical recovery in satisfactory conditions, with dry cavity in the lung. In remote terms the cavities are cicatrized or transform to spurious cysts. Indications for thoracoabscessostomy are formulated. It is method of choice in the treatment of patients with gangrenous lung abscess, when conservative treatment is not effective, but the risk of radical operation is very high.


Ureteroscopic management of renal calculi in anomalous kidneys.
To review our experience with ureteroscopy in treating patients with renal calculi in anomalous kidneys and to evaluate the efficacy of this approach. Eight patients with renal calculi in anomalous kidneys who were managed by ureteroscopic procedures were identified. Demographic information, preoperative stone burden, operative information (ureteroscope size, lithotrite used, instruments used, duration of surgery, complications, stenting), follow-up imaging, and complications were obtained from the medical record. This information was analyzed to determine the most frequently used instruments and stone-free rates. Our cohort consisted of 4 patients with horseshoe kidneys (HSK) and 4 patients with pelvic kidneys (PK) (6 male, 2 female, mean age, 50.6 years). The average preoperative stone burden of the 11 treated calculi was 1.4 cm, with 5 stones located in the renal pelvis, 2 in the upper pole, and 4 in lower pole calyces. A 7.5F flexible ureteroscope, holmium laser lithotripsy, and nitinol baskets and graspers were used in all patients. Six patients had complete clearance of the stone on postoperative imaging (75% HSK, 75% PK), with 88% of patients asymptomatic after their procedure. No patients required additional surgical intervention. Flexible ureteroscopy with holmium laser lithotripsy and the use of nitinol baskets and graspers provides a reasonable alternative to shock wave lithotripsy in the management of patients harboring renal calculi in anomalous kidneys. In addition, ureteroscopy can be considered a primary option for managing select patients with symptomatic stones in PKs before a percutaneous surgical approach.


Sequence evolution and the mechanism of protein folding.
The impact on protein evolution of the physical laws that govern folding remains obscure. Here, by analyzing in silico-evolved sequences subjected to evolutionary pressure for fast folding, it is shown that: First, a subset of residues in the thermodynamic folding nucleus is mainly responsible for modulating the protein folding rate. Second and most important, the protein topology itself is of paramount importance in determining the location of these residues in the structure. Further stabilization of the interactions in this nucleus leads to fast folding sequences. Third, these nucleation points restrict the sequence space available to the protein during evolution. Correlated mutations between positions around these hot spots arise in a statistically significant manner, and most involve contacting residues. When a similar analysis is carried out on real proteins, qualitatively similar results are obtained.


Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure.
Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism. We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism. Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P < .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P < .001). GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism.


Eggshell Biliverdin and Protoporphyrin Pigments in a Songbird: Are They Derived from Erythrocytes, Blood Plasma, or the Shell Gland?
Biliverdin and protoporphyrin pigments are deposited into the eggshell when the developing egg is in the shell gland. However, the site of synthesis of eggshell pigments is still uncertain, although it may influence the possible costs and potential functions of eggshell coloration in avian species. Eggshell pigments may be derived from red blood cells or be produced in other organs and then transferred to the shell gland, or they may be synthesized de novo in the shell gland. We studied in the canary (Serinus canaria) whether eggshell blue-green and brown pigmentations are associated with experimentally elevated anemia, female hematocrit level, immature erythrocyte percentage, and feces and plasma pigment levels during egg laying to find out the possible origin of eggshell pigments. We found no significant effects of hematocrit level or experimentally elevated anemia on intensity of eggshell blue-green and brown pigmentations; therefore, we consider it less likely that eggshell pigments are derived from erythrocytes. In addition, we found no significant associations between female feces biliverdin concentration during egg laying and intensity of eggshell blue-green pigmentation, suggesting that eggshell biliverdin may not originate from the spleen or liver. We found a negative association between plasma and feces protoporphyrin concentrations during egg laying and eggshell brown chroma. This result suggests that an increased production of protoporphyrin in the liver, which could have elevated plasma and feces protoporphyrin concentrations, could inhibit eggshell protoporphyrin pigmentation, probably through affecting enzymatic activities. We suggest that both pigments are produced de novo in the shell gland in the canary, but circulating pigment levels may influence shell gland pigment synthesis, thus connecting the physiological status of the female to eggshell coloration.


The Innate Immunity in Alzheimer Disease- Relevance to Pathogenesis and Therapy.
The genetic, cellular, and molecular changes associated with Alzheimer disease provide evidence of immune and inflammatory processes involvement in its pathogenesis. These are supported by epidemiological studies, which show some benefit of long-term use of NSAID. The hypothesis that AD is in fact an immunologically mediated and even inflammatory pathological process may be in fact scientifically intriguing. There are several obstacles that suggest the need for more complex view, in the process of targeting inflammation and immunity in AD. In our previous studies we proposed a reliable methodology to assess innate immunity in Alzheimer patients and controls. The methodology is based on the phenomenon of human leukocytes being resistant to viral infection. The unspecific character of the resistance, dependent on interferons and tumor necrosis factor, and occurrence in cells ex vivo indicate that an in vivo mechanism of innate immunity may be involved. The above mentioned resistance could be estimated in a test based on peripheral blood leukocytes infection by vesicular stomachs virus.


Penile strangulation by human hair. Report of three cases and review of the literature.
Sixty cases of penile strangulation by human hair are reviewed. The condition has also been labelled 'penile tourniquet syndrome.' It is worldwide in distribution and has been reported from many countries including Algeria, Egypt, England, Germany, Jordan, Lebanon, Saudi Arabia and the United States. Whether accidental, incidental to circumcision or intentional, it could lead to serious complications: urethral fistula, urethral stricture, penile deformity, gangrene and amputation. It is not always easily recognizable and the physician should keep it in mind whenever a boy, or even an older man, presents with unexplained swelling of the penis.


Color Trails Test: A New Set of Data on Cognitive Flexibility and Processing Speed in Schizophrenia.
Although schizophrenia patients have been reported to manifest deficits in cognitive flexibility and lower processing speed (measured with i.a., the Color Trails Test, CTT), there still remain a few matters that require further investigation. We have therefore formulated three research aims: 1) to examine the factor structure of CTT in schizophrenia patients and healthy controls, 2) to compare different CTT performance measures in the two groups, 3) to investigate the relationship between these measures and selected psychopathological symptoms in the patient group. Sixty-seven patients with paranoid schizophrenia and 67 healthy controls, matched for gender, age, number of years of education, and overall cognitive functioning underwent assessment of cognitive flexibility and processing speed with the CTT. Factor analysis of CTT variables based on the principal component method revealed a four-factor solution in both groups. Compared with healthy controls, the patients performed poorer on CTT 1 time, CTT 2 time, 2-1 difference, prompts in CTT 2, and had higher regression factor scores for Factor 1 (reflecting the slower speed of perceptual tracking). Furthermore, significant links were found between some CTT measures, and negative and disorganization symptoms. Schizophrenia patients exhibit problems with speed of perceptual tracking and executive processes dependent on processing speed. Our results may be useful for the development of neuropsychological diagnostic methods for schizophrenia patients. It seems that, compared to other CTT indices, CTT 1 time, CTT 2 time, and 2-1 difference are more appropriate measures of cognitive performance in schizophrenia patients.


Renal action of progesterone and 18-substituted derivatives.
The recently synthesized progesterone (P) derivatives, 18-vinylprogesterone (18VP) and 18-ethynylprogesterone (18EP), are potent inhibitors of aldosterone synthesis by adrenal glands. To evaluate the potential interest of these compounds as antihypertensive drugs, we determined whether they also interact with renal mineralocorticosteroid receptors (MR) in kidney and, if so, whether they mimic or antagonize aldosterone action. For this purpose, we evaluated the potency of 18VP and 18EP 1) to displace [3H]aldosterone binding in cytosolic fractions of kidney from adrenalectomized rats and 2) to interfere with aldosterone-induced stimulation of Na(+)-K(+)-ATPase in the collecting tubule of adrenalectomized rats. The properties of 18VP and 18EP were compared with those of their precursor progesterone and of the antimineralocorticosteroid spironolactone. The binding of [3H]aldosterone was restricted to cytosolic MR by presaturating glucocorticosteroid receptor with RU 38486. All compounds tested displaced [3H]aldosterone binding with the following efficiency: spironolactone greater than aldosterone greater than P greater than 18VP greater than 18EP; apparent Kd varied between 0.66 and 16.4 nM. Spironolactone, P, and 18VP antagonized aldosterone-induced stimulation of Na(+)-K(+)-ATPase in the collecting tubule, whereas 18EP mimicked the mineralocorticosteroid action. The different steroids tested altered Na(+)-K(+)-ATPase stimulation and aldosterone binding with the same order of potency.


The challenge to know and control: disease outbreak surveillance and alerts in China and India.
Since the revisions to the International Health Regulations (IHR) in 2005, much attention has been turned to how states, particularly developing states, will address core capacity requirements. The question often examined is how states with poor health systems can strengthen their capacity to identify and verify public health emergencies of international concern. A core capacity requirement is that by 2012 states will have a surveillance and response network that operates from the local community to the national level. Much emphasis has turned to the health system capacity required for this task. In this article, I seek to understand the political capacity to perform this task. This article considers how the world's two most populous states, 1 China and India, have sought to communicate outbreak events in times of crisis and calm. I consider what this reporting performance tells us of their capacity to meet their IHR obligations given the two countries differing political institutions.


