Aphis consists of more than 500 species, many of them host-specific on a wide range of plants, yet very similar in general appearance due to convergence toward particular morphological types. Most species have been historically clustered into four main phenotypic groups . To confirm the morphological hypotheses between these groups and to examine the characteristics that determine them, multivariate morphometric analyses were performed using 28 characters measured/counted from 40 species. To infer whether the morphological relationships are correlated with the genetic relationships, we compared the morphometric dataset with a phylogeny reconstructed from the combined dataset of three mtDNA and one nuclear DNA regions.The species-rich genus gossypii group unlike in related groups. Most morphological characteristics of the gossypii group were less variable than for the other groups. Due to these, the gossypii group could be morphologically well separated from the craccivora, fabae, and spiraecola groups. In addition, the correlation of the rates of evolution between morphological and DNA datasets was highly significant in their diversification.Based on a comparison of morphological and molecular datasets, we confirmed morphological reduction or regression in the gossypii group and the other species-groups are congruent with their phylogenetic relationships. Analysis of trait evolution revealed that the morphological traits found to be significant based on the morphometric analyses were confidently correlated with the phylogeny. The dominant patterns of trait evolution resulting in increased rates of short branches and temporally later evolution are likely suitable for the modality of Aphis speciation because they have adapted species-specifically, rapidly, and more recently on many different host plants.The morphological separation between the  Aphis Linnaeus, 1758, which contains more than 500 species, is the largest genus within the family Aphididae Aphis species has been based on small differences in morphology, together with host associations, which have played a major part in identifying the species of this group Aphis has diversified to exploit an extremely large number of host plants Aphis species that morphologically resemble one another have been assigned to several groups on the basis of major morphological similarities Aphis fabae Scopoli, 1763, Aphis frangulae Kaltenbach, 1845, and Aphis nasturtii Kaltenbach, 1843, each grouped by morphology and host relationships. In particular, relationships within the species-group of A. fabae in the European region have often been discussed based on host relationships and morphological similarities Aphis species are associated with plant families, such as the craccivora group that feed on plants in the family Fabaceae Aphis species host-specific on Spiraea to the spiraecola group.et al.craccivora group (black-backed species), the fabae group (black species), the gossypii group (frangulae-like species), and the spiraecola group (A. spiraecola), and Kim & Lee Cerosipha del Guercio (gossypii group), Doralis Börner (fabae group), Medoralis Börner (spiraecola group), and Pergandeida Schouteden (craccivora group). Consistent with the morphology-based group designations, the molecular phylogenies showed that members within each species-group are monophyletic fabae group is more closely related to the craccivora and spiraecola groups than to the gossypii group, whose coloration and number and length of setae differ from those of the other three groups. Although these findings imply that in Aphis species, genetic affinities can reflect morphological similarities Recently, two phylogenetic studies using molecular characters confirmed that the associations between species-groups based on morphological similarities are similar to those based on molecular characters Aphis species showing quite small genetic differences Aphis gossypii Glover, 1876 and A. fabae utilizing more than two plant families, most Aphis species are confined to several host plant species within the same genus or to a few genera within the same family Aphis has diversified promiscuously to various unrelated plant families unlike other aphids in the genera Uroleucon, Macrosiphoniella, and Megoura, which have evolved host specialization to one plant family A. taraxacicola, A. clerodendri, A. egomae, and A. sumire within the gossypii group are closely related genetically and morphologically, they feed on host plants belonging to different families, namely Asteraceae, Verbenaceae, Lamiaceae, and Violaceae, respectively Aphis is unusual in aphids, and their adaptation has been predicted to be related to the tendency to morphological simplicity Tests of the evolution morphological characters of Aphis, especially comprising the four species groups, namely the gossypii group, the craccivora group, the fabae group, and the spiraecola group. In particular, morphological separations or affinities were confirmed through comparisons between the species-groups. Multivariate morphometric analysis is generally used to represent complex, multidimensional patterns of variation between host-related populations in polyphagous aphids Aphis. Then, we evaluated the morphometric results in light of the species-group hypotheses and phylogenetic relationships proposed in previous studies Aphis groups. In addition, we examined whether those morphological relationships are correlated with the molecular phylogeny and rates of changes In this study, multivariate morphometric analyses were performed for testing relationships based on morphological similarity of gossypii group (clade G) was highly supported (PP/BL = 1.00/99), and the craccivora, spiraecola, and fabae groups also formed a monophyletic group (clade F) with significant nodal support (PP/BL = 1.00/82). The three unclassified species, A. oenotherae, T. citricidus, and T. odinae, were closely related to clade F, and these three species and clade F formed a sister group to the gossypii group. The remaining unclassified species with morphological characteristics distinct from the species-groups were located in basal positions in the molecular phylogeny. Some species in the fabae or gossypii group (arrowed in The topologies inferred by Bayesian inference (BI) and maximum likelihood (ML) analyses revealed congruent species relationships, as shown in gossypii group species aggregated on the mid-left side and were almost completely separate from species in the fabae + craccivora + spiraecola groups and the unclassified species, which were scattered and mixed on the right side  similarly contributed to the separation by both continuous and meristic characters (figure not shown). The PCA showed . In the axis of PC1, species in the gossypii group were distributed almost entirely according to the order of body size in length.In the first principal component analysis (PCA) plot based on the first two principal components , the ght side . AlthougA showed  that spegossypii and fabae + craccivora groups were almost completely separated by PC1 (55.2%), PC2 (9.0%), and PC3 (5.7%), similar to the first PCA. The plots of gossypii group samples were concentrated on the mid-left side. In contrast, those of the fabae + craccivora groups were largely scattered on the right side. In PC1, the separation of the axis seems to be influenced almost equally by all 14 continuous characters because there is no dominant value among them. Separation by PC2 was caused mainly by two meristic characters: the number of setae on Ant.III and the number of setae on GP. PC3 was largely affected by two continuous characters: the length of SIPH and the length of cauda (figure not shown). In the second PCA  showed that CV1 , CV2 (17.5%), and CV3 (9.7%) separated the  species . The lenaccivora , but thegossypii group from the other species groups  in the first PCA with high significance (P<0.0001)  revealed by PCA or CDA, even although the correlated factors in multivariate analysis, e.g., size-correlation between antenna and HFM, were excluded.In the first ANOVA, seven continuous and two meristic characters separated the <0.0001) . In partgossypii group had relatively shorter branches than did species in the other groups. In the two trees generated using 28 characters and 17 continuous characters, a subclade of eight species in the gossypii group appeared quite divergent from the remaining members, corresponding to a short branch length in the molecular phylogeny and suggestive of rapid diversification in this clade . In particular, the 11 meristic characters were highly correlated with the molecular characters in Mantel test , while the tests with the 17 continuous character set or the 28 all character set were not significant. However, the estimated K-scores indicated that the three distance-optimized trees based on the different morphological datasets were almost congruent in topology and branch lengths, implying similar changes on nodes between the trees.The patristic distances calculated for each morphological dataset were significantly correlated with those of the ML tree estimated from the molecular dataset based on Pearson correlation or Mantel tests . PearsonP<0.05) except for two characters, length of cauda (P = 0.099) and length of setae on Ant.III (P = 0.052). These mean that at least 14 characters, indicating a significance of the group separation in ANOVA (P<0.05), but three others  were rejected by null hypothesis when κ = 1 , which mean that these showed a relatively gradual pace. In particular, the LRs of the 9 characters related to length were estimated to be higher than those of the other meristic characters. The estimates of the parameter δ showed that at least 6 characters indicated temporally later evolution . Although the LRs were estimated relatively low (P>0.05), the other 8 characters ranging from 1.06 to 1.69 also suggested accelerating evolution as time progress, except for two characters, length of 2HT (δ = 0.63) and length of cauda (δ = 0.85), nominally indicating temporally early change of a trait.The estimates of the three scaling parameters and their LR against the log-likelihood of null hypothesis' test fixing parameter  are listed in in ANOVA , are modThe results of LR tests for directional trends showed that the log-likelihood values of Model A  mostly tended to be larger than those of Model B , but length and number of setae on Ant.III similarly showed a directional trend.gossypii group diverged more morphologically from species assigned to the craccivora + spiraecola + fabae groups gossypii group and the cluster of the other three groups in the molecular phylogeny . Consequently, relatively reductive or regressive stasis of morphological characters in the gossypii group made them more morphologically similar to one another than to other species-group.In the morphometric analyses, species in the d Ant.IV , 3. The Aphis, morphological traits appeared to be significantly correlated to molecular characters based on comparisons of rates of evolution  have been become isolated in short divergence times, and this pattern of speciation also similarly appeared in the fabae group  with M. persicaeThe dominant patterns of character evolution revealed by the two parameters, κ and δ, were increased rates in short branches and temporally later evolution . These a rapidly , 4. For P = 0.179 and P = 0.093, respectively). If a directional trend exists, species that have diverged more from the root in the phylogeny will also tend to have changed more morphologically in a given direction Aphis species or divide species-groups, and also have been considered as important diagnostic keys in the taxonomic studies of AphisA. crinosa, A. horii) in the basal position of the phylogeny have longer and much more setae on Ant.III than the others, the directional walk is likely toward regression in Aphis. In particular, these two characters are largely different and tend to diverge between in the gossypii and fabae groups. The former species is characterized by short and sparse setae on Ant.III, while the latter is by relatively long and dense ones. Although we cannot determine what factors historically affected these characteristics to change toward regression in this study, different convergence of these morphological characters between the species-groups need to be considered for their potential adaptive