[Longitudinality in Primary Care and Polypharmacy. A Systematic Review]. / Longitudinalidad en atención primaria y polifarmacia. Una revisión sistemática.

The aim of this work was to collect, evaluate and interpret the available evidence on the relationship between continuity in primary care (i.e., longitudinality), and the prevalence of polypharmacy and its associated problems. Following the PRISMA reporting statement, we carried out a systematic review of the literature searching PubMed and Scopus databases. The screening of titles and summaries and the review of references carried out independently by two authors detected 16 works of potential interest, of which 4 were discarded after the independent review of all the originals because they did not meet inclusion criteria. The 12 papers selected studied the relationship between Longitudinality, measured with various quantitative indices, and the rate of polypharmacy or various associated problems, such as duplicate drugs, inadequate prescriptions or drug interactions. They all showed a significant relationship, often strong (RR>2 or<0.5), between longitudinality indicators and the various dependent variables. Although our knowledge could be improved by prospective studies that more directly evaluate longitudinality and its impact on problems due to excess medication, with the existing evidence, we can affirm that the protection and promotion of continuity in primary care can be a key element for the control of polypharmacy and associated problems.

Tuberculosis genital: diagnóstico e implicaciones en fertilidad. A propósito de un caso / Genital tuberculosis infection: diagnosis and fertility impact. A case report

Resumen CASO CLÍNICO: Paciente de 18 años de edad, sin embarazos previos, que acudió a consulta por dolor y distensión abdominal. La exploración física solo mostró signos de ascitis. La ecografía abdominal reportó líquido libre intraabdominal perihepático, periesplénico y, en ambos flancos. La radiografía de tórax mostró infiltrado intersticial bilateral, de predominio en los campos medios; granuloma calcificado en el lóbulo superior izquierdo. La tomografía toraco-abdomino-pélvica evidenció adenopatías axilares, mediastínicas y cardiofrénicas; útero de tamaño normal y estructuras tubulares pélvicas de 1 cm, bilaterales, compatibles con salpingitis. Ante la sospecha clínica de tuberculosis, se realizó la prueba de Mantoux, que resultó positiva. El estudio ginecológico reportó anejos aumentados de tamaño, duros y de consistencia sólida. La ecografía mostró las trompas de Falopio engrosadas, de morfología arrosariada y vascularización aumentada (53 x 23 mm la derecha y 53 x 14 la izquierda). En la biopsia de endometrio se identificó el bacilo ácido-alcohol resistente. Con estos hallazgos se estableció el diagnóstico de tuberculosis diseminada, con afectación pulmonar y peritoneal. Se prescribió tratamiento con isoniacida, rifampicina, pirazinamida y etambutol, con lo que se observó reacción satisfactoria. La paciente fue dada de alta por disminución de los síntomas, con posterior seguimiento en la consulta de Enfermedades Infecciosas y Ginecología. CONCLUSIÓN: La tuberculosis genital es una alteración poco frecuente en España. El diagnóstico se establece con alta sospecha clínica o durante el estudio de otras enfermedades, pues para su confirmación se requieren medios de cultivo específicos. La importancia del diagnóstico radica en las consecuencias de la fertilidad a futuro, ya que la funcionalidad del aparato reproductor se ve afectada.

Abstract CLINICAL CASE: 18-year-old female patient, who came to the hospital for pain and abdominal distension. Physical examination showed only signs of ascites. Abdominal ultrasound reported perihepatic, perisplenic, and intraabdominal free fluid on both flanks. The radiography showed bilateral interstitial infiltrate, predominantly in the middle fields; Calcified granuloma in the left upper lobe. Thoraco-abdomino-pelvic tomography evidenced axillary, mediastinal and cardiophrenic adenopathies; Uterus of normal size and tubular structures of 1 cm, bilateral, compatible with salpingitis. Before the clinical suspicion of tuberculosis, the Mantoux test was performed, which was positive. The gynecological study reported enlarged aids, hard, solid consistency. Ultrasound showed enlarged fallopian tubes with augmented morphology and increased vascularization (53 x 23 mm on the right and 53 x 14 on the left). Endometrium biopsy identified the resistant acid-bacillus bacillus. With these findings the diagnosis of disseminated tuberculosis with pulmonary and peritoneal involvement was established. Treatment with isoniazid, rifampicin, pyrazinamide and ethambutol was prescribed, with which a satisfactory reaction was observed. The patient was discharged due to decreased symptoms, with subsequent follow-up in the Infectious Diseases and Gynecology service. CONCLUSION: Genital tuberculosis is a rare disorder in Spain. The diagnosis is established with high clinical suspicion or during the study of other diseases, because for its confirmation specific culture media are required. The importance of diagnosis lies in the consequences of future fertility, since the functionality of the reproductive system is affected.

