Frequency-correlated decreases of motor cortex activity associated with subthalamic nucleus stimulation in Parkinson's disease

According to the classical model of basal ganglia organization, deep brain stimulation (DBS) in the subthalamic nucleus (STN) for the treatment of Parkinson's disease (PD) blocks overactive excitatory projections to inhibitory basal ganglia output structures. This would release the break on thalamofrontal neurons alleviating the poverty of movement, the hallmark of PD. Such parallels to a functional lesion certainly simplify the mechanism of STN DBS. Here, we applied parametric analyses of H2(15)O positron emission tomography (PET) scans at rest while systematically varying stimulation frequency in 6 patients with STN DBS for akinetic PD. A strong positive correlation of rCBF to increasing stimulation frequency was detected around the STN bilaterally. More importantly, we show that gradual increases in STN stimulation frequency are tightly correlated with decreases in motor cortex activity. This demonstrates an active modulation of resting activity within the subcortical stimulation target and within motor cortex by STN DBS. Rather than a possible downstream effect, we propose to consider the tight correlations between DBS frequency and motor cortex activity in the context of an upstream modulation of direct efferents to the STN from primary motor and premotor cortices.     

Hyperbaric oxygen therapy in the management of two cases of hydrogen sulfide toxicity from liquid manure

Hydrogen sulfide is a potent lethal gas. Supportive care, nitrite therapy and hyperbaric oxygen are the treatment modalities reported in the literature in cases of hydrogen sulfide exposure. We describe an industrial exposure in which 6 workers inhaled high concentrations of hydrogen sulfide when they entered a closed spreader tank partially filled with liquid swine manure. Five of the 6 lost consciousness, and 2 were agitated and poorly responsive on arrival to the emergency department despite having already received high-flow oxygen for nearly 1 hour. These 2 patients received nitrite therapy followed by orotracheal intubation and hyperbaric oxygen. All patients were discharged home without sequelae after short stays in hospital. The emergency management of hydrogen sulfide exposure is briefly reviewed.     

Behavioral and Economic Impact of a Familial History of Cancers

Background: Misunderstanding of cancer screening recommendations or messages and confidence in the predictive value of positive familial history of disease may converge to stimulate an over-utilization of screening tests in oncology by patients who perceive themselves to be at high risk. Methods: A survey looking for predictors of the uptake of five cancer screening tests (mammography, colonoscopy, Fecal Occult Blood Test, upper digestive tract endoscopy and chest X-ray) was carried out on 4000 healthy adults (mean age 46.4 years). Findings: Based on the results of a multivariate analysis, the survey enlightens the existing relationships between familial history and increasing uptake of medical cancer screening tests, with OR ranging from 1.3 (IC 1.0–1.6) for chest X-ray to 3.0 (IC 2.1–4.1) for colonoscopy In France (60 million inhabitants), a conservative assessment of the annual net number of unhelpful screening tests attributable to positive family history of related cancer with chest X-ray and Upper digestive tract endoscopy lead to a figure of 7000 and 7800 tests respectively corresponding to a total annual cost of more than € 7, million. Interpretation: Clearer messages about hereditary risks and transparency about the efficacy of screening tests are required in order to decrease over utilization of screening tests and their related costs. Partial presentation: Meeting Paper – Society for Risk Analysis Annual Meeting: Risk Exposure Awareness, the Case of Hereditary Risk Factors.     

Association between Cowden syndrome and Lhermitte-Duclos disease: report of two cases and review of the literature

BACKGROUND: The authors describe 2 cases of dysplasic gangliocytoma of the cerebellum or Lhermitte-Duclos disease revealing Cowden disease or multiple hamartoma neoplasia syndrome. Cowden disease is a rare autosomal dominant disorder, now considered as a phakomatosis. Nevertheless, relationships between both conditions still remain unclear, since Lhermitte-Duclos disease can also be sporadic. CASE REPORTS: Two patients, 25 and 27 years old, were admitted to the emergency department for an acute intracranial hypertension. In both cases, magnetic resonance imaging (MRI) scan showed a mass in the cerebellar hemisphere. Pathological examination of surgical resection specimens concluded Lhermitte-Duclos disease. Because of the patients' previous personal and familial medical history, Cowden disease was suspected and confirmed by mutational analysis of the phosphatase and tensin homolog (PTEN) gene. In the first case, a nonsense punctual mutation in exon 8 was found. In the second one, a mutation was revealed in the exon 5, a mutational hot spot encoding the phosphatase catalytic core motif. CONCLUSION: Lhermitte-Duclos disease and Cowden disease can be associated. Germline mutations of PTEN gene are known to be implicated in Cowden disease. This gene, located at chromosome 10q23-3, is a tumor suppressor gene that encodes a protein with phosphatase activity. To date, more than 80 mutations have been reported in Cowden disease. When the diagnosis of either one of these two disorders is established, it is imperative to search for the other one to detect early malignant lesions that occur in Cowden disease. Finally, a long-term follow up of the patient is required and a thorough familial screening is necessary.     