or functional ways  in further study In the analysis of trait evolution comparing Model A and Model B , directiAphis group. Four Toxoptera and Aleurosiphon species were also included in the study due to their close phylogenetic relationship to AphisToxopteraAphis.A total of 40 species were included in the multivariate morphometric analysis . Only thThe specimens examined for this study were obtained from the Insect Museum of the College of Agriculture and Life Sciences in Seoul National University, Seoul, Rep. of Korea; the National Academy of Agricultural Science, Suwon, Rep. of Korea; and the Institute of Czech Academy of Science (Jaroslav Holman & Jan Havelka), Ceske Budejovice, Czech Republic.AphisA morphometric dataset was constructed by measuring/counting 28 characters in 40 species; 17 characters were continuous, and 11 characters were meristic . To obtaAbbreviations for the characters used in the text are as follows: Ant.I, Ant.II, Ant.III, Ant.IV, Ant.V, Ant.VI, Ant.VIb, antennal segments I, II, III, IV, V, VI and the base of Ant.VI, respectively; PT, processus terminalis; ML, mandibular lamina; URS, ultimate rostral segment; HFM, hind femur; HTB, hind tibia; 2HT, second segment of hind tarsus; AbdT.I, AbdT.II, AbdT.III, AbdT.IV, AbdT.V, AbdT.VI, AbdT.VII, AbdT.VIII, abdominal tergite I, II, III, IV, V, VI, VII, VIII, respectively; SIPH, siphunculus; GP, genital plate.c oxidase II ; partial 12S + tRNA-valine + 16S ) and one nuclear gene  for the species including an outgroup species (Schizaphis graminum) from GenBank, and generated corresponding sequences for two species, A. argrimoniae and A. sedi. In addition, sequences of three species  previously used by Coeur d'acier et al. b  sequences for 31 species in this study, as described previously To reconstruct a comprehensive phylogenetic background against which to evaluate morphological relationships between the species groups and to estimate the evolution of characters, we used the phylogeny based on molecular markers which were used in the previous studies L against the generation number using Tracer version 1.4 A maximum likelihood (ML) tree was generated from the combined dataset. The best fit model for each gene was assessed according to the Akaike information criterion as implemented in MrModeltest 2.0 Principal component analysis  was carried out on the morphometric dataset of 40 species using the 28 measured/counted characters to confirm the correlations of species-groups and to determine the main components of variation in the morphological data.A. egomae, A. glycines, A. gossypii, A. ichigo, A. sanguisorbicola, A. sedi, A. sumire) from the gossypii group and seven  from the fabae + craccivora + spiraecola groups, using the 25 morphological characters except for three alate characters (number of rhinaria). Canonical discriminant analysis  was then performed to determine which character(s) contributed most to the separation of each species cluster. We also performed PCA and CDA using 11 meristic characters only, to exclude the effects of highly size-correlated variables between groups.Principal component analysis was performed again on the morphometric dataset of 247 apterous samples from 14 representative species; seven  was performed for each character to evaluate the significances of differences between the Using the ML tree obtained from the combined molecular dataset as a topological constraint, we compared the branch lengths estimated from the three different morphological datasets  used in the first PCA. The lengths of the branches of the morphological datasets were calculated using a Euclidean distance matrix . Comparison of the evolutionary rates between the molecular and morphological traits was conducted using PAUP*4.0b10 We tested hypotheses for the evolution of the 16 major characters, which were estimated as significant according to ANOVA , using PWe first estimated the three scaling parameters, λ (lambda), κ (kappa), and δ (delta), modeled in BayesContinuous, which can allow tests of the tempo, mode, and phylogenetic associations of trait evolution for a given phylogeny For each test, log-likelihood and rate parameter values were explored to find acceptance rates when running the Markov chains of between 20 and 40% as recommended by Pagel and Meade Figure S1Plot of the mean scores on the first two principle components for 14 species representing the gossypii group (red-type symbols) and the craccivora + fabae + spiraecola groups (blue- and purple-type symbols) based on 11 meristic characters.(3.15 MB TIF)Click here for additional data file.Figure S2Plot of the mean scores on the (A) CV1 vs CV2 and (B) CV1 vs CV3 for 14 species representing the gossypii (open circle), the craccivora (blue closed triangle), the spiraecola (red closed square), and the fabae (black closed diamond) groups based on 25 characters.(2.35 MB TIF)Click here for additional data file.Figure S3Plot of the mean scores on the (A) CV1 vs CV2 and (B) CV1 vs CV3 for 14 species representing the gossypii (open circle), the craccivora (blue closed triangle), the spiraecola (red closed square), and the fabae (black closed diamond) groups based on 11 meristic characters.(2.25 MB TIF)Click here for additional data file.Figure S4Picture of the structures and reference parts employed in the morphometric analyses  and alata (H)): A, body; B, antennal segment III; C, second hind tarsal segment; D, ultimate rostral segment; E, seta on abdominal tergite III; F, cauda; G, genital plate; H, antennal segment III–V. Abbreviations are explained in the text.(5.16 MB TIF)Click here for additional data file.Table S1Taxonomic, biological, and species-group information of species used for morphometric analysis.(0.10 MB DOC)Click here for additional data file.Table S2Samples of apterous (Ap.) and alate (Al.) viviparae of species measured/counted for morphometric analysis.(0.07 MB DOC)Click here for additional data file.Table S3GenBank accession numbers of the sequences used in this study.(0.07 MB DOC)Click here for additional data file.


Dear Editor,et al.[We read the article by Parihar et al. and agreet al. Medical et al.4A 32-year-old lady with recurrent episodes of pain and redness in both eyes (BE) for 3 years was referred to our center with uncontrolled high IOP in left eye. She was on topical timolol maleate 0.5%, brimonidine tartrate 0.15%, and dorzolamide 2% twice daily in BE since 6 months and complained of progressive diminution of vision, dark coloration of the sclera, and white opacities on the cornea for 1 year. There was not any history of ocular injury, fever, joint pain, skin lesions, or any other systemic illness.On examination, vision in the right and left eye was 1/60 and 20/200, respectively. Both eyes had vascularized maculoleucomatous corneal opacities, normal anterior chamber depth, annular posterior synechiae, patent peripheral iridectomies, and cataract. She also had bilateral ciliary and intercalary staphyloma more in the right than the left eye. Tonopen reading in the right and left eye was 20 mmHg and 40 mmHg, respectively. Fundus and gonioscopy examination was not possible due to media opacities .B-scan of BE was anechoic. Complete blood counts, ESR, rheumatoid factor, cANCA (antinuclear cytoplasmic antibody), PANCA, antinuclear antibody, HLAB27, chest X-ray, and X-ray of sacroiliac joints were also normal.We diagnosed this patient as bilateral idiopathic healed sclerokeratouveitis with ciliary and intercalary staphyloma with complicated cataract and secondary glaucoma. We planned phacoaspiration with PCIOL and AGV implantation as a single-stage procedure in the left eye under cover of oral prednisolone (1 mg/kg) tapered in 4 weeks. The plate of AGV was placed in the superotemporal quadrant and the tube was covered with the cadaveric scleral graft. Fixing the AGV tube and plate was an extremely uphill task due to thinness of sclera. Using iris retraction hooks, temporal phacoaspiration was performed and a multipiece acrylic foldable PCIOL was implanted in the bag. On the first postoperative day, left eye IOP was 17 mmHg and vision was 20/200. However, on the second day, there were a severe anterior chamber reaction, an exudative membrane over the IOL and iridectomy with an IOP of 22 mmHg and vision of finger counting at 1 m. We performed YAG membranectomy and pigment sweeping of the IOL on the fifth postoperative day. By the seventh day the IOP was 14 mmHg and vision improved to 20/63 and has remained in the lower teens in 2-year follow-up [Figs. We would like to conclude that glaucoma drainage device implantation is an appropriate primary surgical procedure in patients with refractory glaucoma with intercalary staphyloma and can be safely combined with phacoaspiration with PCIOL implantation.


We have investigated whether expression of these trios of genes could predict mammary carcinoma response in dogs and whether tumor slices, which maintain epithelial-mesenchymal interactions, could be used to evaluate drug response Tumors from 38 dogs were sliced and cultured with or without doxorubicin 1 μM for 24 h. Tumor cells were counted by two observers to establish a percentage variation in cell number, between slices. Based on these results, a reduction in cell number between treated and control samples ≥ 21.7%, arbitrarily classified samples, as drug responsive. Tumor expression of PRSS11, MTSS1, CLPTM1 and SMYD2, was evaluated by real time PCR. Relative expression results were then transformed to their natural logarithm values, which were spatially disposed according to the expression of trios of genes, comprising PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2. Fisher linear discrimination test was used to generate a separation plane between responsive and non-responsive tumors.Culture of tumor slices for 24 h was feasible. Nine samples were considered responsive and 29 non-responsive to doxorubicin, considering the pre-established cut-off value of cell number reduction ≥ 21.7%, between doxorubicin treated and control samples. Relative gene expression was evaluated and tumor samples were then spatially distributed according to the expression of the trios of genes: PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2. A separation plane was generated. However, no clear separation between responsive and non-responsive samples could be observed.in vitro responsiveness. Short term culture of mammary gland cancer slices may be an interesting model to evaluate chemotherapy activity.Three-dimensional distribution of samples according to the expression of the trios of genes PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2 could not predict doxorubicin  Human and canine malignant mammary tumors share some epidemiological and clinicopathological features. Incidence in both species increases with age, lifetime exposure to endogenous or exogenous estrogens is a common risk factor, and the majority of malignant mammary gland tumors arises from epithelial tissue -3. In adIn dogs, standard treatment for mammary gland cancer is surgical excision however, chemotherapy recommendation, as well as in women, is based on some prognostic factors. Furthermore, clinical information available in veterinary medicine suggests that drugs that are effective in human breast cancer, such as doxorubicin, cyclophosphamide, 5-fluorouracil and taxanes, may play a role in the treatment of malignant mammary gland tumors in dogs ,9-12.In women, neoadjuvant chemotherapy for breast cancer is associated with the same survival benefit as adjuvant chemotherapy and offers the advantage of an increased likelihood of breast conservation. Many drug regimens have been used for a varied number of cycles and two of the most used drugs, doxorubicin and cyclophosphamide, when given before surgery are associated with 49–85% response rates -15.in vivo assessment of tumor response and the possibility of determination of potential predictive factors, which may influence clinical decision making in the future. However, this potential has yet to be fulfilled, and although predictive factors might help selection of the appropriate treatment for each individual patient, to date, there is no single marker with a predictive value for a patient's response to chemotherapy . Responsive samples were those presenting a reduction in the number of cells equal or higher than 21.7%, between treated