Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia.

Background Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2). Methods Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19). Results The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. Conclusions It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

Frequent clonal loss of heterozygosity but scarcity of microsatellite instability at chromosomal breakpoint cluster regions in adult leukemias.

Microsatellites are important highly polymorphic genetic markers dispersed in the human genome. Using a panel of 22 (CA)n repeat microsatellite markers mapped to recurrent breakpoint cluster regions specifically involved in leukemia, we investigated 114 adult leukemias (25 acute lymphocytic leukemia [ALL], 32 acute myeloid leukemia [AML], 36 chronic lymphocytic leukemia [CLL], and 21 chronic myeloid leukemia [CML] in chronic phase) for somatic mutations at these loci. In each patient, DNA from fresh leukemia samples was analyzed alongside normal constitutive DNA from buccal epithelium. We detected loss of heterozygosity (LOH) in 81 of 114 patients (ALL 16/25, AML 25/32, CLL 30/36, CML 10/21). Deletions were most often seen in ALL at 11q23 and 19p13; in AML at 8q22 and 11q23; in CLL at 13q14.3, 11q13, and 11q23; and in CML at 3q26. Only six deletions were reported in 74 karyotypes analyzed, whereas in these same cases, 91 LOH events were detected by microsatellites. Of 26 leukemias with a normal karyotype, 16 nevertheless showed at least one LOH by microsatellite analysis. Replication errors were found in 10 of 114 patients (8.8%). Thus, microsatellite instability is rare in leukemia in contrast to many solid tumors. Our findings suggest that in adult leukemia, LOH may be an important genetic event in addition to typical chromosomal translocations. LOH may point to the existence of tumor suppressor genes involved in leukemogenesis to a degree that has hitherto been underestimated.

Evolução Demográfica da Ilha de São Vicente do Descobrimento a 1950

Este trabalho propõe-se analisar a evolução demográfica da ilha de São Vicente, desde o seu descobrimento até 1950. A análise é complementada pelo estudo da natalidade e mortalidade desta ilha que, à semelhança do resto do arquipélago, foi marcada histórica e demograficamente por cíclicas crises de mortalidade e uma elevada natalidade. As particularidades da ilha prendem-se com o seu povoamento tardio e com a sua ligação ao Porto Grande que lhe deu uma dinâmica diferente do resto do país. A pesquisa foi desenvolvida nos arquivos da Conservatória do Registo Civil de São Vicente e da Câmara Municipal de São Vicente. The present work aims at analysing the demographic evolution on the island of S. Vicente since its discovery till 1950, being the analysis complemented by a study on birth and mortality rates on this island. Similarly to the other islands, these rates were marked, both historically and demographically, by recurrent mortality crises, as well as by high birth-rate. The island particularities not only result from its late settlement, but also from its close relationship with the “Porto Grande” harbour, which conferred it a different dynamic, if compared to other parts of this country. This research was based on the files recorded at the Registry Office and the Town-Hall, both in S. Vicente.

Primetime for antiangiogenic therapy.

PURPOSE OF REVIEW: To review the current experience with angiogenesis inhibitors in the treatment of gliomas. RECENT FINDINGS: Antiangiogenic therapy has recently reached the clinic with the approval of bevacizumab for recurrent glioblastomas. A number of promising antiangiogenic and vasculature-modifying agents are under investigation for newly diagnosed and recurrent malignant gliomas. A recurrence under ongoing or after antiangiogenic therapy is often characterized by a more aggressive and, in particular, invasive phenotype. SUMMARY: Despite impressively high radiological response rates in patients with recurrent malignant glioma, the duration of response is usually short-lived, and the observed effect to a large extent may be due to normalization of the disrupted blood-brain barrier and less due to a direct antitumor effect. Overall survival remains poor. Induction of invasive phenotypes and escape with proangiogenic alternative pathways are contributing to resistance. Investigation of combination regimes targeting several pathways will determine the possibilities to overcome the resistance to antiangiogenic therapy in malignant gliomas. This article summarizes the results of recent clinical trials in this field, points towards mechanisms of resistance arising under angiogenesis inhibition and discusses the challenges for the future.