Reversible posterior leukoencephalopathy syndrome: a retrospective study in King Chulalongkorn Memorial Hospital.
Reversible posterior leukoencephalopathy (RPLE) or reversible posterior cerebral edema syndrome is a syndrome characterized by transient focal or diffused neurological deficits and reversible neuroimaging changes. RPLE is often associated with hypertension and systemic illness. The classical Magnetic Resonance Imaging (MRl) feature of RPLE is predominately involvement of bilateral posterior cerebral white matter. Due to availability of MRI technology, this entity has been reported more frequently The clinical recordings were searched from data bases at King Chulalongkorn Memorial Hospital from 2003 to 2005. Keywords were "leukoencephalopathy" and "hypertensive encephalopathy". Neuroimaging criteria for the diagnosis of RPLE were bilateral symmetrical cortical-subcortical white matter lesions predominantly affecting the occipital lobe. The data were reviewed. Cases with RPLE were recruited and analyzed. Nine patients (female:male, 8:1), ranged in age from 17 to 39 years (average, 26 years) were analyzed. Five patients had acute hypertension associated with renal failure, 1 had acute hypertension without renal impairment, 2 had eclampsia and 1 was associated with cyclosporine therapy. Most common clinical symptoms were seizure and cortical blindness. MRI revealed bilateral occipital white matter edema in 7/8 patients while computerized tomography demonstrated this feature in 3/9 patients. Other MRI abnormalities were detected in frontal lobes, parietal lobes, deep grey nuclei, brainstem and cerebellum. The patients were treated with antihypertensive drugs, antiepileptics and withdrawal from immunosuppressive therapy. In 8 patients, the neurological deficits recovered within 2 weeks. The case with cyclosporine therapy had residuals in the form of limb weakness and spasticity. RPLE is associated with hypertension, systemic autoimmune diseases, renal impairment, immunosuppressive therapy or eclampsia. The neuroimaging findings reveal characteristic white matter vasogenic edema in occipital lobes as well as other cortical areas and deep grey matter. Good clinical outcomes occur after prompt symptomatic treatment with antihypertensive drugs, antiepileptics or withdrawal from immunosuppressive therapy and repeated neuroimaging may not be necessary.


Contingent screening for Down syndrome--results from the FaSTER trial.
Comparison of contingent, step-wise and integrated screening policies. Mid-trimester Down syndrome risks were retrospectively calculated from FaSTER trial data. For contingent screening, initial risk was calculated from ultrasound measurement of nuchal translucency (NT), maternal serum pregnancy-associated plasma protein (PAPP)-A and free beta-human chorionic gonadotrophin (hCG) at 11-13 weeks, and classified positive (>1 in 30), borderline (1 in 30-1500) or negative. Borderline risks were recalculated using alpha-fetoprotein, hCG, unconjugated estriol (uE3) and inhibin at 15-18 weeks, and reclassified as positive (>1 in 270) or negative. For step-wise screening, initial negative risks were also recalculated. For integrated screening, a single risk was calculated from NT, PAPP-A and the second trimester markers. There were 86 Down syndrome and 32,269 unaffected pregancies. The detection rate for contingent screening was 91% and false-positive rate was 4.5%; initial detection rate was 60%, initial false-positive rate was 1.2% and borderline risk was 23%. Step-wise screening had 92% detection rate and 5.1% false-positive rate; integrated screening had 88% and 4.9% respectively. As predicted by modelling, the contingent screening detection rate for a fixed false-positive rate is comparable with step-wise and integrated screening, but substantially reduces the number needing to return for second trimester testing.


Particularism and the retreat from theory in the archaeology of agricultural origins.
The introduction of new analytic methods and expansion of research into previously untapped regions have greatly increased the scale and resolution of data relevant to the origins of agriculture (OA). As a result, the recognition of varied historical pathways to agriculture and the continuum of management strategies have complicated the search for general explanations for the transition to food production. In this environment, higher-level theoretical frameworks are sometimes rejected on the grounds that they force conclusions that are incompatible with real-world variability. Some of those who take this position argue instead that OA should be explained in terms of local and historically contingent factors. This retreat from theory in favor of particularism is based on the faulty beliefs that complex phenomena such as agricultural origins demand equally complex explanations and that explanation is possible in the absence of theoretically based assumptions. The same scholars who are suspicious of generalization are reluctant to embrace evolutionary approaches to human behavior on the grounds that they are ahistorical, overly simplistic, and dismissive of agency and intent. We argue that these criticisms are misplaced and explain why a coherent theory of human behavior that acknowledges its evolutionary history is essential to advancing understanding of OA. Continued progress depends on the integration of human behavior and culture into the emerging synthesis of evolutionary developmental biology that informs contemporary research into plant and animal domestication.


Quantification of target molecules needed to detect microorganisms by fluorescence in situ hybridization (FISH) and catalyzed reporter deposition-FISH.
Fluorescence in situ hybridization (FISH) with rRNA-targeted oligonucleotide probes is a method that is widely used to detect and quantify microorganisms in environmental samples and medical specimens by fluorescence microscopy. Difficulties with FISH arise if the rRNA content of the probe target organisms is low, causing dim fluorescence signals that are not detectable against the background fluorescence. This limitation is ameliorated by technical modifications such as catalyzed reporter deposition (CARD)-FISH, but the minimal numbers of rRNA copies needed to obtain a visible signal of a microbial cell after FISH or CARD-FISH have not been determined previously. In this study, a novel competitive FISH approach was developed and used to determine, based on a thermodynamic model of probe competition, the numbers of 16S rRNA copies per cell required to detect bacteria by FISH and CARD-FISH with oligonucleotide probes in mixed pure cultures and in activated sludge. The detection limits of conventional FISH with Cy3-labeled probe EUB338-I were found to be 370 +/- 45 16S rRNA molecules per cell for Escherichia coli hybridized on glass microscope slides and 1,400 +/- 170 16S rRNA copies per E. coli cell in activated sludge. For CARD-FISH the values ranged from 8.9 +/- 1.5 to 14 +/- 2 and from 36 +/- 6 to 54 +/- 7 16S rRNA molecules per cell, respectively, indicating that the sensitivity of CARD-FISH was 26- to 41-fold higher than that of conventional FISH. These results suggest that optimized FISH protocols using oligonucleotide probes could be suitable for more recent applications of FISH (for example, to detect mRNA in situ in microbial cells).


Dual therapy of ovarian cancer using measles viruses expressing carcinoembryonic antigen and sodium iodide symporter.
MV-CEA is an oncolytic measles virus currently being tested in patients with ovarian cancer and whose propagation can be monitored by measuring blood carcinoembryonic antigen (CEA) levels. MV-NIS is an oncolytic measles virus coding for the thyroidal sodium iodide symporter (NIS) whose propagation can be mapped by serial radioiodine imaging. Expression of both CEA and NIS genes from a single virus would combine sensitive, quantitative expression monitoring (CEA) with radioisotopic expression mapping (NIS). Because of the unfavorable replication kinetics of measles viruses expressing both CEA and NIS, we explored the feasibility of combining MV-CEA with MV-NIS for comprehensive virotherapy monitoring in ovarian cancer. Mice implanted with i.p. SKOV3ip.1 ovarian cancer xenografts received MV-CEA alone, MV-NIS alone, or a combination of MV-CEA plus MV-NIS. Viral gene expression was monitored by measuring blood CEA levels, and the location of virus-infected cells was monitored by gamma camera imaging. Surprisingly, mice receiving the combination of MV-CEA plus MV-NIS showed greatly superior responses to therapy, but this was associated with 10-fold lower plasma levels of CEA compared with mice treated with MV-CEA alone. In vitro studies showed superior replication kinetics of MV-NIS relative to MV-CEA. The gamma camera scans were considerably less sensitive than the plasma CEA marker for monitoring virus infection. Dual therapy with MV-CEA and MV-NIS is superior to treatment with either virus alone, and it allows noninvasive monitoring of virotherapy via soluble marker peptide and gamma camera imaging. This has important implications for the clinical development of oncolytic measles viruses.


One Who Came So Young and Early
A poem composed as a reflection of emotions of the parents of an extremely premature baby boy born at 23 weeks of gestation. Sadly we could not sustain his precious life beyond the second day. Staff in the neonatal intensive care units (NICU) offer support to such parents during their difficult times and this poem is a tribute to the caring neonatal clinical professionals and the parents who strive to cope when babies are born at the margins of viability.


Understanding Peptide Binding in Class A G Protein-Coupled Receptors.
Many physiologic processes are controlled through the activation of G protein-coupled receptors (GPCRs) by regulatory peptides, making peptide GPCRs particularly useful targets for major human diseases such as diabetes and cancer. Peptide GPCRs are also being evaluated as next-generation targets for the development of novel antiparasite agents and insecticides in veterinary medicine and agriculture. Resolution of crystal structures for several peptide GPCRs has advanced our understanding of peptide-receptor interactions and fueled interest in correlating peptide heterogeneity with receptor-binding properties. In this review, the knowledge of recently crystalized peptide-GPCR complexes, previously accumulated peptide structure-activity relationship studies, receptor mutagenesis, and sequence alignment are integrated to better understand peptide binding to the transmembrane cavity of class A GPCRs. Using SAR data, we show that peptide class A GPCRs can be divided into groups with distinct hydrophilic residues. These characteristic residues help explain the preference of a receptor to bind the C-terminal free carboxyl group, the C-terminal amidated group, or the N-terminal ammonium group of peptides.


Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore.
Many physiological and synthetic agents act by occluding the ion conduction pore of ion channels. A hallmark of charged blockers is that their apparent affinity for the pore usually varies with membrane voltage. Two models have been proposed to explain this voltage sensitivity. One model assumes that the charged blocker itself directly senses the transmembrane electric field, i.e., that blocker binding is intrinsically voltage dependent. In the alternative model, the blocker does not directly interact with the electric field; instead, blocker binding acquires voltage dependence solely through the concurrent movement of permeant ions across the field. This latter model may better explain voltage dependence of channel block by large organic compounds that are too bulky to fit into the narrow (usually ion-selective) part of the pore where the electric field is steep. To date, no systematic investigation has been performed to distinguish between these voltage-dependent mechanisms of channel block. The most fundamental characteristic of the extrinsic mechanism, i.e., that block can be rendered voltage independent, remains to be established and formally analyzed for the case of organic blockers. Here, we observe that the voltage dependence of block of a cyclic nucleotide-gated channel by a series of intracellular quaternary ammonium blockers, which are too bulky to traverse the narrow ion selectivity filter, gradually vanishes with extreme depolarization, a predicted feature of the extrinsic voltage dependence model. In contrast, the voltage dependence of block by an amine blocker, which has a smaller "diameter" and can therefore penetrate into the selectivity filter, follows a Boltzmann function, a predicted feature of the intrinsic voltage dependence model. Additionally, a blocker generates (at least) two blocked states, which, if related serially, may preclude meaningful application of a commonly used approach for investigating channel gating, namely, inferring the properties of the activation gate from the kinetics of channel block.


Proposed equations and reference values for calculating bone health in children and adolescent based on age and sex.
The Dual Energy X-Ray Absorptiometry (DXA) is the gold standard for measuring BMD and bone mineral content (BMC). In general, DXA is ideal for pediatric use. However, the development of specific standards for particular geographic regions limits its use and application for certain socio-cultural contexts. Additionally, the anthropometry may be a low cost and easy to use alternative method in epidemiological contexts. The goal of our study was to develop regression equations for predicting bone health of children and adolescents based on anthropometric indicators to propose reference values based on age and sex. 3020 students (1567 males and 1453 females) ranging in ages 4.0 to 18.9 were studied from the Maule Region (Chile). Anthropometric variables evaluated included: weight, standing height, sitting height, forearm length, and femur diameter. A total body scan (without the head) was conducted by means of the Dual Energy X-Ray Absorptiometry. Bone mineral density (BMD) and the bone mineral content (BMC) were also determined. Calcium consumption was controlled for by recording the intake of the three last days prior to the evaluation. Body Mass Index (BMI) was calculated, and somatic maturation was determined by using the years of peak growth rate (APHV). Four regression models were generated to calculate bone health: for males BMD = (R2 = 0.79) and BMC = (R2 = 0.84) and for the females BMD = (R2 = 0.76) and BMC = (R2 = 0.83). Percentiles were developed by using the LMS method (p3, p5, p15, p25, p50, p75, p85, p95 and p97). Regression equations and reference curves were developed to assess the bone health of Chilean children and adolescents. These instruments help identify children with potential underlying problems in bone mineralization during the growth stage and biological maturation.


Impact of cigarette smoking on kidney transplant recipients: a systematic review.
Cigarette smoking has adverse effects on kidney transplant recipients, causing cardiovascular disease, kidney function impairment, and cancer. However, there are surprisingly few studies on the impact of cigarette smoking among kidney transplant recipients and its consequences after transplantation. We performed a systematic review of the literature to identify the effects of cigarette smoking on patient and graft survival rates among kidney transplant recipients. We searched the PubMed from 1968 to 2009 to identify studies on the effect of cigarette smoking on kidney transplant recipients, using the following keywords: kidney transplantation, cigarette, smoking, tobacco, and nicotine. The electronic and manual searches yielded 357 articles, of which 39 were considered potentially relevant by titles and abstracts and were selected for full text review. Twenty-seven irrelevant reports were excluded. A total of 12 papers were selected for review, comprising of 1801 kidney transplant recipients with a history of smoking. The impact of cigarette smoking on kidney recipient survival was only evaluated by 6 studies and the relative risk of smoking for death was available in 3 reports, varying between 0.8 and 2.2. Cigarette smoking was an independent risk factor for patient death. In addition, on univariable and multivariable analyses, graft survival correlated with a history of cigarette smoking and the relative risk for graft failure ranged from 1.06 to 2.3. Cigarette smoking was associated with an increased risk of death and graft loss. Therefore, every attempt should be made to encourage kidney transplant candidates to stop smoking.


Infant meningococcal vaccination: Advisory Committee on Immunization Practices (ACIP) recommendations and rationale.
At its October 2012 meeting, the Advisory Committee on Immunization Practices (ACIP) voted to recommend vaccination against meningococcal serogroups C and Y for children aged 6 weeks through 18 months at increased risk for meningococcal disease. Meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine (Hib-MenCY-TT [MenHibrix, GlaxoSmithKline Biologicals]) is licensed for active immunization for prevention of invasive disease caused by Haemophilus influenzae type b (Hib) and meningococcal serogroups C and Y. Hib-MenCY-TT is not indicated for prevention of disease caused by meningococcal serogroup B, the most common serogroup causing disease in infants, or serogroups W135 or A, which are represented in quadrivalent meningococcal vaccines. Before licensure of Hib-MenCY-TT, no meningococcal conjugate vaccine was licensed for infants aged 2 through 8 months. MenACWY-D (Menactra, Sanofi Pasteur) is licensed as a 2-dose series for infants and toddlers aged 9 through 23 months, and MenACWY-D and MenACWY-CRM (Menveo, Novartis Vaccines) are licensed for persons aged 2 through 55 years as a single dose. These vaccines are recommended routinely for persons aged 11 through 18 years and persons aged 2 through 55 years at increased risk for meningococcal disease (and persons aged 9 months through 55 years for MenACWY-D). This report summarizes the deliberations of ACIP, the rationale for its decision, and recommendations for use of Hib-MenCY-TT in infants at increased risk for meningococcal disease.


Spontaneous Regression of Primary Cutaneous Diffuse Large B-Cell Lymphoma on Sequential FDG PET.
Primary cutaneous diffuse large B-cell lymphoma, leg type is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. We present a case of an elderly woman with pathology diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type with spontaneous regression without systematic therapy documented by sequential FDG PET scans and clinical follow-up.


Restructured care team design. Managing the trade-off between cost and performance.
The trade-off between team performance and cost-effectiveness is pivotal to identifying care teams that have the best odds for success in a newly restructured environment. Use the framework to picture how those teams might operate. Think about how they may share work or work side-by-side. Use the team performance characteristics as a guide, but don't be afraid to overrule them. By clearly communicating to the organization how each dimension of performance and cost-effectiveness can be used to identify the best teams, you can allay some of the fears and concerns staff may be feeling. Similarly, if administration, using the same criteria, recognizes that every effort has been made to maximize care and minimize expense, their concerns will be met. Both groups can then complete the job of creating effective care team designs.


Results on Low-Mass Weakly Interacting Massive Particles from an 11 kg d Target Exposure of DAMIC at SNOLAB.
We present constraints on the existence of weakly interacting massive particles (WIMPs) from an 11 kg d target exposure of the DAMIC experiment at the SNOLAB underground laboratory. The observed energy spectrum and spatial distribution of ionization events with electron-equivalent energies >200 eV_{ee} in the DAMIC CCDs are consistent with backgrounds from natural radioactivity. An excess of ionization events is observed above the analysis threshold of 50 eV_{ee}. While the origin of this low-energy excess requires further investigation, our data exclude spin-independent WIMP-nucleon scattering cross sections σ_{χ-n} as low as 3×10^{-41} cm^{2} for WIMPs with masses m_{χ} from 7 to 10 GeV c^{-2}. These results are the strongest constraints from a silicon target on the existence of WIMPs with m_{χ}<9 GeV c^{-2} and are directly relevant to any dark matter interpretation of the excess of nuclear-recoil events observed by the CDMS silicon experiment in 2013.


Right ventricle dysfunction in pulmonary hypertension: mechanisms and modes of detection.
This review highlights the right ventricular (RV) involvement in pulmonary hypertension from pathophysiologic changes to current imaging tools used to screen, diagnose and follow up RV function in patients with pulmonary hypertension. Although right heart catheterization is the gold standard for the diagnosis of pulmonary hypertension, other diagnostic methods such as echocardiography, magnetic resonance and nuclear imaging are of great utility in the assessment of the RV in pulmonary hypertension. Apart from its conventional use as a screening tool for pulmonary hypertension, echocardiography allows assessment of RV size and function and has prognostic value. Among the novel applications of echocardiography, exercise echocardiography and measurements of RV strain might help unveil subclinical pulmonary hypertension, whereas three-dimensional echocardiography allows more accurate measures of RV morphology and function. Cardiac magnetic resonance imaging is currently the gold standard noninvasive imaging method to assess RV volume, mass and function and has prognostic value in the assessment of pulmonary hypertension. Finally, positron emission tomography is a promising tool in the metabolic assessment of the RV and pulmonary circulation. RV assessment is essential in the overall evaluation of pulmonary hypertension. Despite the availability of several methods and measurements for this assessment, there is, however, no standard approach or broad consensus on their application.


