Assessment of asthma control in users of oral anti-asthma medications.

BACKGROUND: Despite guidelines recommending inhalation therapy as the preferred choice, oral therapy is still widely used in the treatment of asthma in India. However, data about the level of asthma control and healthcare use in patients on oral anti-asthma medications are scarce.METHODS: A retrospective study was conducted to assess the level of asthma control and healthcare use in patients taking oral anti-asthma medications.RESULTS: The study population consisted of 381 adults randomly selected from health screening programmes. All subjects were already receiving oral anti-asthma medications; however, up to 72% had not been diagnosed with asthma by their treating doctors prior to the screening programmes. The cohort had a mean age of 48.26 ± 13.83 years (70% males) and mean peak expiratory flow of 245 ± 78.93 mL/sec. The mean Asthma Control Questionnaire 5 (ACQ-5) score was 2.53 ± 1.15, with respectively 33%, 49.3% and 32.6% reporting at least one episode of breathlessness, one emergency doctor visit and one hospitalisation due to asthma or its symptoms in the past year.CONCLUSION: Underdiagnosis and inappropriate management, as indicated by the poor asthma control and increased hospitalisations seen in this study, is probably a key contributor to the increased burden of the disease in India.

Characterization of arrhythmias, evaluation of cardiac biomarkers and their association with survival in calves suffering from foot-and-mouth disease.

INTRODUCTION: Foot-and-mouth disease (FMD) causes mortality in calves due to myocarditis; however, the effects of FMD virus on cardiac arrhythmogenesis and Purkinje cells are unknown. Identifying diagnostic and prognostic markers in FMD-affected calves may be useful in disease management in the endemic countries. MATERIALS AND METHODS: A total of 81 FMD-affected calves were prospectively monitored till death or recovery. Foot-and-mouth disease was diagnosed by serology and reverse transcriptase-polymerase chain reaction (RT-PCR). Electrocardiography was recorded and serum cardiac biomarkers were measured. Histopathological examination of the ventricular myocardium was carried out in the calves that died of FMD (n = 33). Apparently healthy calves (n = 15) served as control. RESULTS: Serology and RT-PCR consistently revealed that the FMD was caused by serotype O virus. Arrhythmias occurred in 62 of 81 (76.5%) FMD-affected calves, of which, ventricular premature complexes (VPCs) were the most common type (22%). The combined mortality rate due to ventricular tachycardia, polymorphic VPCs, and atrial fibrillation was 27.6%. Receiver operating characteristic curve analysis revealed that cardiac troponin I (cTnI) concentrations of ≥1.3 ng/mL were diagnostic of myocarditis with a sensitivity and specificity of 90% and 100%, respectively. Similarly, serum cTnI concentrations of <6.4 ng/mL were a good predictor of survival [odds ratio of 263; 95% confidence interval: 29-2371]. Histopathology of the myocardium revealed hyaline degeneration, necrosis, edema, mononuclear cell infiltration, and disruption by fibroblasts. Atrophy of the Purkinje cells was also present. CONCLUSIONS: FMD induces cardiac arrhythmias and Purkinje cell pathology in the calf. Portable ECG coupled with assay of serum cTnI would help in predicting survival in FMD-affected calves.

Pierre Robin sequence: report of two cases.

Pierre Robin sequence (PRS) or anomalad, a well-recognized presentation, is the association of the first brachial arch malformation. It presents with a classic triad of micrognathia, glossoptosis, and cleft palate. In a neonate with a complete cleft palate, problems with feeding are commonly encountered. Presented here are two cases with PRS in whom palatal obturators were constructed.

RURS' elbow guard: an innovative treatment of the thumb-sucking habit in a child with Hurler's syndrome.

Thumb sucking is the process of sucking on the thumb for oral pleasure. Thumb and finger sucking habits, or nonnutritive sucking, are considered to be the most prevalent of oral habits. Some parents are concerned by thumb sucking and may even try to restrain the infant or child. In most cases, this is not necessary. Most children stop thumb sucking on their own. When older children continue to suck their thumbs, it could mean they are bored, anxious, or have emotional problems such as depression. This article presents a case report of a child with Hurler's syndrome along with thumb sucking/biting habit. Hurler's syndrome, also known as mucopolysaccharidosis I, is a rare condition inherited as an autosomal-recessive trait. It represents the classical prototype of mucopolysaccharide disorder. A unique appliance to prevent thumb sucking/biting was developed and termed as "RURS' elbow guard," which was successfully used to break thumb sucking of the child with Hurler syndrome. The present report also describes the steps in fabrication of this new habit-breaking appliance, which is also designed to protect the finger from the effects of the sucking habit.