Family Health Strategy professionals' view on the effects of Hansen's disease training

OBJECTIVEEvaluating how professionals of family health teams from three municipalities of Pernambuco perceive and interpret the effects of Hansen's disease training.METHODSA qualitative study using the perspective of Habermas. Six focus groups, totaling 33 nurses and 22 doctors were formed. The guide consisted of: reactions to training, learning, transfer of knowledge and organizational results.RESULTSThere were recurrent positive opinions on instructor performance, course materials, and an alert attitude to the occurrence of cases; the negative points were about lack of practical teaching, a lot of information in a short period of time and little emphasis on basic content. Low perceived self-efficacy and low locus of control, ambiguity, conflict of skills and the lack of support for the learning application. Nurses showed greater dissatisfaction with the organizational support.CONCLUSIONThe low effectiveness of training reveals the need to negotiate structured training from work problematization, considering performance conditions.

Temozolomide: a milestone in neuro-oncology and beyond?

Temozolomide (Temodal, Temodar), an imidazol derivative, is a second-generation alkylating agent. The orally available prodrug with the capacity of crossing the blood-brain barrier received accelerated US FDA approval in 1999. Three pivotal Phase II trials showed modest activity in the treatment of recurrent anaplastic astrocytoma glioblastoma. In 2005, the FDA and the European Agency for the Evaluation of Medicinal Products approved temozolomide for use in newly diagnosed glioblastoma, in conjunction with radiotherapy, based on an European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Phase III trial. The adverse events associated with temozolomide are mild-to-moderate and generally predictable; the most serious are noncumulative and reversible myelosuppression and, in particular, thrombocytopenia, which occurs in less than 5% of patients. Continuous temozolomide administration is associated with profound CD4-selective lymphocytopenia. Molecular studies have suggested that the benefit of temozolomide chemotherapy is restricted to patients whose tumors have a methylated methylguanine methyltransferase gene promotor and are thus unable to repair some of the chemotherapy-induced DNA damage. Temozolomide is under investigation for other disease entities, in particular lower-grade glioma, brain metastases and melanoma.

In vitro compatibility of remifentanil hydrochloride and sufentanil citrate with selected drugs

: Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in intensive care units. The present study was aimed at investigating the physical compatibility of remifentanil and sufentanil with other drugs (insulin, midazolam, propofol, potassium chloride, magnesium sulfate, furosemide, heparin, monobasic potassium phosphate) that are frequently administered together intravenously. In addition, the physicochemical compatibility of three common associations of drugs was evaluated in glass tube tests and during dynamic simulated Y site administrations (remifentanil-insulin-midazolam; remifentanil-insulin-propofol; sufentanil-insulin-midazolam). Methods Physical compatibility was verified by visual inspection of the various mixtures (two, three or four drugs) in glass tubes and by pH determination of the mixtures collected during simulated Y site administrations. Solutions were considered as compatible in the absence of any visual change in the solution and of any significant variation in pH value. In addition, chemical stability was checked during in vitro dynamic simulations. The solutions were prepared in 50 ml syringes, placed on syringe pumps and connected to a Swan-Ganz catheter; the liquid collected at the tip was assayed by high performance liquid chromatography. Results In the visual examinations, only the associations of remifentanil and furosemide were incompatible. The three assayed associations were compatible in the tested proportion range over 24 h. Conclusions Remifentanil was physically compatible with the tested drugs, except for furosemide (Lasix; Sanofi-Aventis, 250 mg/25 ml) and physicochemically compatible with insulin and midazolam and insulin and propofol. Sufentanil was physically compatible with all tested drugs and physicochemically compatible with insulin and midazolam