Ghrelin,Leptin and Insulin Levels after Restrictive Surgery: a 2-Year Follow-up Study

Background: Ghrelin is a recently discovered orexigenic gastric hormone, whose production is induced by lack of food in the stomach. In morbidly obese individuals, ghrelin levels are low compared to lean persons. During dieting, plasma ghrelin levels increase, leading to an orexigenic signal, which could explain the lack of success of dieting in morbidly obese individuals. Morbid obesity is best treated with bariatric surgery, in which gastric bypass is reported to be more effective than restrictive surgery. A possible explanation could be the difference in plasma ghrelin levels after both operations for bariatric surgery. In this study, plasma ghrelin levels were investigated during a 2-year follow-up. Methods: 17 morbidly obese patients received gastric restrictive surgery. Plasma ghrelin, leptin and insulin levels were evaluated preoperatively and 1 year and 2 years postoperatively. Results: BMI decreased from 47.5 ± 6.2 kg/m² to 33.2 ± 5.8 kg/m² (P <0.001). Plasma ghrelin levels were significantly increased 1 year (P <0.05) and 2 years (P <0.02) postoperatively. Fasting plasma leptin and insulin levels were significantly lower at 2 years after surgery (P <0.001). Conclusion: After gastric restrictive surgery, ghrelin levels increased, in contrast to the reported fall in ghrelin levels after gastric bypass. This difference in ghrelin levels between these operations may be the k ey to understanding the superiority of gastric bypass in sustaining weight loss compared with restrictive surgery.     

Mouse model of X-linked Alport syndrome

X-linked Alport syndrome (XLAS) is a progressive disorder of basement membranes caused by mutations in the COL4A5 gene, encoding the alpha5 chain of type IV collagen. A mouse model of this disorder was generated by targeting a human nonsense mutation, G5X, to the mouse Col4a5 gene. As predicted for a nonsense mutation, hemizygous mutant male mice are null and heterozygous carrier female mice are mosaic for alpha5(IV) chain expression. Mutant male mice and carrier female mice are viable through reproductive age and fertile. Mutant male mice died spontaneously at 6 to 34 wk of age, and carrier female mice died at 8 to 45 wk of age, manifesting proteinuria, azotemia, and progressive and manifold histologic abnormalities of the kidney glomerulus and tubulointerstitium. Ultrastructural abnormalities of the glomerular basement membrane, including lamellation and splitting, were characteristic of human XLAS. The mouse model described here recapitulates essential clinical and pathologic findings of human XLAS. With alpha5(IV) expression reflecting X-inactivation patterns, it will be especially useful in studying determinants of disease variability in the carrier state.     

Plasminogen kringle 5-engineered glioma cells block migration of tumor- associated macrophages and suppress tumor vascularization and progres- sion.

Angiostatin, a well-characterized angiostatic agent, is a proteolytic cleavage product of human plasminogen encompassing the first four kringle structures. The fifth kringle domain （K5） of human plasminogen is distinct from angiostatin and has been shown, on its own, to act as a potent endothelial cell inhibitor. We propose that tumor-targeted K5 cDNA expression may act as an effective therapeutic intervention as part of a cancer gene therapy strategy. In this study, we provide evidence that eukaryotically expressed His-tagged human K5 cDNA （hK5His） is exported extracellularly and maintains predicted disulfide bridging conformation in solution. Functionally, hK5His protein produced by retrovirally engineered human U87MG glioma cells suppresses in vitro migration of both human umbilical vein endothelial cells and human macrophages. Subcutaneous implantation of Matrigel-embedded hK5His-producing glioma cells in nonobese diabetic/severe combined immunodeficient mice reveals that hK5His indaces a marked reduction in blood vessel formation and signiticanfly suppresses the recruitment of tumor-infiltrating CD45（＋）Mac3（＋）Grl （-） macrophages. Therapeutically, we show ill a nude mouse orthotopic brain cancer model that tumor-targeted K5 expression is capable of effectively suppressing glioma growth and promotes significant long-term survival （〉120 days） of test animals. These data suggest that plasminogen K5 acts as a novel two-pronged anticancer agent, mediating its inhibitory effect via its action on host-derived endothelial cells and tumor-associated macrophages, resulting in a potent, clinically relevant antitumor effect.     