Regulation of protein biogenesis at the endoplasmic reticulum membrane.

The biogenesis of most secretory and membrane proteins involves targeting the nascent protein to the endoplasmic reticulum (ER), translocation across or integration into the ER membrane and maturation into a functional product. The essential machinery that directs these events for model secretory and membrane proteins has been identified, shifting the focus of studies towards the molecular mechanisms by which these core components function. By contrast, regulatory mechanisms that allow certain proteins to serve multiple functions within a cell remain entirely unexplored. This article examines each stage of protein biogenesis as a potential site of regulation that could be exploited by the cell to effectively increase the diversity of functional gene expression.

A multistep, ATP-dependent pathway for assembly of human immunodeficiency virus capsids in a cell-free system.

To understand the mechanism by which human immunodeficiency virus type 1 (HIV) capsids are formed, we have reconstituted the assembly of immature HIV capsids de novo in a cell-free system. Capsid authenticity is established by multiple biochemical and morphologic criteria. Known features of the assembly process are closely reproduced, indicating the fidelity of the cell-free reaction. Assembly is separated into co- and posttranslational phases, and three independent posttranslational requirements are demonstrated: (a) ATP, (b) a detergent-sensitive host factor, and (c) a detergent-insensitive host subcellular fraction that can be depleted and reconstituted. Assembly appears to proceed by way of multiple intermediates whose conversion to completed capsids can be blocked by either ATP depletion or treatment with nondenaturing detergent. Specific subsets of these intermediates accumulate upon expression of various assembly-defective Gag mutants in the cell-free system, suggesting that each mutant is blocked at a particular step in assembly. Furthermore, the accumulation of complexes of similar sizes in cells expressing the corresponding mutants suggests that comparable intermediates may exist in vivo. From these data, we propose a multi-step pathway for the biogenesis of HIV capsids, in which the assembly process can be disrupted at a number of discrete points.

A transmembrane form of the prion protein in neurodegenerative disease.

At the endoplasmic reticulum membrane, the prion protein (PrP) can be synthesized in several topological forms. The role of these different forms was explored with transgenic mice expressing PrP mutations that alter the relative ratios of the topological forms. Expression of a particular transmembrane form (termed CtmPrP) produced neurodegenerative changes in mice similar to those of some genetic prion diseases. Brains from these mice contained CtmPrP but not PrPSc, the PrP isoform responsible for transmission of prion diseases. Furthermore, in one heritable prion disease of humans, brain tissue contained CtmPrP but not PrPSc. Thus, aberrant regulation of protein biogenesis and topology at the endoplasmic reticulum can result in neurodegeneration.

A short note on peste des petits ruminants in Karnataka, India.

Retrospective quantitative analysis of epidemiological data on peste des petits ruminants (PPR) from the Department of Animal Husbandry and Veterinary Sciences in Karnataka, southern India, revealed significant information about the disease in this area. In the nine years between April 1998 and March 2007 a total of 624 outbreaks were reported in the state. With the exception of the 12-month period between April 2001 and March 2002 the disease occurred every year. The study shows clearly that incidences were highest during the rainy season and in the dry agro-climatic zones. The density of the PPR-susceptible population in different districts of the state played a major role in disease incidences. Environmental factors also influenced disease occurrence. Vaccination programmes are slowly being taken up in the state. The disease data documented in this study provide information about the endemicity of the disease that can help to formulate an effective strategy for a PPR-control programme in the state.

Effects of periodontal disease on systemic health.

