PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia.

PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are 2 groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in 3 families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial magnetic resonance imaging. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had 2 novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at 4 and 7 years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.

Biogeographical origin and timing of the founder ichthyosis TGM1 c.1187G > A mutation in an isolated Ecuadorian population.

An unusually high frequency of the lamellar ichthyosis TGM1 mutation, c.1187G > A, has been observed in the Ecuadorian province of Manabí. Recently, the same mutation has been detected in a Galician patient (Northwest of Spain). By analyzing patterns of genetic variation around this mutation in Ecuadorian patients and population matched controls, we were able to estimate the age of c.1187G > A and the time to their most recent common ancestor (TMRCA) of c.1187G > A Ecuadorian carriers. While the estimated mutation age is 41 generations ago (~1,025 years ago [ya]), the TMRCA of Ecuadorian c.1187G > A carrier haplotypes dates to just 17 generations (~425 ya). Probabilistic-based inferences of local ancestry allowed us to infer a most likely European origin of a few (16% to 30%) Ecuadorian haplotypes carrying this mutation. In addition, inferences on demographic historical changes based on c.1187G > A Ecuadorian carrier haplotypes estimated an exponential population growth starting ~20 generations, compatible with a recent founder effect occurring in Manabí. Two main hypotheses can be considered for the origin of c.1187G > A: (i) the mutation could have arisen in Spain >1,000 ya (being Galicia the possible homeland) and then carried to Ecuador by Spaniards in colonial times ~400 ya, and (ii) two independent mutational events originated this mutation in Ecuador and Galicia. The geographic and cultural characteristics of Manabí could have favored a founder effect that explains the high prevalence of TGM1 c.1187G > A in this region.

[Utility of various non-invasive methods for fibrosis prediction among Basque Country patients with phenotypic hemochromatosis]. / Utilidad de los diferentes métodos no invasivos de predicción de fibrosis hepática en pacientes del País Vasco con hemocromatosis fenotípica.

OBJECTIVE: To determine whether the product of multiplying age by liver iron concentration (LIC) (fibrosis index; cut-off, 480,000), platelets, transaminases, and ferritin values are related to the risk of high grade fibrosis. METHODS: A retrospective study of 32 patients with hereditary hemochromatosis (HH) with phenotypic expression. All patients had a liver biopsy with LIC. RESULTS: In 7 patients a magnetic resonance imaging (MRI) scan (1.5 T) was obtained with LIC following Alustiza's protocol. Liver biopsy: fibrosis grade (F) 0-2 in 23 patients; F 3-4 in 9. Fibrosis index (FI) showed a specificity of 68%, sensitivity of 85.7%, positive predictive value (PPV) of 42.8%, and negative predictive value (NPV) of 94.4% for high-grade fibrosis. Platelet count ( < 200,000) revealed a NPV of 94.7% for F3-4. Aspartate transaminase (AST) levels above the upper limit of normal showed a NPV of 94.4%; ferritin levels (> 1,000) a NPV of 75%, and MRI-derived LIC x age (> 480,000) a NPV of 80%. The combination of FI (either by biopsy or MRI) with transaminases, and of platelets with transaminases revealed a NPV of 100%. CONCLUSIONS: FI > 480,000 and platelets < 200,000 have the highest sensitivity for high-degree fibrosis prediction. A negative result allows to discard significant fibrosis in 94% of cases. MRI allows a good fibrosis prediction.

[Papillary renal cell carcinoma spectrum]. / El espectro del carcinoma renal papilar.