Embarazo cornual roto. ¿Por qué no debemos olvidar al embarazo como causa de dolor abdominal? / Broken cornual pregnancy. Why not forget pregnancy with abdominal pain?

Resumen ANTECEDENTES: el embarazo ectópico cornual es excepcional y pone en riesgo la vida de la madre. Puede manifestarse con hemorragia materna grave durante la rotura cornual. El embarazo cornual se diagnostica por anamnesis, examen clínico, análisis de laboratorio y ecografía transvaginal. CASO CLÍNICO: paciente de 31 años de edad, con un embarazo ectópico cornual roto que requirió intervención quirúrgica.

Abstract BACKGROUND: Cornual ectopic pregnancy is a rare condition. This is the most dangerous tipe of ectopic pregnancy. A severe maternal hemorrhage can result during a cornual rupture. Cornual pregnancy is diagnosis by anamnesis, clinical examination, plasma markers and transvaginal ultrasound. CLINICAL CASE: We present the case of 31 years old female patient with a ruptured cornual ectopic pregnancy. The patient was submitted to surgery.

[Vulvar squamous cell carcinoma in young women with HPV negative]. / Carcinoma epidermoide de vulva en mujer joven con VPH negative.

BACKGROUND: The vulvar cancer is the fourth more frequent neoplasia after the endometrial, cervix and ovarian cancer. Normally, it has been related to old women of ages from 70 to 80 years old. Rarely, it has been detected cases in adult or young women. However, its incidence has been increased in the last years and in more early years. It is for this change in the incidence and its appearance in early years why a possible etiology has been looked for, opening different hypothesis that go from that related to the HPV to those that study an inflammatory chronic process as the basis for the carcinogenesis. CLINICAL CASE: In this article, it has been presented the case of a woman who is 34 years old with negative VPH that made her debut with epidermoid carcinoma of the vulva moderately different and on purpose of the case, we do a revision of the literature existent. CONCLUSIONS: Vulvar cancer diagnosed in young women as in older, but with different trends, risk factors and natural history. The case reported here escapes the theories studied so far so needed new lines of inquiry to investigate this form of presentation young woman, without HPV infection.

Changes in neurosyphilis presentation: a survey on 286 patients.

Although neurosyphilis (NS) keeps plaguing worldwide, often with oligosymptomatic and atypical manifestations, the most recent reports fail to provide useful information, like details of the clinical history and even of the previous early therapy. We conducted a survey of the literature of the last 5 years on the clinical presentation of NS, recording the aforementioned inaccuracies. One hundred and thirty-seven articles were collected, reporting on 286 patients. General paresis was the commonest form (49%), often manifesting with cognitive impairment and psychiatric symptoms. Syphilitic meningitis was found in 63 patients (22%), mainly with ocular or auditory involvement. Meningovascular and tabetic form were both found in 12% of cases. Gummatous and epileptic manifestations were rare. Perusal of the literature confirms that NS prevalence is increasing, often with manifestations that are atypical for timing and type of lesions. Unfortunately, many articles are lacking of critical information, like an accurate clinical history and timing of the therapy making difficult to assess the effectiveness of penicillin in preventing NS.

Role of Dlx6 in regulation of an endothelin-1-dependent, dHAND branchial arch enhancer.