About one in two adults in the United States has periodontal disease. Chronic periodontitis is an oral disease affecting the supporting structures of the teeth leading to progressive loss of the attachment apparatus and bone around teeth. It is characterized by gingival pocket formation and/or gingival recession. The disease is initiated by bacteria and their components like lipopolysaccharide and causes a heightened host inflammatory response. This cascade of inflammatory response ultimately leads to an increased osteoclastic activity and bone loss. Individuals with periodontitis have increased systemic levels of acute phase proteins, plasma antibody levels, coagulation factor, total white blood cell count, neutrophils, C reactive protein (CRP), and cytokines such as INF- gamma (Interferon gamma), TNF-α (Tumor necrosis Factor- Alpha), IL (Interleukin)-1ß, IL-2 and IL-6. As periodontitis works on the same chronic inflammation model seen in systemic diseases, there is sufficient evidence to suggest a bi-directional link between the two. This article summarizes the established associations between periodontal disease and systemic health.

Identification and characterization of murine caspase-14, a new member of the caspase family.

We report here the identification and characterization of a new member of the mouse caspase family, named caspase-14. Northern blot analysis of mRNA from various tissues with caspase-14-specific probe showed a major transcript size of approximately 2.4 kb and variant transcripts of 2.0 kb and 1.5 kb. The major transcript is detected mainly in the liver and to a lesser extent in the brain and kidney. Caspase-14 cDNA encodes a 257-amino acid-long protein that has significant homology to other members of the caspase family. Like other caspases, caspase-14 has a conserved active site, pentapeptide QACRG. However, it lacks an NH2-terminal prodomain or a caspase recruitment domain, suggesting that it could be a downstream caspase that depends on other initiator caspases for activation. Consistent with this, procaspase-14 can be processed in vitro by the death receptor-associated caspase-8 and caspase-10 but not other caspases, and in vivo after stimulation of cells with anti-Fas agonist antibody or Tumor Necrosis Factor-Related Apoptosis Inducing Ligand. Furthermore, procaspase-14 can be cleaved by granzyme B. These observations suggest that caspase-14 may play a role in death receptor and granzyme B-induced apoptosis.

Death effector domain-containing proteins DEDD and FLAME-3 form nuclear complexes with the TFIIIC102 subunit of human transcription factor IIIC.

Death effector domain-containing proteins are involved in important cellular processes such as death-receptor induced apoptosis, NF-kappaB activation and ERK activation. Here we report the identification of a novel nuclear DED-containing protein, FLAME-3. FLAME-3 shares significant sequence (46.6% identical) and structural homology to another DED-containing protein, DEDD. FLAME-3 interacts with DEDD and c-FLIP (FLAME-1) but not with the other DED-containing proteins FADD, caspase-8 or caspase-10. FLAME-3 translocates to, and sequesters c-FLIP in the nucleus upon overexpression in human cell lines. Using the yeast two-hybrid system to identify DEDD-interacting proteins, the TFIIIC102 subunit of human transcription factor TFIIIC was identified as a DEDD- and FLAME-3-specific interacting protein. Co-expression of either DEDD or FLAME-3 with hTFIIIC102 in MCF-7 cells induces the translocation from the cytoplasm and sequestration of hTFIIIC102 in the nucleus, indicating that DEDD and FLAME-3 form strong heterocomplexes with hTFIIIC102 and might be important regulators of the activity of the hTFIIIC transcriptional complex. Consistent with this, overexpression of DEDD or FLAME-3 in 293 cells inhibited the expression of a luciferase-reporter gene under the control of the NF-kappaB promoter. Our data provide the first direct evidence for the involvement of DED-containing proteins in the regulation of components of the general transcription machinery in the nucleus.

Crystal structure of the E2 DNA-binding domain from human papillomavirus type 16: implications for its DNA binding-site selection mechanism.

The crystal structure of the E2 DNA-binding domain from the high-risk cervical cancer-associated strain human papillomavirus type 16 (HPV-16) is described here. The papillomavirus E2 proteins regulate transcription from all viral promoters and are required for the initiation of replication in vivo. They belong to a family of viral proteins that form dimeric beta-barrels and use surface alpha-helices for DNA interaction. Although all E2 proteins recognize the same consensus, palindromic DNA sequence, proteins from different viral strains differ in their abilities to discriminate among their specific DNA-binding sites. The structure reported here reveals that while the overall fold of the HPV-16 E2 DNA-binding domain resembles that of its counterpart from the related viral strain bovine papillomavirus type 1, the precise placement of the recognition helices is significantly different. Additionally, the charge distribution on the DNA-binding surfaces of the two proteins varies; HPV-16 E2 has a much less electropositive surface. HPV-16 E2 is thus less able to utilize charge neutralization of the phosphate groups on DNA to induce bending. These results correlate well with previous solution studies that showed decreased affinity between HPV-16 E2 and flexible DNA target sequences, and enhanced affinity towards A-tract-containing, pre-bent sequences. In summary, the crystal structure of the HPV-16 E2 DNA-binding domain shows that the protein presents a stereo-chemically and electrostatically unique surface to DNA, characteristics that can contribute to its mechanism of DNA target discrimination.