OBJECTIVES: Significant conceptual expansion of renal cancer continues to increase. The key point to this phenomenon is based on the combination of morphology and molecular data. The result is the new 2004 WHO classification of renal tumors in adults. The apparently never ending advance in molecular genetics is constantly pushing to update recently proposed listings. MATERIAL AND METHODS: Papillary renal cell carcinoma, considered the term in the broader sense, is the subject of this study. This histological phenotype in renal cancer, with an accelerated growth in the last times, is a good example of the never ending evolution of pathology as a clinical discipline. RESULTS: The genetic background and the phenotype of all renal neoplasms with papillary or tubulo-papillary phenotype, or with its genetic background, some of them being very recently described entities even now under discussion is wide and heterogenous: conventional sporadic papillary carcinoma, papillary carcinomas linked to genetic syndromes (hereditary papillary carcinoma, papillary carcinoma associated to hereditary leiomyomatosis, papillary carcinoma associated to hereditary papillary thyroid carcinoma, Birt-Hogg-Dubé syndrome) or to specific genetic disorders (Xp11.2 associated papillary carcinoma), papillary carcinoma with distinct morphology (micropapillary carcinoma, inverted papillary carcinoma, papillary carcinoma with spindle cells and angulated tubules) and new renal carcinomas included within the group of papillary carcinoma (tubulo-cystic carcinoma and tubular, mucinous and spindle cell carcinoma). CONCLUSION: Aside from the classically known histological variants, several new entities, some of them still badly delineated, are progressively enlarging the group of renal carcinomas with papillary phenotype. This growth will continue in the next times on the light of the new findings and pathologists will be main actors in this fact.

[Plasmacytoid urothelial carcinoma of the urinary bladder. A study of 7 cases]. / Carcinoma urotelial plasmocitoide de vejiga urinaria. Estudio de 7 casos.

OBJECTIVE: Plasmacytoid urothelial carcinoma is a rare and aggressive variant of bladder cancer that mimics plasmacytoma histologically and that can be confused with hemolymphoid neoplasms secondarily affecting the urinary bladder. Only single cases and short series have been described so far. PATIENTS AND METHODS: Seven cases of plasmacytoid urothelial carcinoma have been found among 720 high grade urothelial carcinomas of the urinary bladder. RESULTS: In our series, 0.97% of high grade urothelial carcinomas of the urinary bladder show plasmacytoid phenotype. All the cases were smoking males between 58 and 75 years old. Histologically, two cases showed pure plasmacytoid features, while in the other five cases the plasmacytoid phenotype was mixed with conventional transitional cell or glandular histologies. By immunohistochemistry, all the plasmacytoid areas showed fair epithelial differentiation. The clinical behaviour was aggressive in all the cases, with distant metastases at diagnosis in three cases and early tumor recurrence after chemotherapy in four of them. CONCLUSIONS: In our experience, the plasmacytoid urothelial carcinoma of the urinary bladder is a rare tumor that can also be detected in association with areas of conventional urothelial carcinoma. It is mandatory to recognize this histological subtype due to the clinical and prognostic implications of this diagnosis.

[Premedication with intraoperative clonidine and low-dose ketamine in outpatient laparoscopic cholecystectomy]. / Premedicación con clonidina y ketamina intraoperatoria a bajas dosis en la colecistectomía laparoscópica ambulatoria.

OBJECTIVE: To determine the efficacy of premedication with intraoperative clonidine in association with low-dose ketamine to reduce the need for postoperative opiate analgesia in outpatient laparoscopic cholecystectomy. PATIENTS AND METHODS: We performed a prospective study of patients undergoing outpatient laparoscopic cholecystectomy between November 2005 and November 2006. The patients were distributed randomly in 2 groups: patients in the clonidine-ketamine group received clonidine (0.15 mg orally 60 minutes before surgery) and ketamine (20-mg intravenous bolus followed by intraoperative perfusion of 20 mg h(-1)); patients in the control group did not receive this medication. Pain assessed on a verbal numerical scale, number of times rescue analgesia was required to achieve a value below 3, and adverse effects of the medication were recorded in the postoperative period. RESULTS: Thirty-one patients (16 in the clonidine-ketamine group and 15 in the control group) were enrolled. Rescue analgesia was required on 2 occasions by 25% of patients in the clonidine-ketamine group and on 2 or 3 occasions by 533% of patients in the control group. Adverse effects were reported by 87.5% of patients in the clonidine-ketamine group (mainly visual disturbances, sedation, and nausea) and by 46.7% in the control group. This difference was significant during the patients' stay in the postanesthesia recovery unit. CONCLUSIONS: Patients receiving clonidine and ketamine required less additional opiate analgesia to achieve mild pain values (<3 on the numerical verbal scale) but suffered more adverse effects during their stay in the postanesthesia recovery unit. Discharge was not delayed, however.