Neural crest cells play a key role in craniofacial development. The endothelin family of secreted polypeptides regulates development of several neural crest sublineages, including the branchial arch neural crest. The basic helix-loop-helix transcription factor dHAND is also required for craniofacial development, and in endothelin-1 (ET-1) mutant embryos, dHAND expression in the branchial arches is down-regulated, implicating it as a transcriptional effector of ET-1 action. To determine the mechanism that links ET-1 signaling to dHAND transcription, we analyzed the dHAND gene for cis-regulatory elements that control transcription in the branchial arches. We describe an evolutionarily conserved dHAND enhancer that requires ET-1 signaling for activity. This enhancer contains four homeodomain binding sites that are required for branchial arch expression. By comparing protein binding to these sites in branchial arch extracts from endothelin receptor A (EdnrA) mutant and wild-type mouse embryos, we identified Dlx6, a member of the Distal-less family of homeodomain proteins, as an ET-1-dependent binding factor. Consistent with this conclusion, Dlx6 was down-regulated in branchial arches from EdnrA mutant mice. These results suggest that Dlx6 acts as an intermediary between ET-1 signaling and dHAND transcription during craniofacial morphogenesis.

The coding region of the human DLX6 gene contains a polymorphic CAG/CCG repeat.

The region on chromosome 7q21-22 is frequently altered in several human neoplasias such as uterine leiomyoma, myeloid leukemia and breast cancer. The same region has also been linked to split hand/split foot malformation type 1 and to involutional osteoporosis. Our analysis of genes that map to this region has led to the identification of the so far unknown first exon of the homeobox gene DLX6, a mammalian homologue of the Drosophila distal-less gene. Distal-less is a downstream target of the trithorax transcription factors. Translocations involving the mammalian homologue of trithorax, ALL-1, leading to its constitutive activation cause leukemia. We describe here that the first exons of human and mouse DLX6 genes contain a multiple trinucleotide repeat region. We have analyzed the CAG repeat length in 90 subjects and were able to identify five alleles with 11 to 20 CAG repeats.

Multiple functions of Dlx genes.

Dlx genes comprise a highly conserved family of homeobox genes homologous to the distal-less (Dll) gene of Drosophila. They are thought to act as transcription factors. All Dlx genes are expressed in spatially and temporally restricted patterns in craniofacial primordia, basal telencephalon and diencephalon, and in distal regions of extending appendages, including the limb and the genital bud. Most of them are expressed during morphogenesis of sensory organs and during migration of neural crest cells and interneurons. In addition, Dlx5 and Dlx6 are expressed in differentiating osteoblasts. Gene targeting of Dlx1, Dlx2, Dlx3 and Dlx5 in the mouse germ-line has revealed functions in craniofacial patterning, sensory organ morphogenesis, osteogenesis and placental formation. However, no effect on limb development has yet been revealed from gene inactivation studies. A role for these genes in limb development is however suggested by the linkage of the Split Foot/Hand Malformation human syndrome to a region containing DLX5 and DLX6. As for most transcription factors, these genes seem to have multiple functions at different stages of development or in different tissues and cell types.

Alergia al hidrolizado protéico: a propósito de un caso / Allergy to protein hydrolyzate

Las alergias alimentarías son reacciones adversas que pueden o no estar mediadas por Inmunoglobulina E (IgE) y tienen una frecuencia del 2,5-7 por ciento en los menores de 2 años. Las proteínas más comúnmente reconocidas son las de la leche de vaca y soja. Esta patología se resuelve al eliminar la proteína alergizante de la dicta. Se presenta un caso de una niña de 2 meses de vida que debuta con manifestaciones digestivas y fallo de crecimiento, requiriendo internación por diarrea con sangre. El cuadro se acompañó con una forma no muy habitual de presentación como lo es la metahemoglobinemia. Los síntomas persistieron a pesar de la alimentación con hidrolizado proteico, obteniéndose una biopsia de recto e intestino delgado patológica bajo dicho regimen. Al rotar la alimentación a leche de soja los síntomas revirtieron dentro de las 48hs, recuperando el peso a ritmo de catch up y manteniéndolo en su seguimieto ambulatorio a 8 meses del alta. En conclusión se debe tener presente la posibilidad de alergia al hidrolizado de proteína en pacientes con alergia a proteínas de leche de vaca (APLV) ante la existencia o persistencia de manifestaciones digestivas bajo régimen hidrolizado.

Sindrome de Realimentacion en pacientes con anorexia nerviosa / Refeeding Syndrome in patient with nervous anorexia

El Sindrome de Realimentacion (SR) representa las consecuencias metabolicas de la homeostasis del agua con los macro y micro nutrientes como glucosa, el sodio, el potasio, el magnesio, los oligoelementos y las vitaminas

Craniofacial, vestibular and bone defects in mice lacking the Distal-less-related gene Dlx5.