Influence of supragingival biofilm control and smoking habit on Interleukin-1β concentration.
This investigation compared gingival crevicular fluid (GCF) interleukin-1β (IL-1β) concentrations in periodontitis patients subjected to a strict supragingival biofilm control (Supra) for 6 months. Never-smokers (23) and smokers (n = 20; 19.6 ± 11.8 cigarettes/day) moderate-to-severe chronic periodontitis patients underwent a 6 months period of supragingival control with weekly recall visits. Periodontal probing depth (PPD), bleeding on probing (BOP) and GCF samples (from different PPD category sites: 3-5 mm and 6-10 mm) were obtained at the baseline, 30, and 180 days. IL-1β was assessed by enzyme-linked immunosorbent assay. Generalized estimating equations were used to fit prediction models of IL-1β changes, considering the dependence between the examinations, and using only data from experimental sites. Overall IL-1β concentrations decreased from 3.2 pg/µL to 1.9 pg/µL. Higher baseline IL-1β concentrations were associated with higher baseline PPD values in both groups. There were no differences in IL-1β concentrations between never-smokers and smokers over time for any PPD category. Higher baseline PPD values and the presence of BOP on day 180 were significantly associated with higher IL-1β concentrations. A strict Supra regimen reduced IL-1β concentrations over time in periodontitis patients. The benefits observed for smokers underline the importance of oral hygiene measures, even considering the presence of this important risk factor.


From decision to incision: Ideologies of gender in surgical cancer care.
In this paper, I draw on the narratives of 57 individuals whose gender identities and decisions about their bodies trouble the medical protocols for breast and gynecological cancer care. I focus here on the decision-making process for three groups of elective surgeries: hysterectomy, prophylactic bilateral and contralateral mastectomy, and breast reconstruction. These elective surgeries illustrate places in medical interactions where patients and providers rely on frames of gender to determine whether a given surgery is an appropriate option for cancer prevention or care. These cases also explain how patient experiences of medical interactions are shaped by and thus reproduce ideologies of gender through the bodies of patients. While clinical practice and medical decisions are supposedly determined through the principles of evidence-based medicine and patient-centered care, I show that ideas about gender can actually supersede both medical evidence and patient desires for their bodies in the care of gynecological and breast cancers.


Gene therapy for bone regeneration.
Efficacious bone regeneration could revolutionize the clinical management of many bone and musculoskeletal disorders. Bone has the unique ability to regenerate and continuously remodel itself throughout life. However, clinical situations arise when bone is unable to heal itself, as with segmental bone loss, fracture non-union, and failed spinal fusion. This leads to significant morbidity and mortality. Current attempts at improved bone healing have been met with limited success, fueling the development of improved techniques. Gene therapy in many ways represents an ideal approach for augmenting bone regeneration. Gene therapy allows specific gene products to be delivered to a precise anatomic location. In addition, the level of transgene expression as well as the duration of expression can be regulated with current techniques. For bone regeneration, the gene of interest should be delivered to the fracture site, expressed at appropriate levels, and then deactivated once the fracture has healed. Delivery of biological factors, mostly bone morphogenetic proteins (BMPs), has yielded promising results both in animal and clinical studies. There has also been tremendous work on discovering new growth factors and exploring previously defined ones. Finally, significant advances are being made in the delivery systems of the genes, ranging from viral and non-viral vectors to tissue engineering scaffolds. Despite some public hesitation to gene therapy, its use has great potential to expand our ability to treat a variety of human bone and musculoskeletal disorders. It is conceivable that in the near future gene therapy can be utilized to induce bone formation in virtually any region of the body in a minimally invasive manner. As bone biology and gene therapy research progresses, the goal of successful human gene transfer for augmentation of bone regeneration draws nearer.


Variation in hospital length of stay: do physicians adapt their length of stay decisions to what is usual in the hospital where they work?
To test the hypothesis that physicians who work in different hospitals adapt their length of stay decisions to what is usual in the hospital under consideration. Secondary data were used, originating from the Statewide Planning and Research Cooperative System (SPARCS). SPARCS is a major management tool for assisting hospitals, agencies, and health care organizations with decision making in relation to financial planning and monitoring of inpatient and ambulatory surgery services and costs in New York state. Data on length of stay for surgical interventions and medical conditions (a total of seven diagnosis-related groups [DRGs]) were studied, to find out whether there is more variation between than within hospitals. Data (1999, 2000, and 2001) from all hospitals in New York state were used. The study examined physicians practicing in one hospital and physicians practicing in more than one hospital, to determine whether average length of stay differs according to the hospital of practice. Multilevel models were used to determine variation between and within hospitals. A t-test was used to test whether length of stay for patients of each multihospital physician differed from the average length of stay in each of the two hospitals. There is significantly (p<.05) more variation between than within hospitals in most of the study populations. Physicians working in two hospitals had patient lengths of stay comparable with the usual practice in the hospital where the procedure was performed. The proportion of physicians working in one hospital did not have a consistent effect for all DRGs on the variation within hospitals. Physicians adapt to their colleagues or to the managerial demands of the particular hospital in which they work. The hospital and broader work environment should be taken into account when developing effective interventions to reduce variation in medical practice.


[Correction of erectile dysfunction in patients with benign prostate hyperplasia using daily administration of tadalafil 5 mg against the background of combined drug therapy].
The study included 59 patients with benign prostate hyperplasia (BPH) and erectile dysfunction (ED), inhibited inflammation in the prostate gland and with normal or medically normalized levels of total testosterone. All the patients underwent conservative therapy using dutasteride and tamsulosin, 21 of them (group 2) additionally received tadalafil 5 mg daily. Efficacy of treatment was assessed by self-assessment questionnaire of patients before treatment and 12 weeks after therapy. In group 1 of patients, the dynamics of the erectile function, sexual satisfaction and quality of life for patients was not revealed. In the group 2, improvement in erectile function in an average of 19 points was shown (IIEF-5 questionnaire). According to the AMS questionnaire, improvement in sexual function was demonstrated; in patients with compensated androgen deficiency, however, response to the treatment with tadalafil was less pronounced. According to BSFI score after 3 months of therapy with tadalafil, indicator of overall satisfaction of sexual life improved to 2.4 points (p < 0.002). According to the Hospital Anxiety and Depression Scale, anxiety in patients was reduced to the permissible values (p < 0.0002), the level of depression was decreased by almost 2-fold (p < 0.0002). The total IPSS score decreased from 13 to 9 points in average. The inclusion of tadalafil in complex of combined conservative therapy of patients with BPH not only improves sexual function but has a positive effect on symptoms of the disease and the psychological state of the patient.


Cell fate specification along the anterior-posterior axis of the intermediate mesoderm.
The vertebrate intermediate mesoderm (IM) is highly patterned along the anterior-posterior (A-P) axis. In the chick embryo, the kidney tissue, which is a derivative of the IM, is generated only from IM located posterior to the sixth somite axial level, which also marks the border between cranial and trunk segments. The cellular and molecular mechanisms that govern the formation of the anterior border of the kidney morphogenetic field are currently unknown. In this study, we asked whether specific A-P patterning information is conveyed by the movement of cells through the primitive streak (PS) at different time points that consequently affects the expression of kidney genes, or by the environment that these cells encounter during their migration to the IM. In this study, we show that kidney-inductive signals are present along the whole axis, including anterior non-kidney-generating regions. These inductive signals are generated by tissues that are located medial to the anterior IM. We also demonstrate that cells that migrate through the PS of early embryonic stages (Hamburger and Hamilton stage 3-4 and earlier), which will give rise to anterior nonkidney IM, are competent to respond to these inductive factors. This prospective anterior IM tissue loses its competence to respond to kidney inducing signals during its migration from the PS to its final location in the anterior IM. We present here a model in which changes in cell competence determine the formation of the anterior border of kidney gene expression and discuss the possible evolutionary implications of this developmental mechanism.


Risk Stratification in Acute Pulmonary Embolism: The Latest Algorithms.
Pulmonary embolism (PE) is a common clinical entity, which most clinicians will encounter. Appropriate risk stratification of patients is key to identify those who may benefit from reperfusion therapy. The first step in risk assessment should be the identification of hemodynamic instability and, if present, urgent patient consideration for systemic thrombolytics. In the absence of shock, there is a plethora of imaging studies, biochemical markers, and clinical scores that can be used to further assess the patients' short-term mortality risk. Integrated prediction models incorporate more information toward an individualized and precise mortality prediction. Additionally, bleeding risk scores should be utilized prior to initiation of anticoagulation and/or reperfusion therapy administration. Here, we review the latest algorithms for a comprehensive risk stratification of the patient with acute PE.