and untreated samples  electrophoresis in denaturant conditions (ratio > 1.5).Tissue specimens were pulverized  under liquid nitrogen and total RNA was isolated using Trizol reagent , according to the manufacturer's protocol. All RNA samples were treated with DNaseI for 30 min at 37°C to eliminate genomic DNA contamination. RNA quality and integrity was verified by the Absorbance ATwo micrograms of total RNA was reverse-transcribed using oligo(dT) primer and Superscript II (Invitrogen). Real-time (RT)-PCR was performed using SYBR-green I  in a Rotor-gene system .. All sequences were specific for Canis lupus familiaris.PCR primer sets for SYBR-green I RT-PCR were designed based on the full-length sequences from exons, separated by introns, preferentially located in the coding region, closer to the 3' end of the gene , 1.25 units Platinum Taq Polymerase (Invitrogen), 1× polymerase buffer (Invitrogen), 2.0 mM MgCl2, 200 μM each dNTP, 0.2 μM each primer, 5% DMSO, 0.5 μL BSA 10 mg/mL , and 0.1 μL SYBRRelative expression of the genes of interest was calculated based on the expression of the endogenous housekeeping gene GAPDH. A pool of six samples from canine mammary tissue, collected from a mammary gland far away from the primary tumor site and not affected by any kind of tumor, was considered as a reference sample in all determinations. Reactions were performed in duplicate and CT variation between them was < 1.5. Analysis was performed as recommended by Pfaffl  using thRelative expression results were then transformed to their natural logarithm values. Tumor specimens were then spatially disposed according to the expression of trios of genes. Fisher linear discrimination test was used to generate a separation plane between responsive and non-responsive samples.P < 0.001, Mann-Whitney test) was observed upon treatment.Based on the previous established response criterion, a reduction in the cell number ≥ 21.7% upon doxorubicin treatment, nine samples were considered responsive to doxorubicin and 29 non-responsive , we have also determined gene expression, considering the median percentage variation of cell counting between observers (11.7%) as the cut-off value of drug response. Using this parameter, 18 samples would be considered responsive and 20 non-responsive. However, three dimension distribution of samples based on the expression of the same two trios of genes could not separate tumors, according to response to doxorubicin (data not shown).in vitro may be an interesting model to evaluate drug response as it preserves some of the in vivo characteristics, as the epithelial mesenchymal relationship. An important issue is to guarantee a proper diffusion of oxygen and nutrients to the entire slice, as passive diffusion occurs through only 200 μm. In our study, tumor thickness varied between 300–400 μm and each tumor slice was placed on wells filled with culture medium, allowing them to float; conditions which, were previously shown to be appropriate to organ culture [Tumor slices cultured  culture -22.Slices were exposed to doxorubicin at a concentration of 1 μM, which equals the therapeutic dose in dogs. In addition, a similar concentration (0.84 μM) was shown to be the 50% inhibitory concentration in cell culture of mammary gland tumors, obtained from dogs . Hence, In the present study, nine of 38 samples (23.6%) were classified as responsive to treatment. This response rate was inferior to that observed in women with breast cancer, submitted to neoadjuvant chemotherapy consisting of 4 cycles of anthracyclines, whose objective clinical response may vary between 49 and 85% ,15,26. PAnother aspect to take into consideration is the tumor histological grade. In women, increased clinical response rates were associated with high histological grade ,28. The et al. [Clinical response measured as a reduction in tumor dimension reflects a decrease in tumor cell number. We observed a mean reduction of 13.6% on the cell number and, in accordance to our data, Ciftci et al.  observedIn the present series, the expression of trios of genes MTSS1, PRSS11, CLPTM1 and MTSS1, PRSS11, SMYD2, could not cluster canine samples according to response to doxorubicin. Recent studies indicate that tumors with diverse prognosis present a characteristic gene expression. According to this hypothesis, the primary tumor expression profile may identify patients with an indolent disease from those with an aggressive disease ,32. Our ex-vivo model of tissue slice culture, where epithelial-mesenchymal interactions are maintained, may add information to a model where isolated cells are cultured. In addition, an ex-vivo model allows a closer evaluation of cell heterogeneity associated with each individual tumor. However, although this model may be useful to study some aspects underlying chemotherapy response, conclusive data on predictive factors deserves further validation through clinical studies where patients receive chemotherapy.It is important to emphasize that an in vitro and in vivo drug responses to establish their exact correlation are needed. Moreover, our results on the expression of a few genes emphasize the need to obtain a more detailed gene expression profile, associated with chemotherapy response in canine tumors.Our data suggest that short term culture of mammary tumor slices seems to be an interesting model to evaluate doxorubicin activity. However, parallel comparisons between RAS participated in the design of the study, sample collection, tissue slice culture, PCR assays, and helped to draft the manuscript. STH participated in sample collection, tissue slice culture, and cell counting. MLHK participated in the design of the study, tissue slice culture. PCR assays and revised the manuscript for important intellectual content. HB participated in the design of the study and performed statistical analysis and data interpretation. MMB participated in the design of the study and revised the manuscript for important intellectual content. DFCP performed statistical analysis. MAAKF participated in the design of the study, data interpretation and helped to draft the manuscript.


A newborn baby was admitted for respiratory distress, soon after a Caesarian section performed for acute polyhydramnios in the third trimester. The baby had not cried after birth and, at admission, was moaning, cyanosed, drowsy, limp, and not responding to stimuli; APGAR scores were 4/10, 8/10, and 7/10. The baby showed nasal flaring and sternal and substernal retraction. All neonatal reflexes were absent and there was hypotonia of all the muscles. The baby was put under an oxygen hood, but then required mechanical ventilation.Neuro USG showed no hemorrhage in the germinal matrix or the ventricle. Chest radiographs revealed normal lungs on day 1  but showThe baby succumbed to the respiratory distress.What is the Diagnosis?


Oncogenic osteomalacia is a rare metabolic bone disease characterized by phosphate leakage from the kidney and subsequent hypophosphatemia. It is caused by a phosphaturic factor produced by certain tumours. Removal of such tumours can completely cure the condition. Here, we report the case of a patient who was crippled with oncogenic osteomalacia. Extensive study revealed a tumour deeply located in the pelvis; removal of the tumour resulted in complete recovery. The tumour was identified as a mesenchymal tumour (mixed connective-tissue variant). The diagnostic evaluation, differential diagnosis, and treatment are discussed. Removal of the tumour resulted in reversal of all the biochemical abnormalities and disappearance of the clinical manifestations.mri) of the area was negative for disc prolapse. The patient was treated symptomatically with painkillers. Later, he complained of diffuse bone pain, accompanied by generalized muscle weakness, which led to severe debilitation. He had difficulty walking and standing from a sitting position. There was no family history of a similar condition.A 39-year-old man was referred from the orthopedic clinic to the endocrine clinic for re-evaluation because of suspected metabolic bone disease. His illness had started 3 years earlier, when he complained of low back pain that was progressive and associated with pain in the lower limbs and shoulders. A few months later, he developed limping on the left leg. Initially, a lumbar disease was suspected, but magnetic resonance imaging  was 50 pg/mL . Serum 25-hydroxycholecalciferol was 19 ng/L  and 1,25(OH)2- cholecalciferol was low-normal at 48 pmol/L . Serum protein electrophoresis and thyroid function tests were normal. The patient’s urine was negative for protein and glucose, and no metabolic acidosis was present. Urinary inorganic phosphorus excretion was 18.5 mmol/24 h , calcium was 4 mmol/24 h , and creatinine was 20 mmol/24 h . The maximal rate of renal tubular reabsorption of phosphate to the glomerular filtration rate was 1.84 mg/dL  Biochemical evaluation revealed persistent hypophosphatemia 0.6 mmol/L . Multiple determinations of serum calcium were normal: 2.1, 2.2, and 2.3 mmol/L , but serum alkaline phosphatase was 839, 1910, 2093 IU/L . Urea at 6 mmol/L, creatinine at 60 mmol/L, and sodium and potassium levels were normal. Parathyroid hormone  imaging of the neck, chest, left calcaneus, and right patella showed no soft-tissue masses to indicate the possible location of the tumour. Abdominal, renal, and pelvic ct imaging showed right middle calyceal or parenchymal calcifications. A well-defined enhancing soft-tissue-mass lesion measuring 5×1.2×1 cm was seen medially to the left psoas muscle at the level of lumbar vertebra 4 (L4). This mass contained fatty components and appeared adherent to the left transverse process of L4 , and only a slightly elevated alkaline phosphatase was recorded (300 IU/L). Eighteen months later, the patient was re-evaluated. There were no complaints, and all laboratory investigations showed values within normal ranges. Another re-evaluation, 3 years after removal of the tumour, revealed no symptoms or complaints. Laboratory investigations at that time were also normal.2-cholecalciferol The insidious development of progressive bone pain and muscle weakness is a well known feature of osteomalacia, which may have many causes To date, more than 160 cases of oncogenic osteomalacia have been reported in the literature The clinical signs and symptoms of oncogenic osteomalacia as a neoplastic syndrome are nonspecific and often lead to erroneous diagnosis of joint, muscle, or neurologic disorders. Most patients report bone or muscle tenderness and weakness. Our patient complained of diffuse progressive bone pain over 3 years and had difficulty walking.pth adhr and xlhr The biochemical markers of oncogenic osteomalacia include hypophosphatemia, hyperphosphaturia, decreased tubular phosphate reabsorption, increased serum alkaline phosphatase in the presence of normal calcium, 25(OH) vitamin D, and normal or slightly elevated serum adhr or xlhr unlikely in our patient. There was no role for adjuvant therapy. Treatment with large doses of neutral phosphate presents great risk for the development of tertiary hyperparathyroidism in oncogenic osteomalacia ct imaging and was confirmed by mri. Similar diagnostic procedures, and other newer techniques such as combined positron-emission tomography–ct, are used to detect these tumours 2 vitamin D production In the current case, as in others previously described, not all biochemical markers were present fgf23). Evaluation of this substance and of the phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX), whose loss of function causes adhr and whose mutation causes xlhr, may provide diagnostic clues (fgf23 and PHEX were not evaluated because of an impossibility of performing immunohistochemistry at the time.Patients with oncogenic osteomalacia have been found to have high serum levels of fibroblast growth factor 23 (ic clues  4,5,20. For the first time in Jordan, we describe a patient with oncogenic osteomalacia, stemming from an unusually deeply located mesenchymal tumour in the pelvis. Complete reversal of the clinical and biochemical manifestations was achieved after removal of the tumour. For patients who have a clinical and biochemical picture suggestive of oncogenic osteomalacia, it is of crucial importance to perform a meticulous survey to detect the tumour or tumours responsible.