Subunit rearrangement accompanies sequence-specific DNA binding by the bovine papillomavirus-1 E2 protein.

The 2.5 A crystal structures of the DNA-binding domain of the E2 protein from bovine papillomavirus strain 1 and its complex with DNA are presented. E2 is a transcriptional regulatory protein that is also involved in viral DNA replication. It is the structural prototype for a novel class of DNA-binding proteins: dimeric beta-barrels with surface alpha-helices that serve as recognition helices. These helices contain the amino-acid residues involved in sequence-specifying interactions. The E2 proteins from different papillomavirus strains recognize and bind to the same consensus 12 base-pair DNA sequence. However, recent evidence from solution studies points to differences in the mechanisms by which E2 from the related viral strains bovine papillomavirus-1 and human papillomavirus-16 discriminate between DNA targets based on non-contacted nucleotide sequences. This report provides evidence that sequence-specific DNA-binding is accompanied by a rearrangement of protein subunits and deformation of the DNA. These results suggest that, along with DNA sequence-dependent conformational properties, protein subunit orientation plays a significant role in the mechanisms of target selection utilized by E2.

DNA structure and flexibility in the sequence-specific binding of papillomavirus E2 proteins.

The papillomavirus E2 proteins are transcriptional regulators that bind to a consensus DNA sequence ACCG NNNN CGGT. Multiple copies of this binding site are found in the viral genomes. The affinities of the naturally occurring binding sites for the E2 proteins are predominantly dependent upon the sequence of the NNNN spacer. The hierarchies of binding site affinities among the sites present in the viral genomes result in differential occupancy during the viral life-cycle. In turn, this differential binding regulates transcription from viral promoters, including those for the oncogenes E6 and E7. Structural and biochemical studies have shown that E2 proteins bend the DNA to which they specifically bind. Atomic resolution structures of complexes of the bovine papillomavirus strain 1 (BPV-1) E2 protein and DNA show that the protein does not contact the spacer DNA. A direct comparison of the binding of the DNA-binding domains of the E2 proteins from BPV-1 and human papillomavirus strain 16 (HPV-16) to a series of binding sites as a function of the sequence of their central spacer and/or the presence of a nick or gap in one strand of the spacer DNA is presented in this paper. The BPV-1 E2 DNA-binding domain is only moderately sensitive to the nature of the central spacer; less than several fold differences in affinity were observed when the DNA sequence of the spacer was varied and/or a nick or gap was introduced. In contrast, the HPV-16 E2 DNA-binding domain binds to sites containing A:T-rich central spacers with significantly increased affinity. The introduction of a nick or gap into the spacer of these high affinity sequences is very detrimental to HPV-16 E2 binding while comparable nicks or gaps have only small effects in the low affinity sequences. These results suggest that the HPV-16 E2 protein recognizes the structure of the DNA spacer and that the mechanism of DNA-sequence specific binding of the homologous HPV-16 E2 and BPV-1 E2 proteins is significantly different.

Structure of the BPV-1 E2 DNA-binding domain bound to its DNA target.

The dominant transcriptional regulator of papillomaviruses is the E2 protein. In human papillomaviruses, the E2 protein regulates the expression of the E6 and E7 oncogenes. The functions of E2 are mediated subsequent to its specific interaction with a 12 base-pair palindromic DNA target, the E2-BS. Elucidation of the stereochemical basis of DNA target selection by the E2 protein is a key step in understanding transcriptional regulation in these cancer-causing viruses. The crystal structure of the DNA-binding domain of the bovine papillomavirus-1 E2 protein bound to its DNA target reveals a novel DNA-binding and dimerization motif. The protein is a dimeric beta-barrel with alpha helices on the outer surface that function as recognition helices. A complex and interwoven network of hydrogen bonds characterize the specific protein/DNA interface. The DNA is smoothly curved around the E2 beta-barrel and encompasses the recognition helices in successive major grooves.