The expression of DNA methyltransferases and methyl-CpG-binding proteins is not associated with the methylation status of p14(ARF), p16(INK4a) and RASSF1A in human lung cancer cell lines.
Promoter hypermethylation is an important means for the transcriptional repression of a number of cancer-associated genes. However, the underlying mechanism of this aberration in cancer remains unclear. Here, we examined 5' CpG island methylation status and expression of the p14(ARF), p16(INK4a) and RASSF1A tumor suppressor genes, and investigated the relationship of these factors with the mRNA expression of DNA methyltransferases (DNMTs) and/or methyl-CpG-binding proteins (MBPs) in 30 lung cancer cell lines including 12 small cell lung cancers (SCLCs) and 18 non-small cell lung cancers (NSCLCs). When beta-actin was used as an internal control, the mRNA expression of three DNMTs (DNMT1, DNMT3A, and DNMT3B) and five MBPs (MBD1, MBD2, MBD3, MBD4, and MeCP2) was upregulated in SCLC, while only that of DNMT1, DNMT3B and MBD3 was upregulated in NSCLC, compared with normal lung tissues. However, when normalized using proliferating cell nuclear antigen (PCNA) as an internal control, these differences disappeared or diminished; there was even a significant reduction in the expression ratios of DNMT1, MBD2 and MeCP2 in SCLC and DNMT1, MBD2 and MBD4 in NSCLC. Furthermore, although significant correlations between PCNA expression and mRNA expression levels of the three DNMTs and four of the MBPs (excluding MeCP2) were observed, there was no obvious correlation between promoter hypermethylation of these tumor suppressor genes and the expression level of any of the DNMTs or MBPs. Our results suggest that upregulation of DNMTs and MBPs probably reflects an increased cell proliferation in human lung cancers and that there are likely to exist gene-specific mechanisms for epigenetic gene silencing.


The role of intra-articular injection of autologous platelet-rich plasma versus corticosteroids in the treatment of synovitis in lumbar facet joint disease.
To compare the efficacy between platelet-rich plasma (PRP) and corticosteroids (CS) in improving magnetic resonance imaging (MRI)-detected synovitis in correlation with clinical complaints among patients with lumbar facet joint (FJ) disease. This study was carried out at Eldemerdash Hospital, Cairo, Egypt between September 2019 and January 2021. A prospective, randomized, comparative, single blinded study included 30 patients with lumbar FJ disease, divided into 2 equal groups, received PRP and CS injections. Patients were comparatively assessed before and after the intervention according to number of tender lumbar FJs, maximum active lumbar extension range of motion, LBP visual analogue score, LBP functional disability questionnaires and MRI lumbar FJ detected synovitis and their grading. Both groups showed a significant improvement in all mentioned parameters at follow-up after 3 months. However, PRP injections promoted better performance in terms of MRI synovitis grade in all lumbar FJ levels compared to CS injections. Both PRP and CS injections were effective in improving MRI-detected FJ synovitis while concurrently improving all examined parameters at follow-up after 3 months. However, PRP promoted better improvement in MRI-detected synovitis grade, suggesting that it may be a better treatment option for longer duration efficacy.TRN: NCT04860531- 1/3/2021.


Estimating patterns in the under-reporting of suicide deaths in India: comparison of administrative data and Global Burden of Disease Study estimates, 2005-2015.
It has been proposed that the National Crime Records Bureau (NCRB), which reports suicides in India, differentially underenumerates suicides by geographic and demographic factors. We assessed the extent of potential underenumeration by comparing suicides recorded in NCRB data with recent estimates of Indian suicides developed by the Global Burden of Disease (GBD) initiative. Age-standardised suicide rates were calculated for both data sources by sex, age and state, and rate ratios of NCRB to GBD estimates by corresponding strata were compared to ascertain the relative under-reporting in the NCRB report. The GBD Study reported an additional 802 684 deaths by suicide (333 558 male and 469 126 female suicide deaths) compared with the NCRB report between 2005 and 2015. Among males, the average under-reporting was 27% (range 21%-31%) per year, and among females, the average under-reporting was 50% (range 47%-54%) per year. Under-reporting was more evident among younger (15-29 years) and older age groups (≥60 years) compared with middle age groups. Indian states belonging to low Socio-Demographic Index (SDI) generally had greater underenumeration compared with middle and high-SDI states. NCRB data under-report suicides in India, and differentially by sex, age and geographic area, possibly because of lack of community-level reporting of suicides due to social stigma and legal consequences. While the recent decriminalisation of suicide is expected to improve community-level reporting of suicides, suicide prevention policies should be developed, with a priority to address social stigma attached with suicide and suicidal behaviour, especially among females.


High tumor volume and local recurrence following surgery in osteosarcoma: A retrospective study.
Osteosarcoma is a high grade malignant, osteoid forming, primary bone tumor affecting the metaphysis of long bones. Local recurrence (LR) in osteosarcomas is a sinister. Theoretically, a high tumor volume at the time of presentation will limit surgical margins, involve vital neurovascular bundles and show poor response to chemotherapy thereby causing high rates of amputations (as against limb salvage surgery) and should be associated with poor survival rates. This study evaluated objectively if high tumor volume is a significant predictor of local recurrence (LR) in operated cases of osteosarcomas. Operated cases of osteosarcoma (presenting to the Orthopedic outpatient or the Medical Oncology outpatient between January 1, 2004 and January 1, 2011 were included in the study. Their preoperative clinical data and investigations along with the operative notes were traced from the medical/departmental records. Details of chemotherapy received in the neo-adjuvant and postoperative periods were noted. Besides, all demographic data were also noted. Tumor volume was calculated using the available magnetic resonance images using the formula: ([π/6] × length × width × depth). Post data extraction, patients were divided in two groups, Groups I (without LR) and Group II (with LR). A total of 95 cases of biopsy proven osteosarcomas were identified. Of which 64 were male and 31 females. There were 15 (15.8%) local recurrences. 71% (57/80) patients without LR fell in the age group of 10-20 years, while 66% (10/15) patients with LR were in the age group of 10-20 years. Limb salvage surgery was done in 81.05% (77/95) patients while a total of 18 patients underwent amputation. Of the 80 cases in Group I (without LR), 40 (50%) patients had tumor volume >200 c.c., 30 patients (37.5%) had tumor volume between 50 and 200 c.c. while only 10 patients had tumor volumes <50 c.c. This was in contrast to the tumor volume noted in Group II (with LR) of 15 patients where 8 patients had a tumor volume between 50 and 200 c.c., five had bigger tumor volumes of >200 c.c. and only two patients were smaller in size, with a tumor volume <50 c.c. The mean tumor volume in the group without LR was 406.74 ± 771.67 c.c. as compared with 195.77 ± 226.8 c.c. in the group with local recurrence. Using Mann-Whitney test, the difference between the two groups was found to be statistically insignificant (P = 1.403). We conclude that high tumor volume is not a significant predictor of LR in osteosarcomas thus patients with high tumor masses should not be denied limb salvage. However, we recommend that the decision on attempting limb salvage should not only be based on the tumor volume alone.


No Differences Between Beetroot Juice and Placebo on Competitive 5-km Running Performance: A Double-Blind, Placebo-Controlled Trial.
The authors examine the effect of an acute dose of beetroot juice on endurance running performance in "real-world" competitive settings. In total, 70 recreational runners (mean ± SD: age = 33.3 ± 12.3 years, training history = 11.9 ± 8.1 years, and hours per week training = 5.9 ± 3.5) completed a quasi-randomized, double-blind, placebo-controlled study of 5-km competitive time trials. Participants performed four trials separated by 1 week in the order of prebaseline, two experimental, and one postbaseline. Experimental trials consisted of the administration of 70-ml nitrate-rich beetroot juice (containing ∼4.1 mmol of nitrate, Beet It Sport®) or nitrate-depleted placebo (containing ∼0.04 mmol of nitrate, Beet It Sport®) 2.5 hr prior to time trials. Time to complete 5 km was recorded for each trial. No differences were shown between pre- and postbaseline (p = .128, coefficient variation = 2.66%). The average of these two trials is therefore used as baseline. Compared with baseline, participants ran faster with beetroot juice (mean differences = 22.2 ± 5.0 s, p < .001, d = 0.08) and placebo (22.9 ± 4.5 s, p < .001, d = 0.09). No differences in times were shown between beetroot juice and placebo (0.8 ± 5.7 s, p < .875, d = 0.00). These results indicate that an acute dose of beetroot juice does not improve competitive 5-km time-trial performance in recreational runners compared with placebo.


Defining a role for endoscopic ultrasound in staging periampullary tumors.
The goal of the preoperative workup in patients with suspected periampullary carcinoma is to establish the diagnosis with a high degree of certainty. In this study we compared endoscopic ultrasonography (EUS) and computed tomography (CT) scans for the detection of tumor, lymph node metastasis, and vascular invasion in patients with suspected periampullary carcinoma in order to define a role for EUS in the preoperative staging of these patients. Thirty-seven consecutive patients received EUS and CT scanning followed by operation for presumed periampullary carcinoma during a 30-month period. Both imaging modalities were reviewed in a blinded fashion and the results compared with pathology and operative reports on all patients. Sensitivity, specificity, positive predictive value, and negative predictive value for tumor detection by EUS were 97%, 33%, 94%, and 50%, respectively, compared with 82%, 66%, 97%, and 25% for CT scan. For lymph nodes the values were 21%, 80%, 57%, and 44%, respectively, for EUS compared with 42%, 73%, 67%, and 50% for CT. For vascular invasion, the values were 20%, 100%, 100%, and 89%, respectively, for EUS, compared with 80%, 87%, 44%, and 96% for CT. CT is the initial study of choice in patients with suspected periampullary tumors. EUS is superior for detecting tumor and for predicting vascular invasion. Therefore, EUS should be used for patients in whom CT does not detect a mass and for those with an identifiable mass on CT in whom vascular invasion cannot be ruled out.