Adverse effects of intraperitoneal onlay mesh used for incisional hernia repair

Context: In the past 50 years, the use of prosthetic mesh in surgery has dramatically¦changed the management of primary, as well as incisional hernias. Currently, there¦are a large number of different mesh brands and no consensus on the best material,¦nor the best mesh implantation technique to use. The purpose of this study is to¦illustrate the adverse effects of intraperitoneal onlay mesh used for incisional¦hernia repair encountered in patients treated at CHUV for complications after¦incisional hernia repair.¦Materials & Methods: This work is an observational retrospective study. A PubMed¦search and a systematic review of literature were performed. Thereafter, the medical¦records of 22 patients who presented with pain, abdominal discomfort, ileus, fistula,¦abscess, seroma, mesh infection or recurrent incisional hernia after a laparoscopic or¦open repair with intra-abdominal mesh were reviewed.¦Results: Twenty-two persons were reoperated for complications after incisional¦hernia repair with a prosthetic mesh. Ten were male and twelve female, with a¦median age of 58,6 years (range 24-82). Mesh placement was performed by a¦laparoscopic approach in nine patients and by open approach in thirteen others.¦Eight different mesh brands were found (Ultrapro®, Mersilene®, Parietex Composite®,¦Proceed®, DynaMesh®, Gore® DualMesh®, Permacol®, Titanium Metals UK Ltd®).¦Mean time from implantation and reoperation for complication was 34.2 months¦(range 1-147). In our sample of 22 patients, 21 (96%) presented mesh adhesion and¦15 (68%) presented hernia recurrence. Others complications like mesh shrinkage,¦mesh migration, nerve entrapment, seroma, fistula and abscess were also evaluated.¦Conclusion: The majority of articles deal with complications induced by¦intraperitoneal prosthetic mesh, but the effectiveness of mesh has been studied¦mostly on experimental models. Actually and as shown in the present study,¦intraperitoneal mesh placement was associated with severe complications witch may¦potentially be life threatening. In our opinion, intraperitoneal mesh placement should¦only be reserved in exceptional situations, when the modified Rives-Stoppa could not¦be achieved and when tissues covering the mesh are insufficient.

Floating arterial thrombus related stroke treated by intravenous thrombolysis.

BACKGROUND: The effects of intravenous thrombolysis on floating thrombi in cervical and intracranial arteries of acute ischemic stroke patients are unknown. Similarly, the best prevention methods of early recurrences remain controversial. This study aimed to describe the clinical and radiological outcome of thrombolyzed strokes with floating thrombi. METHODS: We retrospectively analyzed all thrombolyzed stroke patients in our institution between 2003 and 2010 with floating thrombi on acute CT-angiography before the intravenous thrombolysis. The floating thrombus was diagnosed if an elongated thrombus of at least 5 mm length, completely surrounded by contrast on supra-aortic neck or intracerebral arteries, was present on CT-angiography. Demographics, vascular risk factors, and comorbidities were recorded and stroke etiology was determined after a standardized workup. Repeat arterial imaging was performed by CTA at 24 h or before if clinical worsening was noted and then by Doppler and MRA during the first week and at four months. RESULTS: Of 409 thrombolyzed stroke patients undergoing acute CT Angiography, seven (1.7%) had a floating thrombus; of these seven, six had it in the anterior circulation. Demographics, risk factors and stroke severity of these patients were comparable to the other thrombolyzed patients. After intravenous thrombolysis, the floating thrombi resolved completely at 24 h in four of the patients, whereas one had an early recurrent stroke and one developed progressive worsening. One patient developed early occlusion of the carotid artery with floating thrombus and subsequently a TIA. The two patients with a stable floating thrombus had no clinical recurrences. In the literature, only one of four reported cases were found to have a thrombolysis-related early recurrence. CONCLUSIONS: Long-term outcome seemed similar in thrombolyzed patients with floating thrombus, despite a possible increase of very early recurrence. It remains to be established whether acute mechanical thrombectomy could be a safer and more effective treatment to prevent early recurrence. However, intravenous thrombolysis should not be withheld in eligible stroke patients.

Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients.