The Dlx5 gene encodes a Distal-less-related DNA-binding homeobox protein first expressed during early embryonic development in anterior regions of the mouse embryo. In later developmental stages, it appears in the branchial arches, the otic and olfactory placodes and their derivatives, in restricted brain regions, in all extending appendages and in all developing bones. We have created a null allele of the mouse Dlx5 gene by replacing exons I and II with the E. coli lacZ gene. Heterozygous mice appear normal. Beta-galactosidase activity in Dlx5+/- embryos and newborn animals reproduces the known pattern of expression of the gene. Homozygous mutants die shortly after birth with a swollen abdomen. They present a complex phenotype characterised by craniofacial abnormalities affecting derivatives of the first four branchial arches, severe malformations of the vestibular organ, a delayed ossification of the roof of the skull and abnormal osteogenesis. No obvious defect was observed in the patterning of limbs and other appendages. The defects observed in Dlx5-/- mutant animals suggest multiple and independent roles of this gene in the patterning of the branchial arches, in the morphogenesis of the vestibular organ and in osteoblast differentiation.

Potentiation of the malignant phenotype of the undifferentiated ARO thyroid cell line by insertion of the bcl-2 gene.

We have reported that bcl-2 is expressed in normal human thyroid epithelium and that its expression is down-regulated in undifferentiated thyroid tumors. Production of IL-6 was concomitantly down-regulated in these forms. Based on these observations, we analyzed whether insertion of bcl-2 would reverse the highly malignant phenotype of a thyroid cell line (ARO) derived from an undifferentiated carcinoma. This cell line fails to produce Bcl-2 and IL-6. By infection with a bcl-2 retroviral vector, ARO cells expressing bcl-2 (ARObcl-2) were obtained. Compared with parental cells, expression of bcl-2 was associated with enhancement of growth potential (DNA synthesis, in vitro proliferation rate, anchorage-independent growth in semi-solid media). Chemotaxis and invasive potential in Boyden chambers were also increased. bcl-2-expressing cells showed a reduced response to apoptotic stimuli (low-serum conditions or anti-neoplastic drugs). Large branched colonies were formed in Matrigel from ARObcl-2 cells but not from parental cells. Finally, ARObcl-2 cells showed a decreased latency of tumor appearance when injected into immunodeficient mice. Potentiation of the malignant phenotype of ARO cells by bcl-2 was not ascribed to altered expression of (i) cytokine/growth factors (IL-4, IL-6, IL-8, IL-10, IL-12, TGF-alpha, TGF-beta), (ii) thyroid-specific transcripts (TG, TPO, TSH-R, PIGF, PAX-8) or (iii) genes influencing tumor aggressiveness [VEGF, HMGI (Y), HMGI-C]. Our data indicate that bcl-2 potentiates the malignant phenotype of ARO cells not only by limiting the response to apoptotic stimuli but also by enhancing proliferation and tumor aggressiveness.

Cyclin D1 and retinoblastoma susceptibility gene alterations in non-small cell lung cancer.

Among the major regulators of the G1 restriction point are cyclin D1 and the retinoblastoma gene product (RB). In non-small cell lung cancer (NSCLC), the cyclin D1 gene is amplified/over-expressed in almost 50% of cases, and RB is inactivated in 6-32% of cases. It is of interest to evaluate concurrently the alterations of both genes on the same series of NSCLCs, to investigate whether cyclin D1 and RB alterations are alternative pathways leading to inactivation of the G1 restriction point or if they can occur in the same tumor, possibly exerting an additive effect on cancer progression. We investigated a series of 57 NSCLCs, analyzing cyclin D1 and RB at the gene and protein levels by Southern blot, Northern blot and immunohistochemistry. The cyclin D1 gene was amplified in 18 cases, cyclin D1 immunoreactivity was seen in 25 tumors. Amplification and expression were significantly associated. RB immunohistochemical expression was absent in 9 of 42 informative cases. RB mRNA expression was low to absent in 9 of 45 informative cases, cyclin D1 amplification was associated with normal RB mRNA, and cyclin D1 over-expression was associated with normal RB immunoreactivity, supporting the hypothesis that alterations of cyclin D1 and RB are alternative mechanisms by which tumor cells may escape the G1 restriction point. A concurrent alteration of RB and cyclin D1 was seen in a small subset of NSCLCs. Abnormalities of cyclin D1 and/or RB at the gene and/or expression level were present in more than 90% of cases, stressing that cyclin D1 and/or RB alterations represent an important step in lung tumorigenesis.