Production and differential endocrine regulation of atrial natriuretic peptide in neuron-enriched primary cultures.
To identify factors that directly regulate the synthesis and secretion of atrial natriuretic peptide (ANP) in neuronal cells, we have developed a neuron-enriched primary culture system from fetal rat brains. A number of factors proved of importance in maintaining adequate levels of ANP secretion in such cultures: 1) cultures derived from diencephalon produced much more ANP than cultures derived from diencephalon produced with the distribution of ANP-containing cells in the rat brain; 2) brains from rats at gestational day 17 proved a better source of ANP-secreting cells than brains from rats at gestational day 16; 3) the presence of serum was required in the latter stages of the culture period to allow expression of the ANP gene; and 4) the cultures secreted more ANP when maintained at 39 C vs. 37 C. ANP mRNA transcripts in the neuron-enriched primary cultures were analyzed by S1 nuclease protection and shown to have a transcription start site similar to that employed by rat atrium and fetal hypothalamus in vivo. Dexamethasone and T3, in contrast to their stimulatory effect on ANP production in cardiocyte cultures, suppressed both the release of immunoreactive ANP and the levels of ANP mRNA in the neuron-enriched primary cultures. The cultures incorporated [35S]cysteine into immunoprecipitable ANP. HPLC analysis of 35S-labeled products in the medium revealed that, unlike neonatal cardiocyte cultures, the majority of secreted immunoreactive ANP migrated with the processed form(s) of ANP rather than the prohormone.


Fully electron-transferred donor/acceptor layered frameworks with TCNQ(2-).
In a series of two-dimensional layered frameworks constructed by two electron-donor (D) and one electron-acceptor (A) units (a D2A framework), two-electron transferred systems with D(+)2A(2-) were first synthesized as [{Ru2(R-PhCO2)4}2(TCNQRx)]·n(solv) (R = o-CF3, Rx = H2 (1), R = o-CF3, Rx = Me2 (2), R = o-CF3, Rx = F4 (3), R = o-Me, TCNQRx = BTDA-TCNQ (4), R = p-Me, TCNQRx = BTDA-TCNQ (5), where TCNQ is 7,7,8,8-tetracyano-p-quinodimethane and BTDA-TCNQ is bis[1,2,5]dithiazolotetracyanoquinodimethane). The D(+)2A(2-) system was synthesized by assembling D/A combinations of paddlewheel-type [Ru2(II,II)(R-PhCO2)4] complexes and TCNQRx that possibly caused a large gap between the HOMO of D and the LUMO of A (ΔEH-L(DA)). All compounds were paramagnetic because of quasi-isolated [Ru2(II,III)](+) units with weakly antiferromagnetically coupled S = 3/2 spins via diamagnetic TCNQRx(2-) and/or through the interlayer space. The ionic states of these compounds were determined using the HOMO/LUMO energies and redox potentials of the D and A components in the ionization diagram for ΔEH-L(DA) vs ΔE1/2(DA) (= E1/2(D) - E1/2(A); E1/2 = first redox potential) as well as by previously reported data for the D2A and DA series of [Ru2]/TCNQ, DCNQI materials. The boundary between the one-electron and the two-electron transferred ionic regimes (1e-I and 2e-I, respectively) was not characterized. Therefore, another diagram for ΔEH-L(DA) vs |(2)E1/2(A) - (1)E1/2(A)|, where (2)E1/2(A) and (1)E1/2(A) are the second and first redox potentials of TCNQRx, respectively, was used because the 2e-I regime is dependent on on-site Coulomb repulsion (U = |(2)E1/2(A) - (1)E1/2(A)|) of TCNQRx. This explained the oxidation states of 1-5 and the relationship between ΔEH-L(DA) and U and allowed us to determine whether the ionic regime was 1e-I or 2e-I. These diagrams confirm that a charge-oriented choice of building units is possible even when designing covalently bonded D2A framework systems.


Deliberate Self-Harm in Older Adults: A General Hospital Emergency Department Survey.
Deliberate self-harm (DSH) increases the danger of future suicide death and the risk increases with age. Self-harm in older adults is often associated with greater suicidal intent and lethality. To investigate clinical and psychosocial variables of older patients (age ≥ 65 years) assessed due to DSH, compared with younger adults. Patients admitted to the Emergency Department following DSH during an 8 year period were included. Of 1149 participants, 187 (16.6%) were older adults (age ≥ 65) and 962 (83.4%) were younger adults (< 65). The older adults reported DSH closer to mid-day (P < 0.01) and suffered more frequently from adjustment disorder and depression. Personality disorders and schizophrenia were less commonly diagnosed (P < 0.001). Prescription medication (sedatives and hypnotics) were a more frequent means (88% vs. 71%) of DSH among older patients. Younger patients with DSH used over-the-counter medications (21.9% vs. 6.4%) three times more than did the older patients (P < 0.01). Past DSH was significantly more frequent in younger adults. Following DSH the older patients were frequently admitted for further general hospitalization (P < 0.001). Older adults with DSH are a unique group with different clinical characteristics. There is a need for targeted prevention strategies and education of caregivers regarding DSH in older adults.


Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome.
Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene on the X chromosome, leading to decreased levels of FMR1 protein (FMRP), which causes the array of neuropsychological impairments that define FXS. Because FXS is an X-linked condition, fewer females display FXS and females with FXS are more mildly affected than males, on average. However, there is a considerable variability in terms of severity of affectedness among females with FXS. The current study was designed to investigate potential genetic (FMRP level and ratio of affected to total chromosomes) and environmental factors (maternal psychological distress and closeness in the mother-child relationship) influencing the cognitive (fluid and crystallized intelligence) and behavioral (anxiety and withdrawal) phenotype of females with FXS. We conducted a prospective 3-year longitudinal study of 16 females with FXS (with up to four assessments, each separated by a year) using an accelerated longitudinal design so that we had coverage of the age range of 10-15 years at study start and 13-18 at study end. We focused on both the level of functioning related to chronological age expectations (standard scores) and absolute change in skill (raw scores) over the 3-year period. At a cross-sectional level, fluid intelligence and crystallized intelligence were both predicted by a closer mother-child relationship and lower maternal psychological distress. However, only fluid intelligence was predicted by a lower ratio of affected to total chromosomes. Anxiety and withdrawal were predicted by a higher ratio of affected to total chromosomes. Withdrawal was also predicted by lower closeness in the mother-child relationship and higher maternal distress. In terms of longitudinal change, gains were observed in fluid and crystallized intelligence, whereas anxious and withdrawn behaviors remained stable over visits. Gains in fluid intelligence were solely predicted by FXS biomarkers (higher FMRP level and lower ratio of affected to total chromosomes), while gains in crystallized intelligence were not predicted by any of the biological and environmental variables. Our results show that FXS biomarkers and maternal variables contribute differentially to the cognitive and behavioral features of the adolescent female with FXS. These findings can help in the design of treatment studies aimed at enhancing cognitive and behavioral abilities in the FXS population.


[A cross-sectional study about mental health of farm-workers from Serra Gaucha (Brazil)].
In view of the shortage of population-based rural studies, this research project evaluated the associations between the characteristics of rural work and the occurrence of minor psychiatric disorders (MPD). A cross sectional study was carried out on the 1,282 farm workers of 446 farms. Information about the farms (land extension, agricultural activities, technology and pesticide use) was collected. Demographic and socioeconomic data, characteristics of the work process and mental health indicators were obtained from the workers. MPD were found in 37.5% of the farm workers. The risk was higher on farms with a land extension of from 26 to 50 hectares, and lower where there was an increased level of job technology and schooling. The prevalence of MPD was higher among bean producers and lower among apple producers. Despite the impossibility of defining the direction of the causal link, pesticide poisoning was strongly associated with MPD. The results call attention to the dimension of the problem and to the importance of adopting new policies for the protection of farm workers' mental health.


Prison life: television, sports, work, stress and insomnia in a remand prison.
To compare how prisoners complaining of insomnia and prisoners without sleep problems describe their daily activities, stress factors and the perceived reasons for their sleep quality in prison. 102 randomly chosen remanded prisoners complaining of insomnia and 61 randomly chosen prisoners who did not complain of insomnia. Prisoners complaining of insomnia and those reporting good sleep differed significantly in their lifestyle in prison. A significantly higher percentage of the former than of the latter reported writing letters, diaries or a book in prison, as well as doing "arts-related" activities such as painting and listening to music. A significantly higher percentage of non insomniac prisoners than of prisoners complaining of insomnia practiced sports in prison, watched television, and spent their day discussing and meeting other detainees. PSQI and GHQ scores were significantly different between insomniac and non insomniac prisoners. Insomniac prisoners complained significantly more often than non-insomniac prisoners about sleep disturbances, in the first place by roommates, but also by guards. Activities in prison and stressful events were significant factors associated with the variable "insomnia versus no insomnia" Worries about medical problems (odds ratio: 12.9), being separated or divorced (odds ratio: 8.8), having experienced stressful events during the past week (odds ratio: 8.7), "art" activity (odds ratio: 8.6), and having a GHQ score>10 (odds ratio: 7.7) had the highest odds ratios among the tested covariates. No sports in prison and some activities were also predictors of insomnia when entered separately or conditionally. Our study provides arguments on how to alleviate insomnia in prison: changing conditions of imprisonment is of public health benefit. Increased opportunities to practice sports in prison as well as adequate care for medical problems and psychological support to reduce context related stress should be routinely offered to insomniac prisoners.