OBJECTIVE: To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients. DESIGN: Randomized, prospective, double-blind, placebo-controlled study. SETTING: Two university-affiliated hospitals in Switzerland. PATIENTS: Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages. INTERVENTIONS: Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition. MEASUREMENTS AND MAIN RESULTS: Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS: Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.

Efficacy of clinical guideline implementation to improve the appropriateness of chest physiotherapy prescription among inpatients with community-acquired pneumonia

BACKGROUND: Although there is no strong evidence of benefit, chest physiotherapy (CP) seems to be commonly used in simple pneumonia. CP requires equipment and frequently involves the assistance of a respiratory therapist, engendering a significant medical workload and cost. AIM: To measure and compare the efficacy of two modalities of chest physiotherapy (CP) guideline implementation on the appropriateness of CP prescription among patients hospitalised for community-acquired pneumonia (CAP). PATIENTS AND METHODS: We measured the CP prescription rate and duration in all consecutive CAP inpatients admitted in a division of general internal medicine at an urban teaching community hospital during three consecutive one-year time periods: (1) before any guideline implementation; (2) after a passive implementation by medical grand rounds and guideline diffusion through mailing; (3) after adding a one-page reminder in the CAP patient's medical chart highlighting our recommendations. Death and recurrent hospitalisation rates within one year after hospitalisation were recorded to assess whether CP prescription reduction, if any, impaired patient outcomes. RESULTS: During the three successive phases, 127, 157, and 147 patients with similar characteristics were included. Among all CAP inpatients, the CP prescription rate decreased from 68% (86/127) to 51% (80/157), and to 48% (71/147), respectively (P for trend <0.01 for trend). A significant reduction in CP duration was observed after the active guideline implementation (12.0, 11.0, 7.0days, respectively) and persisted after adjustment for length of stay. Reductions in CP prescription rate and duration were also observed among CAP patients with COPD CP prescription rate: 97% (30/31), 67% (24/36), 75% (35/47), respectively (P<0.01 for trend). The mean cost of CP per patient was reduced by 56%, from $709 to $481, and to $309, respectively. Neither the in-hospital deaths, the one-year overall recurrent hospitalisation nor the one-year CAP-specific recurrent hospitalisation significantly differed between the three phases. CONCLUSION: Both passive and active implementation of guidelines appear to improve the appropriateness of CP prescription among inpatients with CAP without impairing their outcomes. Restricting CP use to patients who benefit from this treatment might be an opportunity to decrease CAP medical cost and workload.

The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging.

BACKGROUND AND PURPOSE: Stroke registries are valuable tools for obtaining information about stroke epidemiology and management. The Acute STroke Registry and Analysis of Lausanne (ASTRAL) prospectively collects epidemiological, clinical, laboratory and multimodal brain imaging data of acute ischemic stroke patients in the Centre Hospitalier Universitaire Vaudois (CHUV). Here, we provide design and methods used to create ASTRAL and present baseline data of our patients (2003 to 2008). METHODS: All consecutive patients admitted to CHUV between January 1, 2003 and December 31, 2008 with acute ischemic stroke within 24 hours of symptom onset were included in ASTRAL. Patients arriving beyond 24 hours, with transient ischemic attack, intracerebral hemorrhage, subarachnoidal hemorrhage, or cerebral sinus venous thrombosis, were excluded. Recurrent ischemic strokes were registered as new events. RESULTS: Between 2003 and 2008, 1633 patients and 1742 events were registered in ASTRAL. There was a preponderance of males, even in the elderly. Cardioembolic stroke was the most frequent type of stroke. Most strokes were of minor severity (National Institute of Health Stroke Scale [NIHSS] score ≤ 4 in 40.8% of patients). Cardioembolic stroke and dissections presented with the most severe clinical picture. There was a significant number of patients with unknown onset stroke, including wake-up stroke (n=568, 33.1%). Median time from last-well time to hospital arrival was 142 minutes for known onset and 759 minutes for unknown-onset stroke. The rate of intravenous or intraarterial thrombolysis between 2003 and 2008 increased from 10.8% to 20.8% in patients admitted within 24 hours of last-well time. Acute brain imaging was performed in 1695 patients (97.3%) within 24 hours. In 1358 patients (78%) who underwent acute computed tomography angiography, 717 patients (52.8%) had significant abnormalities. Of the 1068 supratentorial stroke patients who underwent acute perfusion computed tomography (61.3%), focal hypoperfusion was demonstrated in 786 patients (73.6%). CONCLUSIONS: This hospital-based prospective registry of consecutive acute ischemic strokes incorporates demographic, clinical, metabolic, acute perfusion, and arterial imaging. It is characterized by a high proportion of minor and unknown-onset strokes, short onset-to-admission time for known-onset patients, rapidly increasing thrombolysis rates, and significant vascular and perfusion imaging abnormalities in the majority of patients.