The geographic mosaic of Ecuadorian Y-chromosome ancestry.

Ecuadorians originated from a complex mixture of Native American indigenous people with Europeans and Africans. We analyzed Y-chromosome STRs (Y-STRs) in a sample of 415 Ecuadorians (145 using the AmpFlSTR® Yfiler™ system [Life Technologies, USA] and 270 using the PowerPlex®Y23 system [Promega Corp., USA]; hereafter Yfiler and PPY23, respectively) representing three main ecological continental regions of the country, namely Amazon rainforest, Andes, and Pacific coast. Diversity values are high in the three regions, and the PPY23 exhibits higher discrimination power than the Yfiler set. While summary statistics, AMOVA, and RST distances show low to moderate levels of population stratification, inferred ancestry derived from Y-STRs reveal clear patterns of geographic variation. The major ancestry in Ecuadorian males is European (61%), followed by an important Native American component (34%); whereas the African ancestry (5%) is mainly concentrated in the Northwest corner of the country. We conclude that classical procedures for measuring population stratification do not have the desirable sensitivity. Statistical inference of ancestry from Y-STRS is a satisfactory alternative for revealing patterns of spatial variation that would pass unnoticed when using popular statistical summary indices.

Evaluating the Calling Performance of a Rare Disease NGS Panel for Single Nucleotide and Copy Number Variants.

INTRODUCTION: Variant detection protocols for clinical next-generation sequencing (NGS) need application-specific optimization. Our aim was to analyze the performance of single nucleotide variant (SNV) and copy number (CNV) detection programs on an NGS panel for a rare disease. METHODS: Thirty genes were sequenced in 83 patients with hereditary spastic paraplegia. The variant calls obtained with LifeScope, GATK UnifiedGenotyper and GATK HaplotypeCaller were compared with Sanger sequencing. The calling efficiency was evaluated for 187 (56 unique) SNVs and indels. Five multiexon deletions detected by multiple ligation probe assay were assessed from the NGS panel data with ExomeDepth, panelcn.MOPS and CNVPanelizer software. RESULTS: There were 48/51 (94%) SNVs and 1/5 (20%) indels consistently detected by all the calling algorithms. Two SNVs were not detected by any of the callers because of a rare reference allele, and one SNV in a low coverage region was only detected by two algorithms. Regarding CNVs, ExomeDepth detected 5/5 multi-exon deletions, panelcn.MOPs 4/5 and only 3/5 deletions were accurately detected by CNVPanelizer. CONCLUSIONS: The calling efficiency of NGS algorithms for SNVs is influenced by variant type and coverage. NGS protocols need to account for the presence of rare variants in the reference sequence as well as for ambiguities in indel calling. CNV detection algorithms can be used to identify large deletions from NGS panel data for diagnostic applications; however, sensitivity depends on coverage, selection of the reference set and deletion size. We recommend the incorporation of several variant callers in the NGS pipeline to maximize variant detection efficiency.

Carborane-stilbene dyads: the influence of substituents and cluster isomers on photoluminescence properties.