Therapy in endocrine disease: treatment of hirsutism in the polycystic ovary syndrome.
Hirsutism is a common medical complaint among women of reproductive age, and it affects the majority of women with the polycystic ovary syndrome (PCOS). Increased rate of androgen production and its availability in tissue represent the main pathophysiological mechanisms responsible for hirsutism. In addition, androgens may be generated de novo in the hair follicle; therefore, circulating androgen levels do not quantify the real exposure of the hair follicle to androgens, as a quota is locally generated. Hirsutism is a clinical sign and not a disease in itself; its presence does not therefore necessarily require treatment, particularly in mild-to-moderate forms, and when an affected woman does not worry about it. Physicians should decide whether hirsutism is to be treated or not by evaluating not only the severity of the phenomenon but also the subjective perception of the patient, which does not necessarily correspond to the true extent of hair growth. In any case, a physician should manage a woman with hirsutism only on the basis of a diagnosis of the underlying cause, and after a clear explanation of the efficacy of each therapeutic choice. Cosmetic procedures and pharmacological intervention are commonly used in the treatment of hirsutism and are discussed in this paper. Importantly, there are different phenotypes of women with hirsutism and PCOS that may require specific attention in the choice of treatment. In particular, when obesity is present, lifestyle intervention should be always considered, and if necessary combined with pharmacotherapy.


The quality of the diet in Malawian children with kwashiorkor and marasmus.
Nutritionists have suggested that kwashiorkor is related to low dietary protein and/or antioxidant intake. This study explored the hypothesis that among Malawian children with severe malnutrition, those with kwashiorkor consume a diet with less micronutrient- and antioxidant-rich foods, such as fish, eggs, tomatoes and orange fruits (mango, pumpkin and papaya), than those with marasmus. A case-control method with a food frequency questionnaire was used to assess the habitual diet. Children with severe childhood malnutrition presenting to the central hospital in Blantyre, Malawi during a 3-month period in 2001 were eligible to participate. The food frequency questionnaire collected data about foods consumed by siblings <60 months of age in the home. It was assumed that the habitual diet of all siblings 1-5 years old in the same home was similar. Dietary diversity was assessed using a validated method, with scores that ranged from 0 to 7. Regression modelling was used to control for demographic and disease covariates. A total of 145 children with kwashiorkor and 46 with marasmus were enrolled. Children with kwashiorkor consumed less egg and tomato than those with marasmus: 17 (15) vs. 24 (31) servings per month for egg, mean (SD), P < 0.01 and 27 (17) vs. 32 (19) servings per month for tomato, P < 0.05. Children with kwashiorkor had a similar dietary diversity score as those with marasmus, 5.06 (0.99) vs. 5.02 (1.10), mean (SD). Further research is needed to determine what role consumption of egg and tomato may play in the development of kwashiorkor.


[Fungal keratitis: review of diagnosis and treatment].
Fungal keratitis is a characteristic infection upon tropical zones, associated with vegetal trauma. Doubt exists about the best diagnostic test and the effectiveness of available treatment. Which is the best diagnostic method for fungal keratitis? And, which is the best management? Fungal culture remains as diagnostic gold standard of fungal elements. As of treatment, natamycin and amphotericin B are the most popular drugs for fungal keratitis and they have not shown effectiveness in randomized controlled trials or systematic reviews. Voriconazole showed effectiveness and security in multiple fungal infections. It may be the drug of choice in optimal conditions, because of its better ocular penetration and wider coverage. However, its high price difficult general application. This review establishes management recommendations and the need to perform studies that address cost-effectiveness analysis of voriconazole for fungal keratitis.


Intracavitary Coronary Artery: An Unusual Coronary Anomaly.
A few case reports of intracavitary coronary arteries (ICCA) have been reported and only a single case series on the coronary computed tomography angiography (CCTA) prevalence rate of ICCA of the right coronary artery (RCA). We describe several cases of ICCA that were noted incidentally and also determine the overall prevalence rate of anomalous ICCA. A retrospective analysis of ICCA was performed consisting of consecutive CCTA cases as well as a group of ICCA from teaching files. To establish a prevalence rate, we reviewed 464 consecutive CCTA referred to our center for transcatheter aortic valve replacement. The presence of ICCA and several imaging features were evaluated. Our cohort comprises a total of 12 patients with ICCA, with 1 patient containing 2 anomalous ICCA. 83.3% of affected patients were adult males, with an average age of 69.8 years. The RCA was the most commonly affected vessel (53.8%). The mean length of the intracavitary segment was 33.4 mm for the RCA and 27 mm for the LAD. No cases involved the left circumflex coronary artery. Six of the cases were identified routinely as part of clinical practice and therefore not included in the prevalence analysis. On review of our transcatheter aortic valve replacement database, there was a 1.3% prevalence rate of ICCA. RCA had a prevalence of 0.4%, whereas LAD had a prevalence of 0.9%. Although rare, our study suggests that ICCA may be more common than previously described. Its presence is important to communicate to clinicians prior to invasive cardiac procedures to prevent potentially catastrophic outcomes.


Serum total protein, albumin and A/G ratio in different grades of protein energy malnutrition.
The serum total protein, albumin and serum A/G ratio was studied on 20 healthy children and 30 children suffering from protein energy malnutrition of different grade such as grade-I grade-II and grade-III. Serum total protein and albumin levels in grade-I grade-II and grade-III PEM were significantly lowers than control. Serum total protein between different grades of PEM was changed but not significantly. Serum A/G ratio of grade-1 & grade-II PEM were high than that of control, but not significantly. Serum A/G ratio of grade I and grade II PEM were higher than that of control, but not significantly. But in grade-III PEM this values were significantly higher than that of control. When comparison were done within the different grades of PEM, it was found that their A/G ratio were changed but not significantly.


Early results of two methods of posterior spinal stabilization in Nigerians.
In this study, early outcomes of the spinous process wiring with vertical strut (SPWVS) were compared with that of standard pedicle screw and rod (PSR) in our patients. We obtained patients' bio-data, diagnosis, investigations, cost of implant, operative circumstances, complications, and outcomes from clinical documentation. Outcome measures, including postoperative infection and persistent/recurrent instabilities, implant related problems, operative blood loss and time and cost, were compared in the two groups of patients. Forty one (M:F-0.9:1) patients had PSR and 35 (M:F-2.2:1) had SPWVS. There was no difference in the occurrence of post-operative instability ( P = 0.630), surgical site infection ( P ≥ 0.416), neurological deficits ( P ≥ 0.461) and implant related complications ( P ≥ 0.461) in the two groups of patients. Cost of implant in the PSR group range from N138,000 (for 2 level fusion) (1USD = N159) to N246,000 (for 4 level fusion) with an average of N192,000 (Standard deviation [SD] N44,090.81) depending on the number of level fused while the cost of implant for SPWVS was N8,000 irrespective of the number of level of fusion being carried out ( P = 0.000). Mean estimated blood loss intra-operatively was higher for PSR (761.33 [SD 396.24] ml) than SPWVS (524.58 [SD 504.70] ml) ( P = 0.005). Mean operation time was 397.17 (SD 122.183) min and 249.44 (SD 130.31) min PSR and SPWVS ( P = 0.000). SPWVS appears to be a good alternative to PSR, especially in our resource limited environment, in view of similar post-operative infection rate, implant complication, stability and post-operative neurological deterioration as well as shorter operation time, less estimated blood loss and much cheaper cost of implant in the former.


Effects of sedimentary sootlike materials on bioaccumulation and sorption of polychlorinated biphenyls.
Bioaccumulation of hydrophobic organic chemicals from sediments containing soot or sootlike materials has been hypothesized to be limited by strong sorption of the chemicals to the soot matrixes. To test this hypothesis, we quantified bioaccumulation of 11 polychlorinated biphenyls (PCBs) into the aquatic oligochaete Limnodrilus sp. exposed to spiked sediment with and without the sootlike materials coal and charcoal. In addition, sorption experiments with sediment containing varying amounts of coal or charcoal were performed to elucidate the accumulation mechanism. Results showed that coal and charcoal (at realistic levels of 1.5% on a dry-wt basis) reduced PCB accumulation in worms 1.2 to 8.5 times when expressed on a mass basis. Moreover, whereas bioaccumulation from pure sediment increased with molecular planarity of the PCBs (toxic potency), it decreased in case of sediments containing coal and charcoal. In contrast to this advantageous effect, it was hypothesized that coal and charcoal had an adverse influence on the habitat quality of oligochaetes: Organisms inhabiting sediment containing coal or charcoal had significantly reduced lipid contents as compared to organisms from pure sediment. Because of these reduced lipid contents, lipid-normalized PCB concentrations in worms and biota-to-sediment accumulation factors (BSAFs) for most PCBs were higher in sediments containing the sootlike materials as compared to those for reference sediment. Also, measured BSAFs for coal- and charcoal-containing sediments appeared to be much higher than estimated on the basis of equilibrium partitioning theory. Sorption experiments revealed that this was caused by much weaker sorption to the sediment-coal/charcoal mixture than calculated assuming linear additivity of sorption capacities of the distinct phases. It was hypothesized that this weaker sorption resulted from competition between PCBs and dissolved organic carbon molecules for sorption sites on coal/charcoal. This points to a sorption process that is much more complicated than generally assumed.