Exercise and nonspecific low back pain: a literature review.

We reviewed the literature to clarify the effects of exercise in preventing and treating nonspecific low back pain. We evaluated several characteristics of exercise programs including specificity, individual tailoring, supervision, motivation enhancement, volume, and intensity. The results show that exercise is effective in the primary and secondary prevention of low back pain. When used for curative treatment, exercise diminishes disability and pain severity while improving fitness and occupational status in patients who have subacute, recurrent, or chronic low back pain. Patients with acute low back pain are usually advised to continue their everyday activities to the greatest extent possible rather than to start an exercise program. Supervision is crucial to the efficacy of exercise programs. Whether general or specific exercises are preferable is unclear, and neither is there clear evidence that one-on-one sessions are superior to group sessions. Further studies are needed to determine which patient subsets respond to specific characteristics of exercise programs and which exercise volumes and intensities are optimal.

Forced diuresis improves the diagnostic accuracy of 18F-FDG PET in abdominopelvic malignancies.

Our aim was to evaluate the role of forced diuresis in improving the diagnostic accuracy of abdominopelvic (18)F-FDG PET. METHODS: Thirty-two patients were enrolled. Besides the presence of known intravesical tumors or undefined renal lesions on the initial PET scan, the inclusion criterion was the appearance of indeterminate or equivocal (18)F-FDG foci that extended along the course of the urinary tract and could not confidently be separated from urinary activity. For each patient, a second abdominopelvic PET study was performed after intravenous injection of 0.5 mg of furosemide per kilogram of body weight (maximum, 40 mg) coupled with parenteral infusion of physiologic saline. RESULTS: Forced diuresis coupled with parenteral hydration eliminated any significant (18)F-FDG activity from the lower urinary tract in 31 (97%) of 32 patients after the bladder had been voided 3 successive times. Twelve intravesical lesions were visualized with outstanding clarity, whereas radiologic suspicion of locally recurrent bladder tumors was ruled out in 3 patients. Among 14 indeterminate or equivocal extravesical foci, 7 were deemed of no clinical value because they disappeared after furosemide challenge, whereas 7 persisting foci were proven to be true-positive PET findings. The performance of (18)F-FDG PET in characterizing 3 renal-space-occupying lesions could not be improved by our protocol. CONCLUSION: Furosemide challenge has the potential to noninvasively resolve the inherent (18)F-FDG contrast handicap in the lower urinary tract.

Allergies aux produits de contraste radiologiques [Allergy to radiographic contrast media].

Allergy to radiographic contrast media Hypersensitivity reactions to radio-contrast media are common in the daily practice. These products are responsible for immediate (< or = 1 hour after administration) and non immediate (> 1 hour after administration) hypersensitivity reactions. A diagnostic work-up by an allergologist with skin tests and in some cases provocation tests is of value in reducing the risk of recurrent hypersensitivity reactions to iodinated contrast media. A careful selection of the patients is required because the incidence of breakthrough reactions is still concerning, even with proper premedication. Practical recommendations are presented in this article. For gadolinium-based contrast agents, data in the literature is not sufficient for suggesting guidelines.