Two novel styrene-containing meta-carborane derivatives substituted at the second carbon cluster atom (Cc) with either a methyl (Me) or a phenyl (Ph) group are introduced herein along with a new set of stilbene-containing ortho- (o-) and meta- (m-) carborane dyads. The latter set of compounds have been prepared from styrene-containing carborane derivatives via a Heck coupling reaction. High regioselectivity has been achieved for these compounds by using a combination of palladium complexes [Pd2(dba)3]/[Pd(t-Bu3P)2] as a catalytic system, yielding exclusively E isomers. All compounds have been fully characterised and the crystal structures of seven of them were analysed by X-ray diffraction. The absorption spectra of these compounds are similar to those of their respective fluorophore groups (styrene or stilbene), showing a very small influence of the substituent (Me or Ph) linked to the second Cc atom or the cluster isomer (o- or m-). On the other hand, fluorescence spectroscopy revealed high emission intensities for Me-o-carborane derivatives, whereas their Ph-o-carborane analogues evidenced an almost total lack of fluorescence, confirming the significant role of the substituent bound to the adjacent Cc in o-carboranes. In contrast, all the m-carborane derivatives display similar photoluminescence (PL) behavior regardless of the substituent attached to the second Cc, demonstrating its small influence on emission properties. Additionally, m-carborane derivatives are significantly more fluorescent than their o-counterparts, reaching quantum yield values as high as 30.2%. Regarding solid state emission, only stilbene-containing Ph-o-carborane derivatives, which showed very low fluorescence in solution, exhibited notable PL emission in films attributed to aggregation-induced emission. DFT calculations were performed to successfully complement the photoluminescence studies, supporting the experimentally observed photophysical behavior of the styrene and stilbene-containing carborane derivatives. In conclusion, in this work it is proved that it is possible to tailor the PL properties of carborane-stilbene dyads by changing the Cc substituent and the carborane isomer.

[Accidental dural puncture during epidural injection of corticosteroids: a different approach?]. / Punción dural accidental en la infiltración epidural con corticoide. Un abordaje diferente?

We report 6 cases diagnosed with accidental dural puncture after epidural injection of corticosteroids for low back pain. All the patients reported postdural puncture headache during their stay in the postanesthetic recovery unit. For 3 patients, pain resolved with treatment given in the recovery unit. Two other patients also required mild analgesics for 1 week. In the last patient, a blood patch was used to treat incapacitating headache 22 days after the epidural procedure and mild analgesics were needed for 4 more weeks. It is important to establish a protocol for treating postdural puncture headache in pain clinics to facilitate decision making. Good physician-patient communication is necessary to avoid refusals for permission for other epidural techniques and to facilitate management of symptoms.

Cloning and mapping of genes involved in wheat-leaf rust interaction through gene-expression analysis using chromosome-deleted near-isogenic wheat lines.

Molecular markers on wheat chromosome 6BL were isolated using mRNA differential display. Two wheat isolines inoculated with Puccinia recondita were analysed: Sinvalocho MA line carrying the Lr3 gene for leaf rust resistance on distal chromosome 6BL, and a rust-susceptible derivative of the Sinvalocho MA line with a deletion at the distal end of chromosome 6BL. Comparison of mRNA fingerprinting profiles, obtained from control and rust-inoculated plants, let to the isolation of 34 differentially displayed cDNAs. All these genes, except TaRr16, were up-regulated in the rust-inoculated resistant line. TaRr16 has constitutive expression in the rust-resistant line while no expression was detected in the rust-susceptible line. A number of those cDNAs revealed homology to genes previously identified in other plant-pathogen interactions. Two out of the 34 cDNAs, mapped in the distal part of chromosome 6BL and TaRr16, was genetically linked to the Lr3 gene. DNA sequence differences and differential expression between non-allelic copies of TaRr16, are also reported.

Where there is a doctor: strategies to increase productivity at lower costs. The economics of rural health care in the Dominican Republic.

The study of a rural health district in the Dominican Republic found relatively high levels of public and out-of-pocket primary health expenditures and poor quality of care. The inefficient use of public resources and low efficacy were attributed to: (1) underutilization of health services, (2) low productivity of human and physical resources, which in turn were caused by poor managerial practices, shortages of medicines, dispersion of the population and the compulsory 1-year rural social service required from all graduating physicians (known as pasantía in some Latin American countries and medicatura rural in others). Out-of-pocket health expenditures responded to unnecessary self-referrals and excessive self-medications. The findings suggest that the quality of care can be improved and the public and out-of-pocket expenditures reduced by: (1) the replacement of the social service (pasantía) by permanent physicians, (2) the organization of communal pharmacies and (3) the establishment of outreach health posts. It is argued that today in the Dominican Republic as in many other Latin American countries unemployed or underemployed physicians are willing to take permanent positions in rural areas. The study suggests that rural physicians need and will be willing to accept the fact that much of their medical training has no applicability to the rural setting. The retraining or recycling of rural physicians for their new health roles is discussed also.