Medical students' experiences of a longitudinal integrated clerkship: a threshold concepts analysis.
Longitudinal Integrated Clerkships (LIC) are known to provide several pedagogical advantages including transformational educational experiences. The study explored the learning experience of undergraduate medical students who undertook a rural LIC in a Scottish primary care setting. This paper presents an analysis of the transformative role of LIC placements using the Threshold Concept (TC) theory. This qualitative study gathered students' perceptions of their LIC experience longitudinally through written and audio diaries over a period of 1-2 months. The issues narrated in diaries were followed-up in individual semi-structured interviews. Transcripts were thematically analysed to identify key characteristics of TCs using a criterion-based approach. Data from 12 audio and nine written diaries, and five interviews led to identification of three inter-connected themes associated with the LIC year: professional identity formation, becoming an agentic learner and comfort with uncertainty. These appeared transformative in nature and resembled threshold concepts in their character and effect. An active and legitimate role in the healthcare team, longitudinality and transdisciplinary learning during LIC placements were contributary towards navigating these thresholds. The LIC exposure provided transformative learning experiences, and a stable environment that facilitated acquisition of specific TCs in the medical students' journey towards becoming a doctor. LIC affordances fostered a transformed view of self, which was more confident in dealing with uncertainty, comfortable in the emerging professional identity, and described having enhanced agentic capabilities.


A Prospective Analysis of Meat Mutagens and Colorectal Cancer in the Nurses' Health Study and Health Professionals Follow-up Study.
Heterocyclic amines (HCAs) in cooked meats may play a role in colorectal cancer (CRC) development. We aimed to prospectively examine the association between estimated intakes of HCAs and meat-derived mutagenicity (MDM) in two cohorts of health professionals, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). In 29,615 men and 65,875 women, intake of the HCAs 2-amino-3,8-dimethylimidazo(4,5-j)quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo(4,5-f)quinoxaline (DiMeIQx), and MDM was estimated using a 1996 cooking questionnaire, the 1994 food frequency questionnaire, and an online database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and to adjust for potential confounders. Estimates for both cohorts were pooled using random-effects meta-analysis. Between 1996 and 2010, 418 male and 790 female CRC cases were identified. Meat mutagen intake was not statistically significantly associated with risk of CRC [highest vs. lowest quintile, pooled HR (95% CI) for MeIQx: 1.12 (0.93, 1.34), p for trend 0.23; PhIP: 1.10 (0.90, 1.33), p for trend 0.35; MDM: 1.03 (0.86, 1.24), p for trend 0.75] or subtypes of CRC defined by tumor location (proximal or distal colon, or rectum). When analyzed by source of meat, PhIP from red but not from white meat was nonsignificantly positively associated with CRC and significantly positively associated with proximal cancers [HR (95% CI) per standard deviation increase of log-transformed intake: PhIP red meat: CRC: 1.06 (0.99, 1.12), proximal: 1.11 (1.02, 1.21); PhIP white meat: CRC: 0.99 (0.94, 1.04), proximal: 1.00 (0.93, 1.09)]. Estimated intakes of meat mutagens were not significantly associated with CRC risk over 14 years of follow-up in the NHS and HPFS cohorts. Results for PhIP from red but not from white meat warrant further investigation. Le NT, Michels FA, Song M, Zhang X, Bernstein AM, Giovannucci EL, Fuchs CS, Ogino S, Chan AT, Sinha R, Willett WC, Wu K. 2016. A prospective analysis of meat mutagens and colorectal cancer in the Nurses' Health Study and Health Professionals Follow-up Study. Environ Health Perspect 124:1529-1536; http://dx.doi.org/10.1289/EHP238.


Effects of surgical septal myectomy on survival in patients with hypertrophic obstructive cardiomyopathy.
The purpose of this study was to determine the effects of surgical resection of muscle layer on the long-term survival of patients with hypertrophic obstructive cardiomyopathy (HOCM). The original study cohort consisted of 552 patients with hypertrophic cardiomyopathy (HCM), including 380 patients with HOCM and 172 patients with nonobstructive HCM. All these patients had a definite diagnosis in our center from October 1, 2009, to December 31, 2012. They were divided into three groups, viz., HOCM with myectomy group (n=194), nonoperated HOCM group (n=186), and nonobstructive HCM group (n=172). Median follow-up duration was 57.57±13.71 months, and the primary end point was a combination of mortality from all causes. In this survival study, we compared the prognoses of patients with HOCM after myectomy, patients with nonoperated HOCM, and patients with nonobstructive HCM. Among the three groups, the myectomy group showed a lower rate of reaching the all-cause mortality with statistically indistinguishable overall survival compared with patients with nonobstructive HCM (p=0.514). Among patients with left ventricular outflow tract (LVOT) obstruction, the overall survival in the myectomy group was noticeably better than that in the nonoperated HOCM group (log-rank p<0.001). Parameters that showed a significant univariate correlation with survival included age, previous atrial fibrillation (AF), NT-proBNP, Cr, myectomy, and LV ejection fraction. When these variables were entered in the multivariate model, the only independent predictors of survival were myotomy [hazard ratio (HR): 0.109; 95% CI: 0.013-0.877, p<0.037], age (HR: 1.047; 95% CI: 1.007-1.088, p=0.021), and previous AF (HR: 2.659; 95% CI: 1.022-6.919, p=0.021). Patients with HOCM undergoing myectomy appeared to suffer from a lower risk of reaching the all-cause mortality and demonstrated statistically indistinguishable overall survival compared with patients with nonobstructive HCM. Multivariate analysis clearly demonstrated myectomy as a powerful, independent factor of survival, confirming that the differences in long-term survival recorded in this study may be due to surgical improvement in the LVOT gradient.


Failure to eradicate ovine footrot associated with Dichelobacter nodosus strain A198 by repeated daily footbathing in zinc sulphate with surfactant.
To investigate the effect of repeated daily footbathing in zinc sulphate on virulent ovine footrot associated with S1, U1 and U5 zymogram types of Dichelobacter nodosus, including the highly virulent S1 strain A198. A field trial with experimentally infected sheep. At week 0, 50 sheep were infected with D. nodosus strains A198 (S1), C305 (U1), BC3993 (U5) and BC3995 (U5). At weeks 1 and 47, respectively, 169 and 235 uninfected sheep were added. At week 60, sheep were allocated to control and treatment groups each containing 220 sheep. Every 2 or 4 weeks to week 113, feet were inspected, and lesions were scored and sampled. Treatment sheep were footbathed in 15 to 18% (w/v) zinc sulphate with surfactant for 5 consecutive days (10 min per day) during week 61. During week 110, the footbathing protocol was applied again, this time to all surviving treatment and control sheep. BC3993 and A198 were isolated from 57% (162 of 285) and 20% (58 of 285), respectively, of new lesions sampled between weeks 3 and 13, and 21% (57 of 271) and 50% (136 of 271) between weeks 49 and 59. Percentages of new lesions associated with C305 and BC3995 remained constant. During the initial 17 weeks after footbathing at week 61, 90% (75 of 83) and 19% (95 of 490) of lesions in treatment and control sheep, respectively, were score 4 or 5, and 94% (47 of 50) and 38% (33 of 87) of those were associated with A198. Repeated daily footbathing did not eradicate virulent ovine footrot because strain A198 produced deep, covert lesions that facilitated the survival of D. nodosus.


A new model of self-organizing neural networks and its application in data projection.
In this paper a new model of self-organizing neural networks is proposed. An algorithm called "double self-organizing feature map" (DSOM) algorithm is developed to train the novel model. By the DSOM algorithm the network will adaptively adjust its network structure during the learning phase so as to make neurons responding to similar stimulus have similar weight vectors and spatially move nearer to each other at the same time. The final network structure allows us to visualize high-dimensional data as a two dimensional scatter plot. The resulting representations allow a straightforward analysis of the inherent structure of clusters within the input data. One high-dimensional data set is used to test the effectiveness of the proposed neural networks.


[The internationalization of health: contextual elements and institutional frameworks of Brazilian cooperation].
The article contextualizes the emergence of an international policy for the Brazilian Unified Health System as the common agenda of the Pan American Health Organization (PAHO) and the Brazilian Ministry of Health. For this purpose, two contextual axes were explored throughout the work. The first discusses the explicit relationship between the development-cooperation-health triad from an international perspective. The second examines the recent evolution of Brazilian foreign policy, particularly with respect to the role it is playing in South-South cooperation on health matters. The contextual framework that defines Brazilian international cooperation with PAHO is emphasized, above all with regard to the implementation of a specific cooperation agreement. The article concludes that this agreement, within the framework of South-South cooperation, is one of the principal institutional mechanisms established to bring about technical cooperation in health in the current setting.