Chamomilla recutita (L.) Rauschert (Asteraceae), popularly known as chamomile, is a plant used in traditional medicine for various therapeutic purposes. Chamomile essential oil (CEO) is particularly known to inhibit the genotoxic damage produced by mutagens in mice somatic cells. The aim of this research was to determine the inhibitory potential of CEO on the genotoxic damage produced by daunorubicin (DAU) in mice germ cells. We evaluated the effect of 5, 50, and 500 mg/kg of essential oil on the rate of sister chromatid exchange (SCE) induced in spermatogonia by 10 mg/kg of the mutagen. We found no genotoxicity of CEO, but detected an inhibition of SCE after the damage induced by DAU; from the lowest to the highest dose of CEO we found an inhibition of 47.5%, 61.9%, and 93.5%, respectively. As a possible mechanism of action, the antioxidant capacity of CEO was determined using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging method and ferric thiocyanate assays. In the first test we observed a moderate scavenging potential of the oil; nevertheless, the second assay showed an antioxidant capacity similar to that observed with vitamin E. In conclusion, we found that CEO is an efficient chemoprotective agent against the damage induced by DAU in the precursor cells of the germinal line of mice, and that its antioxidant capacity may induce this effect. Each human cell metabolizes approximately 1012 molecules of oxygen per day to generate ATP; however, about 1% of the process results in the production of reactive oxygen species (ROS). ROS are also generated by exposure to radiation and chemical carcinogens ,4.Chamomilla recutita) is an asteraceae plant native to Europe and distributed around the world, except in tropical and polar regions. This plant has been used for its curative properties since ancient Egyptian and Greek times, and at present is frequently used as an antiseptic, antiflogistic, diuretic, expectorant, febrifuge, sedative, anti-inflammatory and anticarcinogen [-bisabolol, guargazulene, and chamazulene [Chamomile  free radical scavenging method, and by determining the total antioxidant activity according to the ferric thiocyanate method.The essential oil extracted from the chamomile flower varies from 0.42 to 2%, and consists of compounds such as bisabolol, chamazulene, ciclic sesquiterpenes, bisabolol oxides, and other azulenes and terpenes ,10. We hChamomilla recutita by steam distillation, and then it was analyzed by gas chromatography to identify the chemical species. Thirteen compounds were determined with this assay, including bisabolol and its oxides, β-farnecene, chamazulene, germacrene, and sesquiterpenes . It was extracted from flowers of terpenes .For the SCE assay, the following chemicals were used: activated charcoal, purchased from Sigma Chemicals , sifted in a sieve (number 200), and neutralized to pH 7.4 with continuous washes of chloridric acid 1M , sodium hydroxide 1M , and deionized water . Corn oil, colchicine, bromodeoxyuridine (BrdU), Hoescht 33258, PBS, EDTA, trypsin, DPPH, α–tocopherol, phosphate buffer, α-cariophylene, and dextrose were purchased from Sigma Chemicals . Linoleic acid was obtained from Fluka Chemicals . Ferrous chloride, iron free ethanol and methanol, amonium thiocyanate, chlorhidric acid, potassium chloride, dibasic sodium phosphate, monobasic potassium phosphate, sodium citrate, citric acid, sodium bicarbonate, sodium chloride, and acetic acid were acquired from J.T. Baker (Mexico City). The Giemsa stain was obtained from Merck (Mexico City), and DAU, 97% pure, from Lemery Laboratories (Mexico City).ad libitum, in a 12 h light-dark period, adjustment time period for the animals was of one week before the administration of the treatments. The protocol was approved by the Committee of Ethics and Biosecurity of the National School of Biological Sciences.The animals used for the SCE study were male mice strain NIH with a mean weight of 25 g. They were obtained from the National Laboratories of Public Health (Mexico City), and maintained in our laboratory in metallic cages at a temperature of 23 °C and 60% humidity, with food  and water Six groups with five animals each were organized for this assay: a negative control group that was administered corn oil orally (0.1 mL), a group positive treated with corn oil (0.1 mL) and DAU administered by intramuscular injection (10 mg/kg), a group administered with 500 mg/kg of CEO, and three groups treated with DAU and CEO  respectively.et al. [Immediately after administration of corn oil and CEO, all animals were treated by intraperitoneal route with an aqueous suspension of BrdU adsorbed to activated charcoal (1.2 mg/kg) so as to obtain the chromatid differential labeling . Twelve et al. . The aniet al. . Six droThe method used was the one described by Burtis and Bucar (2000). Methanolic solutions of CEO , α-tocopherol (1 mg/mL), and α-cariophylene (100 mg/mL) were prepared. Then, aliquots of 50 μL of each solution were added to 5 mL of a methanolic solution of DPPH (0.004%) and vortexed. Every assay was repeated 5 times. The absorbance was measured at 517 nm 30 minutes after the addition of the tested substances to the colored reactive.et al. (1999). Ethanolic solutions of CEO and α–tocopherol were prepared , then, 200 μL of each solution were added to the reaction mixture: 800 μL of ethanolic solution of linoleic acid 2.25%, 1600 μL of phosphate buffer pH = 7, 600 μL of absolute ethanol (iron free), and 800 μL of deionized water. The mixture was placed in a vial protected from light, and stirred in a vortex. Then, five vials were prepared for each tested concentration of CEO, α-tocopherol, in the linoleic acid control group. The mixtures were incubated at 40 °C for 24, 48, 72, 96, 120, 168, 192, and 226 h, and at each time, 50 μL of each vial was diluted in 4.85 mL of 75% ethanol. Then, we added 50 μL of a 30% ammonium thiocyanate solution, as well as 50 μL of a 20 mM solution of ferrous chloride made in 3.5% chlorhidric acid. The absorbance was measured at 500 nm, 3 min after the addition of ferrous chloride.This assay was made according to the one described by Ono Data obtained from the three methods were analyzed using the statistical program INSTAT version 3.0, ANOVA to determine if data were normally distributed within all groups. Thereafter a Student t test was performed to establish the statistical differences between groups in each assay.The results obtained in the SCE assay are shown in in vivo, which concurs with the absence of any acute toxicity and collateral damage in consumers of chamomile.The majority of chemopreventive studies using plant extracts have been made in somatic cells. However, the inhibition of germ cell alterations is also important because of the potential relationship with gonadal tumors and reproductive damage. Anthracyclins such as adriamycin, a chemical structurally related to DAU, and etoposide, are known to alter male germ cells ; moreoveEssential oils of plants are mixtures formed by a variety of chemicals, including terpenes, compounds that are related to different biological effects, such as anti-inflammatory, antioxidant and antimutagenic activities ,19,20. Iin vitro methods in an attempt to explore if this effect is relevant for the chemoprotective action of the oil. The DPPH assay is designed to determine the free radical scavenging capacity of a substance, and DAU can act as an inducer of free radicals increasing the oxidative damage to DNA through various pathways [The antioxidant capacity of CEO was evaluated using two pathways , in partpathways . The tespathways . Our respathways .On the other hand, the ferric thiocyanate assay determines the total antioxidant activity of a substance measuring the inhibition of the amount of peroxide produced during the initial stages of oxidation. The high absorbance indicates the autooxidation of the linoleic acid emulsion due to the formation of alcoxy and hydrogen peroxide radicals ,26. In oIn the present investigation we demonstrated that treatment with CEO significantly prevents the damage induced by DAU in mice, thereby reducing the level of spermatogonial SCE. Our data also suggest that the antioxidant capacity of the oil may be involved in that effect.