Controlled transperitoneal percutaneous cecostomy as a therapeutic alternative to the endoscopic decompression for Ogilvie's syndrome

Acute colonic pseudo-obstruction, the so-called Ogilvie's syndrome, results in massive colonic dilation without mechanical obstruction. In most cases, a conservative treatment with or without endoscopic decompression is sufficient. In rare cases of relapses or failures, a cecostomy has to be performed. A surgical cecostomy is associated with high morbidity and mortality. However, a percutaneous cecostomy could be an interesting alternative treatment. We report the case of a 67-yr-old male with colonic pseudoobstruction for which both the conservative and the endoscopic treatments were unsuccessful. A percutaneous cecostomy was performed, and for the first time in this indication, a transperitoneal access was used with the help of nylon T-fasteners.     

Mechanosensory transduction of vagal and baroreceptor afferents revealed by study of isolated nodose neurons in culture

Changes in arterial pressure and blood volume are sensed by baroreceptor and vagal afferent nerves innervating aorta and heart with soma in nodose ganglia. The inability to measure membrane potential at the nerve terminals has limited our understanding of mechanosensory transduction. Goals of the present study were to: (1) Characterize membrane potential and action potential responses to mechanical stimulation of isolated nodose sensory neurons in culture; and (2) Determine whether the degenerin/epithelial sodium channel (DEG/ENaC) blocker amiloride selectively blocks mechanically induced depolarization without suppressing membrane excitability. Membrane potential of isolated rat nodose neurons was measured with sharp microelectrodes. Mechanical stimulation with buffer ejected from a micropipette (5, 10, 20 psi) depolarized 6 of 10 nodose neurons (60%) in an intensity-dependent manner. The depolarization evoked action potentials in 4 of the 6 neurons. Amiloride (1 microM) essentially abolished mechanically induced depolarization (15 +/- 4 mV during control vs. 1 +/- 2 mV during amiloride with 20-psi stimulation, n = 6) and action potential discharge. In contrast, amiloride did not inhibit the frequency of action potential discharge in response to depolarizing current injection (n = 6). In summary, mechanical stimulation depolarizes and triggers action potentials in a subpopulation of nodose sensory neurons in culture. The DEG/ENaC blocker amiloride at a concentration of 1 microM inhibits responses to mechanical stimulation without suppressing membrane excitability. The results support the hypothesis that DEG/ENaC subunits are components of mechanosensitive ion channels on vagal afferent and baroreceptor neurons.     

High-titer measles vaccination before 9 months of age and increased female mortality: do we have an explanation?

In 1989, high-titer (HT) Edmonston-Zagreb measles vaccine with a titer more than 10(4.7) plaque-forming-units was recommended by the World Health Organization for use in areas with a high incidence of measles in children younger than 9 months. In 1992, the recommendation was rescinded following reports from Guinea-Bissau, Senegal, and Haiti showing an increased incidence of female mortality occurring after administration of HT Edmonston-Zagreb vaccination. We reviewed 9 studies of HT measles vaccines that reported data on mortality. These reports included 4 randomized trials comparing HT vaccine administered to children younger than 9 months with standard-titer (ST) vaccines (10(3.0) to 10(4.0) plaque-forming-units) given at 9 months of age. Five studies from Zaire, Haiti, Senegal, Rwanda, and Zaire had no control group receiving ST vaccine at 9 months of age, but investigators were able to examine the female-to-male mortality ratio within these HT studies. Investigators have hypothesized that HT vaccine had caused immune suppression similar to that of measles infection. The present review suggests first that the HT vaccine itself is unlikely to be the cause because the effect was not found in all studies. Second, the increased mortality started only after 9 to 10 months of age when controls received ST measles vaccine, and HT groups received the "control vaccine." It was not found in the studies that provided another measles vaccine instead of control vaccine. Third, because the HT studies with excess mortality rates showed increased female mortality rates, we need to find environmental or contextual conditions associated with increased female mortality rates in some studies to explain the problem associated with HT measles vaccination.