Polyethylenimine-based intravenous delivery of transgenes to mouse lung.

Generally, cationic vector-based intravenous delivery of DNA is hindered by interactions of positively charged complexes with serum proteins. However, if optimally formulated, cationic vectors can provide reasonable levels of transfection in the lung either by intravenous or intrapulmonary routes. We investigated the in vivo transfection capacity of a cationic polymer: linear, 22 kDa polyethylenimine. PEI/DNA complexes were formulated in 5% glucose and delivered into adult mice through the tail vein. Two marker genes were used, beta-galactosidase and luciferase. High levels of luciferase expression (10(7) RLU/mg protein) were found in the lung when DNA was complexed with PEI at a ratio of 4 nitrogen equivalents per DNA phosphate. Lower levels of transfection were found in the heart, spleen, liver and kidney. Expression was dose- and time-dependent in all tissues examined. In the lung, beta-galactosidase staining showed transgene expression in clusters of 10 or more pulmonary cells including the alveolar endothelium, squamous and great alveolar epithelial cells (type I and II pneumocytes) and septal cells. These findings indicate that the complexes pass the capillary barrier in the lung. Although the delivery mechanism requires elucidation, linear PEI has promise as a vector for intravenous transfer of therapeutic genes.

Down-regulation of the nm23.h1 gene inhibits cell proliferation.

nm23 gene expression is strictly related to the state of cell growth. The level of its expression parallels the fraction of thymidine-incorporating cells (S-phase cells) in neoplastic mammary tissues and in the synchronously cycling fraction of MCF 1OA cells. nm23.h1 reaches a peak of expression in the S-phase, and is present at very low level during the GO/G1 phase. Two strategies are used to demonstrate the direct involvement of the nm23.h1 gene in the process of cell proliferation. The first consists of transient inhibition of nm23.h1 expression by using anti-sense oligonucleotide treatment; weak inhibitory effect on cell proliferation is observed. The second strategy involves the stable inhibition of nm23.h1 expression by transfection of MCF1OA cells with a plasmid vector expressing the human nm23.h1 anti-sense mRNA. The anti-sense-transfected cells show consistently slower proliferative activity than the control.

Enriched SSCP: a highly sensitive method for the detection of unknown mutations. Application to the molecular diagnosis of lung cancer in sputum samples.

Detection of gene mutations by sensitive polymerase chain reaction (PCR)-based methods can allow to identify occult neoplastic cells in a great excess of nonmalignant cells. These molecular approaches have an enormous potential in terms of early diagnosis, detection of occult micrometastases of solid tumors, and minimal residual disease in patients with hematopoietic malignancies. Currently, the applications of such methods are limited, mainly because the high sensitivity required for the identification of rare mutated alleles can be achieved only in cases in which mutations occur in few specific codons of a gene or when the mutation is already known. No methods are available by which few alleles with unknown mutations in tumor genes can be recognized in a great excess of wild-type alleles. We have developed an extremely sensitive method, termed enriched single-strand conformational polymorphism (E-SSCP), which permits detection of a rare alleles with unknown mutations. The method is based on the observation that after a conventional SSCP analysis the vast majority of mutated bands migrate close to the wild-type bands. The area of the gel having the highest chance to hold mutated alleles is physically isolated and is used as substrate for a second round of SSCP. Serially diluted DNA samples containing gene mutations demonstrated detection of 1 mutant/10(6) normal alleles. The E-SSCP assay was first applied to six sputum samples of patients affected by lung cancers with known p53 mutations showing in sputa the same mutations observed in tumors. The technique was then applied to eight cytologically negative sputum samples obtained from patients who later developed a clinically manifested lung carcinoma. In three cases, harboring a p53 mutation in tumor tissue, the E-SSCP analysis allowed the detection of the mutations in sputa months before clinical diagnosis. In conclusion, we have presented a general, highly sensitive technique for the detection of unknown mutations that may have several potential applications and may hold considerable promise for the early detection and study of cancer.