Little is known about the effect of family structure on childhood obesity among US children. This study examines the effect of number of parents and number of siblings on children's body mass index and risk of obesity.We conducted a secondary data analysis of the Early Childhood Longitudinal Study — Kindergarten Cohort (ECLS-K), which consists of a nationally representative cohort of children who entered kindergarten during 1998-1999. Our analyses included 2 cross-sectional outcomes and 1 longitudinal outcome: body mass index (BMI) calculated from measured height and weight, obesity defined as BMI in the 95th percentile or higher for age and sex, and change in BMI from kindergarten through fifth grade.P = .05). Children with siblings had lower BMI and were less likely to be obese than children without siblings. We also found that living with a single mother or no siblings was associated with larger increases in BMI from kindergarten through fifth grade.Other things being equal, children living with single mothers were more likely to be obese by fifth grade than were children living with 2 parents (26% vs 22%, Children from single-mother families and, especially, children with no siblings are at higher risk for obesity than children living with 2 parents and children with siblings. These findings highlight the influential role that families play in childhood obesity. Additionally, they suggest that health care providers should consider the structure of children's families in discussions with families regarding childhood obesity. For children, family represents the primary source of social learning, influence, and exposure to and adoption of health habits . Family More recently, studies have found that family structure also affects children's health care and physical health outcomes ,6. Studioverweight has been applied to children whose body mass index (BMI) is at or above the 95th percentile, on the basis of sex-specific BMI-for-age growth charts  is conducted by the National Center for Education Statistics using a nationally representative cohort of children who entered kindergarten during 1998-1999. The sample was drawn from approximately 1,000 schools, including public and private schools and full-day and part-day programs ,18. SampWe used the ECLS-K Longitudinal Public-Use Data File, which combined data from kindergarten, first grade, third grade, and fifth grade, and included 17,565 children at baseline. We constructed the analytic sample as follows. First, we identified children in each round who were from either 2-parent or single-mother families . Next, we included only children who had complete child direct assessment data  from kindergarten , third grade , and fifth grade . Last, we included only observations with positive person-level sample weights.2) and is widely considered one of the best clinical weight criterion for children because BMI in childhood tracks well into adulthood for developing obesity (The study outcomes were 1) BMI as a continuous variable, 2) obesity as a binary variable, and 3) change in BMI from kindergarten to fifth grade as a continuous variable. We used BMI to categorize children's weight status. BMI is calculated by dividing weight in kilograms by the square of height in meters  and indicator variables for the number of siblings, categorized as none (the omitted category), 1, 2, or 3 or more. We defined 2-parent families as families in which both the father and the mother  were living with the child in the household. Correspondingly, we defined single-mother families as families in which the child's mother was living with the child but the father was absent. We excluded single-father families because of their small number.The covariates in the models included the following sociodemographic characteristics: indicator variables for the child's age; sex; race/ethnicity, categorized as non-Hispanic white (the omitted category), non-Hispanic black, Hispanic, or other; family income, categorized as poor , low-income (1.00-1.99 times poverty), middle-income (2.00-3.99 times poverty), or high-income ; mother's education, categorized as high school or less (omitted), high school graduate, some college, or bachelor's degree or higher; and mother's age (at time of child's enrollment in the study), categorized as 24 years or younger (omitted), 25 to 34 years, 35 to 44 years, or 45 years or older. We used the other covariates to capture the child's health at birth: premature birth of more than 2 weeks; birth weight, categorized as less than 2,000 g (omitted), 2,000 to 2,499 g, 2,500 to 2,999 g, 3,000 to 3,499 g, and 3,500 g or more; birth order, categorized as first (omitted), second, or third or higher. We combined birth weight less than 1,500 g with birth weight less than 2,000 g because of the small sample size of very low birth weight children in the ECLS-K cohort .We weighted all analyses by using sample weights provided by ECLS-K that reflect the sample design and survey nonresponse, and we adjusted all standard errors for clustering by using the Huber-White sandwich estimator ,22. We cTo facilitate interpretation of the regression results, we used the method of recycled predictions to obtain the predicted mean values of the study outcomes for each type of family while adjusting for the covariates ,23. SpecAt enrollment in the study , excluding single-father and other family types, approximately one-fourth of the children were from single-mother families . Nearly 2, and 13.0% of the children were obese. In third grade, mean BMI was 18.6 kg/m2, and nearly 21% of the children were obese. In fifth grade, mean BMI was 20.6 kg/m2, and 24% of the children were obese (data not shown).Among all children with measured height and weight in kindergarten, mean BMI was 16.3 kg/mP = .05). Similarly, in third grade, 23% of children from single-mother families were obese, compared with 20% of children from 2-parent families (P = .03). In fifth grade, 28% of children from single-mother families were obese, compared with 22% of children from 2-parent families (P = .003). Moreover, in each grade the number of siblings was negatively associated with the rate of obesity. We also observed similar associations between family structure and BMI.Family structure was significantly associated with the obesity rate . In eachP = .05) were more likely to be obese than their peers from 2-parent families (22%). In every grade we found that children with no siblings had higher BMI and a higher probability of being obese than children with siblings (We obtained adjusted results for BMI and risk of obesity by using the multivariate models and recycled prediction . The numsiblings .P = .02); 3.8 for children with 2 siblings (P = .01); and 3.7 for children with 3 or more siblings (P = .006) (data not shown). However, the increase in BMI from kindergarten to fifth grade did not differ significantly by number of parents in the household.Children living with no siblings had a larger increase in BMI than children living with siblings. The increase in BMI was 4.7 for children with no siblings; 4.2 for children with 1 sibling (P = .02) and Hispanic  children were obese than were white children (12%), and more poor children were obese (15%) than were children from high-income families . Similarly, in third grade, more black  and Hispanic  children were obese than white children (18%), and more poor children  were obese than were children in high-income families (16%). Mother's education also became a significant predictor of obesity in third grade . Results for fifth grade were similar to those for third grade.In kindergarten, more black , 1 to 2 years, 2 to 3 years, or 3 or more years. We found that age spacing between siblings was not associated with BMI or risk of obesity, and accounting for age spacing did not change our other findings.We also examined several variables, including time spent watching television (in fifth grade), fast-food consumption (in fifth grade), exercise (in fifth grade), and child care before kindergarten, to assess whether they mediated or moderated the associations of family structure with BMI and risk of obesity that we found. Among these variables, only weekly television hours  exhibited a small mediation effect for the association of single-mother family with risk of obesity. We found no other mediation effects and no moderation effects.This is the first US study to link family structure to children's BMI and childhood obesity by using a nationally representative cohort . PreviouThe mechanisms through which family structure affects children's weight may be related to differences across types of families in the amount of time and attention parents can devote to nurturing and providing for their children, and to the nature and extent of interactions among siblings ,8,25-27.Whereas having more siblings has been found to have deleterious effects on other indicators of children's well-being, such as cognitive development or educational attainment, we found that having more siblings is associated with lower rates of obesity. Social scientists have observed that additional children in the family may dilute available parental time and resources ,27. TimeOur study has several limitations. As with any observational study, our findings may be subject to omitted variable bias from unobserved parental or family characteristics. In particular, single mothers may differ from married mothers in their attitudes about family, work, and parenting, and these differences in attitudes may influence a child's home and family environment as well as parent-child relationships. These differences in attitudes could also influence parents' choices regarding food or activity for their children. Second, we did not study single-father families or other less common family types; thus, our findings cannot be generalized to these families. Third, CDC growth charts and BMI percentiles are based on data collected when BMI-for-age was stable among children, and thus may not accurately depict current distributions of BMI-for-age .Despite these limitations, our study sheds new light on the role of families in childhood obesity. Our findings suggest that children are vulnerable to increases in BMI and risk obesity in relation to the makeup of their families. A potential implication is that health care providers who treat children should plan and monitor their care in the context of family circumstances. Policies that provide additional support for single mothers, such as increased family leave time or flexible work hours, may help them to achieve healthier lifestyles for their children. Researchers and advocates should consider intervention and prevention strategies that integrate family dynamics, including the promotion of sibling interactions and collaborative activities. National and local initiatives may be more effective with the provision of additional support for single parents. School-based efforts may consider focusing on the promotion of physical activities among children without siblings. Additional research into the mechanisms underlying these relationships could be helpful in addressing childhood obesity in the United States.


Sir,To report a case of serotonin syndrome (SS) resulting in a patient with tramadol abuse being on regimen of sertraline, trazodone for major depression and insomnia.A 55-year-old white man on therapy for major depressive disorder with Zoloft and trazodone since the last 1 year developed sudden delirium, confusion, agitation, tremor, insomnia, diaphoresis, myoclonus, hyperreflexia in lower extremities, mydriasis, tachycardia, and low grade fever with the recent tramadol abuse secondary to worsening knee pain. He had been stable on this medication regimen for 1 year and tramadol was the probable culprit behind the adverse reaction. Battery of lab tests were run on the patient including CBC, BMP, Ammonia level, UDS, BAL, CT Head w/o contrast, MRI Brain, EEG, LP with CSF analysis which were negative. CPK was mildly elevated at 400. He had fever of 100.2 F, fine tremors were present in the upper and lower extremities and myoclonic jerks were noticed. He admitted to tramadol abuse secondary to the worsening knee pain in the last 4-5 days. No evidence of any other co-ingestion. Presumptive diagnosis of Serotonin syndrome was made and the trazodone, sertraline, tramadol were discontinued. Patient required use of chemical restraints on admission secondary to agitation and physical restraints were used for 2 hours due to delirium. Benzodiazepines were given for sedation and control of agitation. He was placed on a cardiac monitor for keeping a watch on the vitals and circulation. His short term memory were impaired and his behavior improved significantly within 24 hours of discontinuation of the offending agents.SS is a potentially life threatening complication of serotonergic polypharmacy. Considered iatrogenic in presentation, it typically occurs after initiation, dose up-titration or abuse of the offending agent to a regimen including other serotonergic agents. All drugs that directly or indirectly increase central serotonin neurotransmission at postsynaptic 5-HT(1A) and 5-HT(2A) receptors can produce SS. Development of SS also varies from person to person depending on individual vulnerability. It is likely due to the serotonin reuptake inhibition by sertraline and trazodone and (+) enantiomer of tramadol. Tramadol is metabolized to an active metabolite, M1, by the CYP2D6 enzyme.Clinicians should be aware of the potential for SS when psychotropic and nonpsychotropic agents are coadministered to certain patients.