Studies of powder flow using a recording powder flowmeter and measurement of the dynamic angle of repose.

This paper describes the utility of the dynamic measurement of the angle of repose for pharmaceutical systems, using a variable rotating cylinder to quantify powder flow. The dynamic angle of repose of sodium chloride powder sieve fractions was evaluated using a variable rotating cylinder. The relationship between the static and the dynamic angle of repose is discussed. The dynamic angle of repose of six lots of a multivitamin preparation were compared for inter- and intralot variation. In both cases, no significant differences (p greater than 0.05) were observed. In the multivitamin formulation, lubricants at lower concentration levels did not show a significant effect (p greater than 0.05) on the dynamic angle of repose when compared with flow rates. The effect of different hopper sizes and geometry has been evaluated using the recording powder flowmeter. The results indicate that although different hoppers affect the quantitative nature of the results, the same general trends are apparent. Thus, it appears possible to use a recording powder flowmeter with small quantities of material to predict the effect of formulation and processing variables on the flow of production scale quantities. This paper does not describe a comprehensive evaluation of the pharmaceutical utility of measuring the dynamic angle of repose. However, the results discussed are not encouraging and suggest that the recording powder flowmeter is more sensitive to the effects of formulation and production variables on powder flow.

How much do rural Hispanics know about the adverse health risks of smoking?

The object of this study was to measure knowledge in a rural Hispanic community about the adverse health effects of smoking and to compare knowledge between current smokers and nonsmokers. A survey was administered to waiting room patients (n =137) over 16 years old at three predominantly Hispanic rural community health centers in the central San Joaquin Valley of California. Proportions of respondents who believed that smoking caused a specific consequence were calculated and compared between smokers and nonsmokers by chi-square tests. Likelihood of attributing negative health consequences to smoking was determined and compared between smokers and nonsmokers. A majority of all participants (smokers and nonsmokers) knew that smoking causes lung cancer (93 percent) and emphysema (91 percent). Many fewer participants knew that smoking contributes to problems such as osteoporosis (39 percent) or sexual dysfunction (33 percent). Current smokers were less likely than nonsmokers (P=0.01) to say that smoking causes any adverse health outcome, including those not known to be related to smoking. Although this is a culturally, ethnically and geographically unique group, knowledge of smoking risks among smoking and nonsmoking rural Hispanics is similar to that found in the general population. When compared with nonsmokers, current smokers underestimate the risk that smoking poses to health.

Pseudocyst of the auricle: a new method of treatment.

Pseudocyst of the auricle is a condition where spontaneous serous fluid collection is seen on the lateral surface of the pinna. The aetiology of this condition is not known. Several methods of treatment have been advocated in the past. We report 10 cases of unilateral pseudocyst who were treated with aspiration and pressure dressing by a plaster of Paris cast over the pinna for two weeks.

Red cell distribution width in the diagnosis of iron deficiency anemia.

OBJECTIVE: 1. To compare peripheral smear (PS) and Red cell distribution width (RDW) in diagnosis of Iron deficiency anemia (IDA) in various grades. 2. To study the changes in RDW and PS after therapy. METHODS: Children in the age group of six months to five years with microcytic (MCV<80fl) anemia (Hemoglobin <11 g%) were evaluated. Those who had received blood transfusion and /or were already on iron therapy were excluded. Evaluation included clinical examination, complete blood count (CBC), RDW estimation microscopic examination of peripheral smear, measurement of serum iron and transferrin saturation. Children with IDA were treated with oral iron for 8 weeks and PS, CBC including RDW were repeated. RESULT: Of the 100 children evaluated, 89 had IDA. 48% had mild, 42% had moderate and 10% had severe anemia. Transferrin saturation correlated with severity of anemia. Peripheral smear showed microcytosis and hypochromia in all cases with severe anemia, 61.5% and 22.5% of those with moderate and mild anemia respectively. RDW was suggestive of iron deficiency in 100%, 82.05% and 100% of patient with mild, moderate and severe anemia respectively. CONCLUSION: In the diagnosis of mild and moderate iron deficiency anemia, RDW had a higher sensitivity than PS. Red cell morphology, Hb, PCV and RDW showed significant improvement after iron-therapy.