Ideological dimensions of community participation in Latin American health programs.

A comparative analysis of community participation in urban and agricultural programs, and health programs in Latin America suggests that the promotion of community participation was based in all cases on two false assumptions: the belief that the traditional values of the poor were the main obstacle for development and for health improvement; and the idea that the poor were incapable of organizing themselves. A country by country examination indicates that health participation programs in Latin America, in spite of promotional efforts by international agencies, have not succeeded. Then, the article discusses the political objectives behind international support for these programs. It is argued that, through symbolic participation, international agencies had two purposes in mind: the legitimization of low quality care for the poor, also known as primary health; and the generation of much needed support from the masses for the liberal democracies and authoritarian regimes of the region.

Improving the use of pharmaceuticals through patient and community level interventions.

Pharmaceuticals represent an increasing share of private and public health care expenditures. However, while most governments are interested in ensuring availability and access to drugs, the issue of adequate use of drugs remains a low priority in most third world countries. This paper summarizes the results of interventions conducted in developing countries aimed at improving patients' compliance with the advice of health professionals and/or to decrease the unnecessary use of drugs by the general population. Forty-five studies were identified through literature searches and networking; and only about a third of them fulfilled the eligibility criteria for inclusion in the review. Given the paucity of information available and the importance of the topic the authors report on all 45 studies identified. Although much remains to be explored there are several interventions that deserve to be highlighted. The authors argue that improving the use of pharmaceuticals through interventions directed only to consumers may have a small impact and suggest that in order to obtain meaningful changes it might be necessary to design interventions to modify the behavior of all the actors in the medication cycle (manufacturers, health professionals, retailers, consumers and governments). They suggest that the extraordinary therapeutic effects of antibiotics, coupled with the problems that may arise when they are inappropriately used and with the extraordinary amount of resources spent on antibiotics worldwide justify a global effort to reduce their inappropriate use and promote their adequate administration. The complexity of this type of intervention would require the support of the pharmaceutical industry, governments, private foundations, and international organizations.

Towards an epidemiology of political violence in the Third World.

Political violence is distressingly widespread in many parts of the world. This paper reviews the forms and effects of political violence and devotes particular attention to experiences from Central America and Southern Africa. The forms of violence vary from those which are extensive such as civil unrest and war, to those which are intensive, such as assassinations, disappearances and torture. The effects of violence on health may be direct, such as deaths, disabilities, psychological stress and the destruction of health services, or indirect such as the erosion of innovative health policies in favour of increased military expenditure. Health workers have a role to play in opposing political violence, providing care for those affected by violence, and documenting and analysing its impact on health. Research needs include documenting the impact of different forms of violence on health, and analysing the social and political factors which promote and support political violence. It is hoped that increasing recognition of political violence and man-made violence as being of major public health concern will play a part in promoting a more peaceful world.

Plasmacytoid myoepithelioma of the soft palate. Report of a case with cytologic, immunohistochemical and electron microscopic studies.

BACKGROUND: The plasmacytoid variant is a rare and controversial subtype of myoepithelioma that lacks myogenic differentation and the cytologic findings of which have not been reported previously. CASE: A 46-year-old man presented with a painless tumor located in the soft palate. Fine needle aspiration cytology (FNAC) showed odd-shaped cellular aggregates and single cells with round nuclei and finely granular cytoplasm resembling plasma cells together with strands of metachromatic stroma. The light, immunohistochemical and ultrastructural studies performed on the surgical specimen confirmed the initial cytologic diagnosis. CONCLUSION: Recognition of the cytologic findings of plasmacytoid myoepithelioma on needle aspirates allows a reliable and quick diagnosis that prompts correct management.