Legionella pneumophila.A case of a previously healthy lady with community-acquired pneumonia who progressed to severe acute respiratory distress syndrome, acute renal failure, disseminated intravascular coagulation and sepsis is reported. Treatment with antibiotics and various modes of mechanical ventilation in the intensive care unit were successful. A urinary legionella antigen test was positive for  Legionella is a cause of both community and nosocomial pneumonia. A recent study found that it accounted for 2 to 9% of community-acquired pneumonia. Unless anti-Legionella antibiotics are selected, the mortality of legionellosis has been reported to be 60-70%; the use of appropriate antibiotics decreases mortality to 10-20%. We report a case of severe Legionella pneumonia that was successfully treated with antibiotics, corticosteroid and various modes of mechanical ventilation in the intensive care unit.A 58-year-old white Caucasian British lady, came to the emergency department with a 2 day history of high fever (38.6°C) shortness of breath, productive cough and diarrhoea 3 days after she had arrived from New Jersey.In the emergency department, her respiratory rate was 21/min, blood pressure 88/57 mmHg, and heart rate 116/min and regular and Arterial oxygen saturation was 77% on room air and increased to 90% on 100% oxygen via a face mask. Rales were present in one third of the lung fields bilaterally and Percussion revealed dullness at the base of the right lung, with poor air entry in the right lower base. Additionally, her blood gas results were her blood gas results were, pH: 7.49, PaO2: 4.9 mmHg, PaCO2: 3.8 mmHg, HCO-3: 24 mM, BE: -0.5 mM and SaO2 77%. Her CURB score surprisingly was 1, one point for Low blood pressure.A chest radiograph showed extensive consolidation present throughout the right lung Figure  and therDue to septic shock, acute respiratory distress syndrome and disseminated intravascular coagulation The patient was admitted to the ITU and she was placed on CPAP initially and inotropes were started. The patient's hypoxemia increased, and there was marked progression of the bilateral shadows on chest X-ray, suggestive of ARDS. Hence, the patient was placed on mechanical ventilation, steroid infusion and an antibiotic regime of clarithromycin, ceftriaxone, rifampicin and clindamycin commenced. Because she did not show any signs of improvement, she was transferred to another hospital for ECMO , which she had for 5 days. On hospital day 6, her urine output was low and so she was put on RRT .Legionella antigen was detected in the urine, the diagnosis of Legionella pneumonia was confirmed. Also, Bacteriological examination of sputum disclosed Legionella pneumophila. All her antibiotics were stopped except ceftriaxone, and she was continued on prednisolone for 3 more weeks.On the seventh day after admission, st hospital day, the radiographic findings gradually improved, the patient was taken off the ventilator and placed on CPAP. Moreover, her kidney functions recovered and RRT was stopped and she was moved to a respiratory ward, where she remained for another 4 weeks during which she had nutritional and physiotherapy support. The lady was discharged with almost full range of mobility and independency in day 70th. Table After the 21L pneumophila, which causes an atypical pneumonia. The natural habitat for L pneumophila is fresh water or protozoan biofilms, in which the bacteria parasitize and proliferate inside the protozoa. Once the water is transferred into man-made water reservoirs, the Legionella organisms proliferate. Legionella is transmitted to humans via inhalation of colonized aerosols or droplets, which are produced by air conditioners, cooling towers and condensers, water fountains, shower heads, faucets, whirlpools, ice machines, spas, nebulizers, and humidifiers. Advanced age, immunocompromised state, cigarette smoking, chronic lung disease, and male sex are all risk factors for Legionnaire's disease [Legionnaire's disease is due to  disease .The signs and symptoms are nonspecific and are similar to those of an atypical pneumonia, but more severe. The incubation period is 2 to 10 days; during this time, the signs and symptoms are typically mild. The cough at first is mild and only slightly productive. symptoms are often prominent with diarrhea, nausea, vomiting, and abdominal pain. Examination of the lungs may initially reveal focal rales that will eventually become diffuse. Findings on an initial radiograph of the chest may be normal, but eventually a pulmonary infiltrate will develop .• Cough - 41 to 92 percent• Chills - 42 to 77 percent• Fever > 38.8°C - 88 to 90 percent• > 40°C - 20 to 62 percent• Dyspnea - 25 to 62 percent• Headache - 40 to 48 percent• Myalgia/arthralgia - 20 to 40 percent• Diarrhea - 21 to 50 percent• Nausea/vomiting - 8 to 49 percent• Neurologic abnormalities - 4 to 53 percent• Chest pain - 13 to 35 percentLegionella has a high specificity, but the lowest sensitivity, in part because a 4-fold increase in antibody levels is necessary for detection of the antibodies. Additionally, an antibody response may not be detectable until after 4 to 12 weeks of infection. DNA amplification by polymerase chain reaction (PCR) of Legionella has been reported from patients with pneumonia using throat swab specimens, bronchoalveolar lavage (BAL), urine, and serum. To date, clinical experience has not shown PCR to be more sensitive than culture, and therefore the Centers for Disease Control and Prevention (CDC) does not recommend the routine use of genetic probes or PCR for the detection of Legionella in clinical samples [Four tests are predominantly used: culture of specimens, direct fluorescent antibody test, urine antigen test, and serum antibody assay. The urine antigen test is highly specific, provides rapid results, and is particularly useful because the fact that test positivity can persist for days even during administration of antibiotic. The major disadvantage of the urinary antigen test is that it is specific for L. pneumophila, serogroup 1 only. However, the vast majority of Legionnaires' disease cases from the community are caused by this species and serogroup. specifity of suptum culture is high, however, obtaining an adequate sputum specimen can be difficult. The test for serum antibodies to  samples .Legionella species. The American Thoracic Society and Infectious Diseases Society of America consensus committees on community-acquired pneumonia recommend empiric therapy with azithromycin, either as monotherapy or combined with a β-lactam agent. Monotherapy with a respiratory quinolone such as levofloxacin also is acceptable [The treatment of community-acquired pneumonia without the benefit of diagnostic testing should include empiric treatment for infections caused by several microorganisms, including ceptable ,8.''Started with sever Flu-like symptoms in mid-September, remember nothing until mid- October. Loss of use of limbs continues with tracheotomy made situation very frightening. However, mostly recovered apart from weakness of limbs generally. On- going stomach problems still to be investigated by the GP. My thanks to staff a Glan Clwyd Hospital and at Leicester (ECHO machine) who probably saved my life".Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.IA: analyzed and interpreted the patient data, performed the physical examination, and was a major contributor in writing the manuscript. KK: major contributor in writing the manuscript. SAH: major contributor in writing the manuscript. RH: major contributor in reading and correcting any misspellings in the manuscript. All authors read and approved the final manuscript


To explore the feasibility of bone marrow mesenchymal stem cells (MSCs) transdifferentiating into corneal epithelial cells in a limbal stem cell deficiency (LSCD) model in rats.Rat MSCs were isolated and purified using a gradient isolation procedure. The cells were induced by rat corneal stromal cells (CSCs) in a transwell co-culture system. The induced MSCs were identified by immunofluorescence staining, flow cytometry, and scanning electron microscopy (SEM). A corneal LSCD model was produced in the right eyes of 48 rats by alkali injury. The eyes of 12 rats without any transplant served as controls (Group 1). Amniotic membranes , uninduced MSCs (Group 3), or MSCs induced by CSCs (Group 4), were transplanted onto the cornea of the model (n=12 each). The therapeutic effects of the four groups were evaluated by slit lamp observation, hematoxylin and eosin staining, immunohistochemistry staining, and confocal laser corneal microscopy.Cultivated MSCs were positive for CD29, CD44, and CD90, but negative for CD34, CD45, CD133, and CK12, with typical MSCs characteristics revealed by SEM. After co-culture with CSCs, the induced MSCs expressed positive staining for CK12 with corneal epithelial cell characteristics confirmed by SEM; the induced MSCs were unchanged on the amnion. Compared with the other three groups, the corneal opacity, fluorescence staining, and neovascularization grades were significantly decreased in the induced MSCs group, both on postoperative week four and ten.MSCs induced by CSCs can transdifferentiate into corneal epithelial cells in vitro. The induced MSCs on an amniotic membrane have remarkable effects on the treatment of corneal alkali burn and the reconstruction of the corneal surface of rats. Corneal damage can result from a variety of corneal disorders including keratitis, Stevens-Johnson syndrome, and chemical, mechanical, or thermal injuries. In a severe injury, both the eye limbus and central epithelium could be lost, accompanied by inflammation, neovascularization, and conjunctivalization ,2. The pA lack of LSCs will lead to severe ocular surface abnormalities. In a severely injured cornea, both limbal and central epithelia are absent and conjunctival epithelial cells invade the corneal surface, resulting in an abnormal conjunctiva covering the corneal surface. This process is accompanied by chronic inflammation, persistent epithelial defects, stromal scarring, and neovascularization , produciHowever, because of the exiguity of autograft material, it is not suitable for binoculus sufferers who are unwell as it risks damaging the comparatively healthy eye. Therefore, the key method to resolving this problem is to look for cells that can be easily collected with sufficient quantity and that have the ability to replace LSCs after transplantation .The development of tissue engineering technology has brought hope to address this issue. Research has shown that adult bone marrow has multi-potential mesenchymal stem cells (MSCs) that are easy to isolate and can be directly induced to differentiate into cardiac cells, fat cells, epithelial cells, endothelial cells, nerve cells, bone, cartilage, tendon, and bone marrow stromal cells under different conditions in vitro -13.In this study, we tested whether MSCs have the potential to differentiate into corneal epithelial cells and whether they can be used to treat LSCD. We evaluated the characteristics of MSCs co-cultured with CSCs in a transwell system and further transplanted the induced MSCs seeded on an AM in an LSCD rat model to study the biologic functions of corneal surface reconstruction.Male and female inbred Sprague Dawley (SD) rats aged 6 to 8 weeks were obtained from the Animal Facility of the Fourth Military Medical University, Xi’an, China. All the rats were treated according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.The following antibodies were obtained from Chemicon : CD29/34/45 mAbs. CK12/13 mAbs and phycoerythrin (PE) labeled CD34 were purchased from Santa Cruz . Anti-CD44-fluoroscein isothiocyanate (FITC) was purchased from AbD Serotec . Anti-CD45-FITC, anti-CD90-FITC, anti-CD34-PE, and anti-CD133-PE were purchased from Miltenyi Biotec . Anti-CD71-FITC and anti-CD29-PE came from BD PharMingen . FITC or PE labeled Mouse antirat IgG was purchased from BD Biosciences . Normal Mouse antirat IgG was purchased from Sigma-Aldrich . The transwell system (aperture 0. 45 μm) came from Millipore .6/cm2, which was maintained in a humidified atmosphere of 5% CO2 at 37 °C . Af. Af17]. The selected 48 rats were randomly divided into four groups: the control group , simple AM group , uninduced MSCs seeded on the AM group , and MSCs induced by CSCs seeded on the AM group .The damaged corneal epithelium was carefully keratectomized under anesthesia and then rinsed with normal saline. The grafts were transplanted onto the corneal surface using 10–0 nylon sutures, with the seeded cells face up. After transplantation, a 0.05% dexamethasone gentamicin solution was applied. Finally, the lids were sutured and the sutures were removed seven days later. Dexamethasone gentamicin was applied to the right eye of each rat three times a day. The ocular surface of each rat was evaluated for ten weeks after surgery. The rats were sacrificed and the corneas were extracted and processed for H&E and immunofluorescence staining.t-test; p<0.05 was regarded as statistically significant.All data obtained from corneal surface evaluation were processed by an SAS software package and analyzed by an LSD-Three days after culture, the bone marrow cells began to stretch. The non-adherent cells were removed by changing the cultured media. The spindle-like MSCs distributed widely. There were larger clones on day seven, and the cells grew rapidly and became fibroblast-like with rich cytoplasm and a large nucleus. The cells were tightly adherent and not easy to digest. After three subcultures, the cells were confluent and had a spiral whorl-like outlook .Immunofluorescence staining showed that MSCs expressed the mesenchymal cell marker CD29 , but didAfter culturing for two days, CSCs extended and showed a spindle or irregular triangles outlook. An oval-shaped nucleus was in the middle of the cell and the cytoplasm extended outward. Three days later, the number of cells gradually increased and the cells grew rapidly. The primary cells became confluent on day seven. After passage, the second generation of CSCs was used for the co-culture system.MSCs and CSCs were cocultured in a transwell system for seven days. About half of the induced MSCs’ morphology was square and flat and they gradually became larger . The num6/cm2. The cells began to adhere after 4 h, and fully extended after 28–48 h. The cells grew rapidly and had good viability under the phase contrast microscope. The cells formed single-layer integration on day three, which were clear and did not significantly change morphology compared with the pre-vaccination , cornea neovascularization ≥ 2 (mean 2.42±0.5), and fluorescence staining ≥ 3 (mean 3.25±0.44) were selected for the study. Four rats were not included in the experiment because of a corneal perforation in two and a mild corneal alkali burn in the other two.Four weeks after transplantation, 80% of the rats in the control group showed extremely severe corneal opacity (3.70±0.48) and obvious neovascularization  in Group 1 (control). Neovascularization was seriously invasive (3.13±0.84), while fluorescein staining declined slightly compared with week four ; Table 2LSD-t analysis showed that there were significant differences between Group 1 and the three other groups on corneal opacity, neovascularization grades, and fluorescence staining at both four and ten weeks after transplantation (p<0.05). Meanwhile, the differences were significant between Group 4 and Groups 2 and 3 at ten weeks (p<0.05), but were not significant between Groups 2 and 3 p>0.05; ; Table 2Ten weeks after surgery, in Group 1, the cornea was severely damaged without intact configuration with numerous inflammatory cells and neovascularization infiltration in the stroma . In GrouTen weeks after surgery, the corneal epitheliums of the four groups were evaluated by immunofluorescence staining of CK12 and CK13. In the induced MSCs group, CK12 staining was positive, while CK13 was negative, suggesting that the epithelium was corneal but not conjunctival-derived. In the three other groups, CK12 was negative, while CK13 was positive, suggesting that the epithelium may be conjunctival-derived .Ten weeks after transplantation, in the control group, the cornea cells’ structure was disordered with an ambiguous boundary. Neovascularization appeared in the anterior matrix, while the posterior matrix remained normal. The epithelial cells of the AM group were disarranged with an enhanced reflection, neovascularization and cavity existed in the anterior stroma. In the induced MSCs group, the surface epithelial cells were integrated closely with clear boundaries. There was some neovascularization in the stroma, though the stroma cells proliferated moderately .The stability of the corneal surface plays an important role in maintaining the transparency of the cornea. Above all, LSCs are the source of corneal epithelial cell regeneration. The deficiency of LSCs will lead to serious ocular surface abnormalities, resulting in corneal opacity, diminished vision, etc. At present, there is still no satisfactory treatment for these diseases. It is reported that a limbal stem cell autograft has some positive effects ,2. HowevThe cornea matrix is the micro-environment of the corneal epithelium and LSCs, and plays an important role in maintaining the characteristics of corneal epithelial cells. CSCs can secrete some kinds of autocrine and paracrine cytokines, which would maintain the normal differentiation and proliferation of LSCs with no access to the ultimate division. Recently, it was reported that the niche structure of CSCs has the ability to induce non-corneal epithelial cells to differentiate into corneal epithelial cells . In a trOur study aims to find a better and more convenient seed cell for corneal tissue engineering. We used MSCs to replace LSCs, and found that they could be induced to corneal epithelial cells in vitro by CSCs, in accordance with the other article . Next, wOur results showed that compared with other groups, the induced MSCs group can significantly improve corneal opacity and neovascularization invasion. Ten weeks after the transplantation of the induced MSCs, the corneal epithelium was transparent in 75% of the rats, neovascularization was limited within 2 mm of the limbus, and fluorescence staining and inflammatory cells infiltration were negative. While in the non-induced MSCs and AM transplantation group, the corneal epithelium appeared partially conjunctivalized and various degrees of inflammatory response could be seen. However, the corneal opacity and epithelial defected area were gentler in the Groups 2 and 3 than in the control group. Results of HE staining showed that the corneas in Groups 1, 2, and 3 had epithelial coverage, but this was more likely conjunctival epithelial derived rather than corneal epithelium derived, which was proven by immunohistochemistry results. Corneal confocal laser microscopy results were in line with the above-mentioned results. The results here showed that cultured corneal epithelial cells autologous transplantation seems to be an ideal way to treat corneal surface diseases, which could prevent both allogeneic transplant rejection and ethical problems, though the long-term prognosis needs further study.In conclusion, our findings clearly indicate that MSCs can be cultivated and induced to transdifferentiate into corneal epithelial cells by CSCs in a transwell system. MSCs seeded on a human AM can form an epithelial graft that can be transplanted and that reconstruct the corneal epithelial surface of a rat’s eyes with an alkali burn injury. However, there are still several problems left, such as whether the extrinsic transplanted MSCs can keep the epithelial cell characteristics in the recipient eye and whether these cells have stem cell function to maintain the normal corneal homeostasis for long-term observation. Further studies are needed to provide more reliable proof for the clinical application of MSCs in the future.


Simvastatin reduces cardiovascular mortality and morbidity but, as with other HMG-CoA reductase inhibitors, can cause significant muscle toxicity and has been associated with elevations of liver transaminases.Muscle and liver adverse effects of simvastatin 40 mg daily were evaluated in a randomized placebo-controlled trial involving 20,536 UK patients with vascular disease or diabetes .The excess incidence of myopathy in the simvastatin group was < 0.1% over the 5 years of the trial, and there were no significant differences between the treatment groups in the incidence of serious hepatobiliary disease.Among the many different types of high-risk patient studied , there was a very low incidence (< 0.1%) of myopathy during 5 years treatment with simvastatin 40 mg daily. The risk of hepatitis, if any, was undetectable even in this very large long-term trial. Routine monitoring of liver function tests during treatment with simvastatin 40 mg is not useful.ISRCTN48489393 The HMG-CoA reductase inhibitor simvastatin is widely used to lower LDL cholesterol and reduce cardiovascular risk. The subSince their introduction in the 1980s, statins have been recognised to have occasional adverse effects on muscle and liver, with the former of greater clinical importance. Few drugs have toxic effects on skeletal muscle, but all statins occasionally cause myopathy -13. In tTreatment with lipid lowering therapy, including statins, tends to increase hepatic transaminases, but clinical hepatitis is uncommon during statin therapy,17. Rout) and are summarised below. The study was carried out in accordance with the principles of the Declaration of Helsinki and had ethics approval from Local Research Ethics Committees at each of the study sites (the study commenced prior to the advent of Multicentre Research Ethics Committees in the UK).Details have been reported previously-6,8-10 ; their own doctor considered statin therapy to be clearly indicated or contraindicated; they had suffered a stroke, myocardial infarction or hospitalisation for angina pectoris within the previous 6 months; they had chronic liver disease or evidence of abnormal liver function  any adverse effects, appeared to be non-compliant or wished to drop out for any reason during run-in were not to be randomized. The use of simvastatin during run-in also allowed an indirect randomized comparison of post-randomization outcomes in participants who appeared to have a large cholesterol-lowering response to simvastatin versus those with a small response between the screening and randomization visits.Participants were randomly allocated to receive simvastatin 40 mg daily or matching placebo tablets for about 5 years . RandomIf any SAEs were considered by the participant, study nurse or managing clinician to be possibly drug-related, or if there were potentially serious abnormalities in any safety blood tests, the participant was advised, at least temporarily, to stop the relevant study treatment. The protocol defined the following algorithms for the assessment of possible muscle or liver abnormalities during follow-up:Symptoms of myopathy  would rALT >4 × ULN was to be checked within about 1 week, while ALT >2 × ULN but ≤ 4 × ULN was to be checked within about 3 weeks. If the repeat ALT was >4 × ULN, then study treatment was to be stopped temporarily; whereas if it was >2 but ≤ 4 × ULN, ALT was to be checked again in about 3 weeks, with study treatment then stopped temporarily only if ALT remained >2 × ULN. After stopping study treatment temporarily, ALT was to be checked again in about 6 weeks and study treatment stopped permanently if still >1.5 × ULN . If, on the other hand, ALT was ≤ 1.5 × ULN, then the allocated study treatment would be started again, with 2 further early recall visits at 3-week intervals at which ALT must remain ≤ 2 × ULN, otherwise the study treatment was to be stopped permanently.Differences in proportions of those allocated simvastatin versus those allocated placebo were assessed using standard parametric methods and an intention-to-treat approach. No adjustment has been made for multiple hypothesis testing, but due allowance is made in the interpretation of the results.The investigators were responsible for the study design, data collection, data analysis, data interpretation, and writing of the report, independently of all funding sources.Between July 1994 and May 1997, 63,603 people were screened in 69 UK study clinics. Of these, 32,145 patients entered the pre-randomization run-in period, and 20,536 patients were randomized. Reasons for not entering the run-in period have been reported previously. Of thosTwo of 32,145 patients who entered the run-in period developed myopathy while taking simvastatin and did not proceed to randomization. One of them was hospitalized with worsening renal failure, but both patients recovered. In addition, one patient had a serious rectal bleed during run-in which was attributed to an interaction between simvastatin and his anti-coagulation medication leading to a high international normalised ratio (INR). Other than these 3 patients, none of the 410 patients  and 5082 women were randomized. Mean age at study entry was 64.0 years (SD 8.4), with 5806 aged at least 70 years. The mean duration of follow-up was 5.0 years for all randomized participants: 5.3 years for those who survived to the scheduled end of study treatment and about half that for those who did not . Baseline characteristics, compliance with study medication and changes in blood lipid levels have been presented previously  simvastatin vs 5 [0.22%] placebo).Among 32,145 patients who started the run-in period for HPS, 2% (656) of patients with abnormal liver function tests in blood collected at the screening visit were withdrawn during the placebo phase. No patient who attended the randomization visit failed to proceed to randomization because of an abnormal liver function test after taking 4–6 weeks of active simvastatin during the run-in period, but 6 randomized patients were subsequently found to have ALT >3 × ULN in blood collected at the randomization visit. None of these elevations persisted on repeat testing when these patients were no longer taking simvastatin  and none was discontinued from study treatment. Consequently, the pre-randomization run-in period in HPS is not likely to have biased the assessment of the effects