[Decentralization of the health sector in Latin America]. / Descentralización del sector salud en América Latina.

This paper analyzes the Latin American experience of decentralizing health services within the context of health reform. We examine the meaning of the term decentralization and discuss the various modalities of this concept: geographical, institutional and functional. The objectives that, in general, these objectives have not been achieved. After reviewing the literature and drawing on our own fieldwork, we conclude that in many instances the Latin American decentralization programs have produced results opposite to those intended, i.e., these programs have increased inequality and the cost of services and have reduced efficiency and quality of care. We point out that existing information is insufficient to determine with exactitude whether the failure of decentralization is due to the selection of inappropriate policies or to failures in the implementation process. Decentralization is a complex political process, policy makers should decide on the modality of decentralization they wish to implement, estimate the costs, identify the potential obstacles that could surface during the implementation phase and provide solutions. We conclude by suggesting that the multilateral banks have erred by pressing governments to improvise the implementation of decentralization programs without taking into account the different historical, political and socioeconomic contexts.

[Health services privatization: the experiences of Chile and Costa Rica]. / Privatización de los servicios de salud: las experiencias de Chile y Costa Rica.

This study questions the premises that justify the neoliberal privatization of financing, managing and delivering health services. It also analyses the meaning of privatization and its strategies. We compare privatization in Chile and Costa Rica and suggest that the more limited, selective and locally designed privatization process in Costa Rica has resulted in a more equitable, and efficient health system than the imported privatization model introduced in Chile. The Costa Rican system also produces greater patient satisfaction and at the same time preserves the solidarity principle.

International migration from the Dominican Republic: findings from a national survey.

PIP: Results of a survey which sought to provide a profile of international Dominican migrants indicate that international migration from the Dominican Republic is primarily a middle class urban phenomenon, with rural unemployment representing only a small segment of the migration flow. The strongest reasons for emigrating were economic, and most migrants tended to leave the Dominican Republic at the peak of their productivity. The profile of the migrant which emerged from the survey does not fit the stereotype of an illiterate, unskilled, and unemployable individual who decides to emigrate to receive welfare. Results also show that about 40% of migrants had returned at the time of the survey, and suggest that the poorer the migrant, the less likely it is he/she will return. Most persons migrating in order to study tend to return after their studies are over, and a large number of migrants have trouble adjusting to a foreign society. Finally, international net migration does not seem to be increasing; in fact the findings suggest that net migration declined considerably in the 1970s, after reaching a peak in the 1960s.^ieng

[Postoperative autotransfusion in primary knee replacement surgery]. / Autotransfusión postoperatoria en la cirugía protésica primaria de rodilla.

OBJECTIVE: To assess the efficacy of postoperative autologous transfusion to reduce homologous blood transfusion needs in primary knee replacement surgery. PATIENTS AND METHODS: A prospective study was carried out in 33 consecutive patients with diagnoses of arthrosis scheduled for primary knee replacement surgery with postoperative autotransfusion using a CBCII Constavac-Stryker (Stryker Instruments, Michigan, USA) recovery system from June through October 2002. We analyzed patient age, sex, preoperative and postoperative (24 hours) hemoglobin and hematocrit values, autologous blood reinfused and homologous blood transfusion incidence rate (if hematocrit was below 25%). RESULTS: Of the 33 patients receiving postoperative autotransfusion, one also needed homologous blood transfusion (3%). The mean volume of filtered whole blood reinfused was 538.63+/-261.23 mL, 1100 mL being the largest volume reinfused. We observed no complications related to use of autotransfusion devices during the perioperative period. CONCLUSIONS: Postoperative autotransfusion as the only blood salvage technique in primary knee prosthesis surgery nearly eliminates homologous transfusion needs. In addition, it is a safe, simple procedure and has replaced our hospital's preoperative autologous transfusion procedure.