of 5 years of treatment with simvastatin 40 mg daily on the risks of clinical hepatitis. Consequently, most regulatory agencies have now allowed the recommendations in the prescribing information for simvastatin to indicate that routine liver monitoring is not needed for doses of simvastatin up to and including 40 mg daily. It remains uncertain whether, these conclusions can be extrapolated to simvastatin 80 mg daily , and this is now being assessed as part of a large-scale direct randomized comparison of 80 mg versus 20 mg simvastatin daily,25.The present results provide further evidence of the safety of long-term treatment with simvastatin 40 mg daily. The risk of myopathy was rare, with an incidence of less than 0.1% over 5 years, and there was no evidence that simvastatin 40 mg daily causes clinical hepatitis. Routine monitoring of liver function tests during treatment with simvastatin at daily doses up to 40 mg did not appear to be of value, at least in patients with liver function tests that were normal prior to starting treatment.The Clinical Trial Service Unit has a staff policy of not accepting honoraria or other payments from the pharmaceutical industry, except for the reimbursement of costs to participate in scientific meetings. Coordinating centre members of the writing committee  have, therefore, only had such costs reimbursed. J Tobert is a retired employee of Merck and Co, holds stock options granted when he was an employee, and has provided consultant services to Merck and other companies with lipid-lowering products.MRC/BHF Heart Protection Study Collaborative GroupWriting Committee-Jane Armitage, Louise Bowman, Rory Collins, Sarah Parish and Jonathan TobertJA was involved in data collection, analysis and interpretation, and drafted the manuscript. LB was involved in data collection, analysis and interpretation, and drafting of the manuscript. RC conceived and designed the study, was involved in data collection, analysis and interpretation, and drafting of the manuscript. SP was involved in data collection, analysis, validation and interpretation. JT was involved in the study design and interpretation, and drafted the manuscript. All authors provided comments on and approved the final manuscript.Steering Committee-R Collins , T Meade (chairman), P Sleight (vice-chairman), J Armitage , S Parish and R Peto (statisticians), L Youngman (laboratory director), M Buxton, D de Bono (deceased), C George, J Fuller, A Keech, A Mansfield, B Pentecost, D Simpson, C Warlow; J McNamara and L O'Toole (MRC observers).Data Monitoring Committee-R Doll , L Wilhelmsen (vice-chairman), K M Fox, C Hill, P Sandercock.Collaborators-listed in reference 3.The pre-publication history for this paper can be accessed here:


Heart failure is one of the major health care issues in the Western world. An increasing number of patients are affected, leading to a high rate of hospitalization and high costs. Even with administration of the best available medical treatment, mortality remains high. The increase in left ventricular volume after a myocardial infarction is a component of the remodeling process. Surgical Ventricular Restoration (SVR) has been introduced as an optional therapeutic strategy to reduce left ventricular volume and restore heart geometry. So far, it has been established that SVR improves cardiac function, clinical status, and survival in patients with ischemic, dilated cardiomyopathy and heart failure. Since its first description , SVR has been refined in an effort to standardize the procedure and to optimize the results. This review will discuss the rationale behind surgical reversal of LV remodeling, the SVR technique, its impact on cardiac function and survival, and future expectations. Heart failure (HF) remains a major public health problem. Almost 5 million patients in the United States are affected, and 30 to 40% of patients die from HF within 1 year after receiving the diagnosis , 3. HearLeft ventricular remodeling is the process by which mechanical, neurohormonal, and possibly genetic factors, alter ventricular size, shape, and function. Remodeling occurs in several clinical conditions, including myocardial infarction (MI), cardiomyopathy, hypertension, and valvular heart disease.Myocardial infarcts (MI), particularly large, transmural infarcts, result in a number of structural changes involving both the infarcted and non-infarcted zones . LV remoSVR has been developed with the goal of improving cardiac function through a reduction in LV wall tension in accordance with the principle of Laplace’s law. Since LV wall tension is directly proportional to the LV internal radius and pressure, and inversely proportional to wall thickness, any intervention to optimize this relationship would be beneficial in terms of improving wall compliance and reducing filling pressure. Optimization may also be beneficial in terms of enhancing the contractile performance of the LV by increasing the extent and velocity of systolic fiber shortening .2 for preoperative LVEDV < 150 mL/m2 or 70 mL/m2 for preoperative LVEDV > 150 mL/m2. It was removed before closure of the ventricle. Later, the procedure was adopted by many skilled and creative surgeons without real standardization, making results difficult to compare. McCarthy described a no-patch, double purse-string suture technique [TM, Chase Medical Richardson, TX), which is illustrated in Fig. (1) [After the first description of the linear suture by Cooley in 1958 , and theechnique ; MenicanFig. (1) . The man2) [The mannequin is removed before closure of the LV cavity, which is done with a direct suture if it is less than 3 cm large, or with an elliptical, synthetic patch if greater than 3 cm. Regardless, the mannequin is useful in giving the surgeon the correct position of the apex and avoiding sphericalization of the ventricle. The reconstruction of the apex can be difficult when the apical and inferior regions are severely dilated. To overcome this difficulty, Menicanti applied a modification of the Dor procedure that involves plication of the distal inferior wall before patch placement, thus placing the apex in a more anterior position as illustrated in Fig. (2) , 22.When indicated, the mitral valve is repaired through the ventricular opening with a double arm stitch running from one trigone to the other, embedding the two arms in the posterior annulus of the mitral valve. After that, the suture is tied to undersize the mitral orifice . 2. This study reported an improvement in EF from 29.6 ± 11.0% preoperatively to 39.5 ± 12.3% postoperatively (p < 0.001) and a decrease in LVESVI from 80.4 ± 51.4 ml/m2 preoperatively to 56.6 ± 34.3 ml/m2 postoperatively (p < 0.001). Thirty-day mortality after SVR was 5.3%, with this value being higher among patients in whom mitral valve repair was performed along with SVR (8.7%), versus patients in whom no mitral valve procedure was required . The overall five-year survival was 68.6 ± 2.8%. After five years, 78% of patients were not readmitted to the hospital for CHF. Surprisingly, in 2004, Mickleborough reported the results from a smaller group of patients (245) showing a lower in-hospital mortality rate (2.8%); one, five, and ten- year survivals were 92%, 82%, and 62% [1 shows a summary of the data from the literature.The first consistent results using SVR were reported by Dor and co-authors. They showed that the procedure improves LV function, NYHA functional class, and survival by reducing ventricular volumes and increasing the ejection fraction (EF). These results were observed not only in patients with classic dyskinetic aneurysms, but also in those with dilated ischemic cardiomyopathy and severe LV dysfunction. -26. More and 62% . PatientHow and when mitral regurgitation should be corrected during SVR, is still a topic of debate. In the failing heart, mitral regurgitation occurs secondarily to annular dilatation, altered left ventricular geometry, and papillary muscle dysfunction , 41. VolSVR has the potential to improve mitral functioning by reducing LV volumes, papillary muscles distances , and rebuilding a more normal heart geometry , 48, 49.Despite excellent contributions supporting SVR as a therapeutic strategy for patients with ischemic HF, few data are available on LV diastolic function (DF) in patient undergoing SVR. The ventricular remodeling following an acute myocardial infarction is accompanied by changes in diastolic properties of the LV due to scar formation. This, in turn, increases chamber stiffness and compensatory hypertrophy of the remote zone, which causes delayed relaxation . In turn3) [It is reasonable to assume that the geometric implications, as well as the volume of the residual LV cavity, may affect the diastolic function in patients undergoing SVR. We addressed this issue in a recent paper . One hun3)  and the The complex sequence of the events leading to LV remodeling involves the presence of electrically unexcitable scars. This predisposes the LV to electrical heterogeneity, which in turn, induces non-uniform contraction, relaxation, and filling with further deterioration of global systolic and diastolic function. Cardiac resynchronization therapy (CRT) has resulted in enhanced quality of life, improved symptoms, and improved survival in patients with refractory heart failure due to systolic dysfunction and mechanical dyssynchrony as defined by wide QRS , 61. AltWith an eye to the fact that SVR attempts to exclude the scarred tissue, our group reported data from a prospective study conducted on thirty patients undergoing SVR at the Cardiothoracic Center of Monaco . PatientThe increased risk for life-threatening arrhythmias after a myocardial infarction is related to the complex sequence of events leading to LV remodeling. These events include LV dilatation, which, in turns, increases wall stress and stretch (stretch is arrhythmogenic per sè), and to the presence of electrically unexcitable scars. Our group has previously demonstrated that patients with ventricular arrhythmias (spontaneous or inducible) have end-diastolic and end-systolic volumes significantly larger than those seen in non-inducible patients , 66. SVRBrain natriuretic peptide (BNP) and its precursor, N-terminal pro-brain natriuretic peptide (NT-pro-BNP), are synthesized in the myocytes and released during hemodynamic stress. This stress occurs when ventricles are dilated, hypertrophic, or subject to increased wall tension . The proPrevious studies have demonstrated that BNP is a valuable biomarker for LV remodeling as its activation is more pronounced in patients with functional MR rather that in those with organic MR, and it may predict mortality and morbidity in patients with chronic HF -74. UsinTo date, the data reported in the literature support the benefit of SVR in improving cardiac function and survival in patients with dilated ischemic cardiomyopathy and heart failure. However, the limitations of different studies are still considerable and make the results presently inconclusive. First, the majority of studies are retrospective and are not powered to address specific end-points either for the number of patients, the limited number of events, or for the length of the follow-up. Second, physiologic studies based on invasive measurements (pressure-volume relationships) have been conducted only on small series of patients. Also, the postoperative measurements were made immediately after the completion of the surgical procedure, or at most, ten days after surgery. Additional information will be provided from these studies performed at later time points. Third, the lack of a control group is one of the major limitations of these studies, and the combination of SVR and coronary artery bypass surgery in the majority of the study groups does not allow for evaluation of the specific role of each procedure. Fourth, different surgical techniques and operative protocol must be taken in account in interpreting the results.Surgical Treatment for Ischemic Heart Failure), sponsored by the National Institutes of Health, is a multicenter, international, randomized trial designed to assess the potential superiority of CABG over intensive medical therapy in improving long-term survival (“the revascularization hypothesis”). It also assesses the benefit of surgical ventricular restoration combined with CABG in improving survival free of hospitalization for cardiac cause compared to CABG alone in patients with LV dysfunction ( EF < 35%) and coronary artery disease suitable for surgical revascularization (“the reconstruction hypothesis”). Patients will undergo cardiac magnetic resonance imaging, echocardiography, neurohormonal and genetic profile, and radionuclide studies to ensure consistent testing practices and standardization of data collection. Testing will also identify eligible patients and address specific questions related to the primary hypotheses. Until the results of this study are available, a close collaboration between cardio-logists and cardiac surgeons in patient selection, perioperative management, and long-term follow-up is critical to definitively change the clinical decision making in the treatment of ischemic heart failure.The STICH Trial (