Control and assist-control modes of mechanical ventilation

Control ventilation is a mode of ventilation in which the respirator delivers the preset volume or pressure regardless of the patient's own inspiratory efforts. It is indicated in patients with severe neurological alterations, deep sedation, shock or severe respiratory failure. In this mode, breathing is performed by the respirator, diminishing energy expenditure and reducing the risk of hypo- and hyperventilation. In the assist-control ventilation mode the respirator delivers the preset number of breaths and the patient may also obtain further breaths by making a sufficient respiratory effort to open the triggering sensor. All respiration (preset and patient initiated) is performed by the respirator. Assist-control ventilation is indicated inpatients without deep sedation who are able to initiate respiration but who cannot maintain spontaneous respiration.     

Arginine deficiency affects early B cell maturation and lymphoid organ development in transgenic mice

Apart from its role in the synthesis of protein and nitric oxide (NO), and in ammonia detoxification, the amino acid arginine exerts an immunosupportive function. We have studied the role of arginine in immune defense mechanisms in the developing postnatal immune system. In suckling mice, arginine is produced in the small intestine. In F/A-2(+/+) transgenic mice, which overexpress arginase in their enterocytes, circulating and tissue arginine concentrations are reduced to 30-35% of controls. In these mice, the development and composition of the T cell compartment did not reveal abnormalities. However, in peripheral lymphoid organs and the small intestine, B cell cellularity and the number and size of Peyer's patches were drastically reduced, and serum IgM levels were significantly decreased. These phenotypes could be traced to an impaired transition from the pro- to pre-B cell stage in the bone marrow. Cytokine receptor levels in the bone marrow were normal. The development of the few peripheral B cells and their proliferative response after in vitro stimulation was normal. The disturbance in B cell maturation was dependent on decreased arginine levels, as this phenotype disappeared upon arginine supplementation and was not seen in NO synthase- or ornithine transcarbamoylase-deficient mice. We conclude that arginine deficiency impairs early B cell maturation.     

Therapeutic effect of camostat mesilate on Duchenne muscular dystrophy in mdx mice

Duchenne muscular dystrophy is known to be caused by a defective gene of dystrophin, a 427-kDa cytoskeletal protein, but the effective therapeutic drug is presently unavailable. We previously reported that a trypsin-like protease designated as dystrypsin is markedly activated in the muscle microsomal fraction immediately before onset of the clinical signs in mdx mice, a dystrophin-deficient hereditary animal model for human Duchenne muscular dystrophy. In order to examine the possible participation of dystrypsin in the occurrence of the disease, we investigated the therapeutic effects of dystrypsin inhibitors on the occurrence and progress of muscular dystrophy. Here, we show that camostat mesilate, a low-molecular-weight inhibitor of trypsin-like proteases, including dystrypsin, is a candidate drug for Duchenne muscular dystrophy.     

Pharmacological characterization of RS-1259, an orally active dual inhibitor of acetylcholinesterase and serotonin transporter, in rodents: possible treatment of Alzheimer's disease

A dual inhibitor of acetylcholinesterase (AChE) and serotonin transporter (SERT), RS-1259 (4-[1S)-methylamino-3-(4-nitrophenoxy)]propylphenyl N,N-dimethylcarbamate (fumaric acid)(1/2)salt), was newly synthesized. RS-1259 simultaneously inhibited AChE and SERT in the brain following an oral administration in mice and rats. Actual simultaneous elevation of extracellular levels of 5-HT and ACh in the rat hippocampus was confirmed by microdialysis. The compound was as effective as SERT inhibitors such as fluoxetine and fluvoxamine in a 5-hydroxytryptophan-enhancing test in mice. Spatial memory deficits in the two-platform task of a water maze in aged rats were ameliorated by RS-1259 as well as donepezil. Both RS-1259 and donepezil increased the awake episodes in the daytime electroencephalogram of rats. Although RS-1259 was weaker than donepezil in enhancing central cholinergic transmission, as observed by ACh elevation in the hippocampus and memory enhancement in aged rats, the efficacy of RS-1259 on the consciousness level, which reflects the whole activity in the brain, was almost the same as that of donepezil. These results suggest that both cholinergic and serotonergic systems are involved in maintaining brain arousal and that a dual inhibitor of AChE and SERT may be useful for the treatment of cognitive disorders associated with reduced brain activity such as in Alzheimer's disease.     

Arsenic in drinking water and skin lesions: dose-response data from West Bengal,India

BACKGROUND: Over 6 million people live in areas of West Bengal, India, where groundwater sources are contaminated with naturally occurring arsenic. The key objective of this nested case-control study was to characterize the dose-response relation between low arsenic concentrations in drinking water and arsenic-induced skin keratoses and hyperpigmentation. METHODS: We selected cases (persons with arsenic-induced skin lesions) and age- and sex-matched controls from participants in a 1995-1996 cross-sectional survey in West Bengal. We used a detailed assessment of arsenic exposure that covered at least 20 years. Participants were reexamined between 1998 and 2000. Consensus agreement by four physicians reviewing the skin lesion photographs confirmed the diagnosis in 87% of cases clinically diagnosed in the field. RESULTS: The average peak arsenic concentration in drinking water was 325 microg/liter for cases and 180 microg/liter for controls. The average latency for skin lesions was 23 years from first exposure. We found strong dose-response gradients with both peak and average arsenic water concentrations. CONCLUSIONS: The lowest peak arsenic ingested by a confirmed case was 115 microg/liter. Confirmation of case diagnosis and intensive longitudinal exposure assessment provide the basis for a detailed dose-response evaluation of arsenic-caused skin lesions.     

Duty to third parties: a new worry for doctors

The Hawaii Supreme Court ruled on June 10, 2002, that physicians might be liable to non-patient third parties if they fail to warn their patients regarding a medication's adverse effect on driving. Conceivably, this liability may also extend to physicians who fail to inform their patients and/or the Department of Motor Vehicles of medical conditions that affect operating a vehicle safely. Physicians must be cognizant of every medication's impact on driving ability, inform their patients of these adverse effects, and should consider asking their patients to stop driving if the risks are substantial.     

Heliotropium huascoense resin exudate: chemical constituents and defensive properties

From the resinous exudate of Heliotropium huascoense a new compound, rel-(8R,9R)-carrizaloic acid, (1) (3-[rel-(8R,9R-9-hydroxy-9,13,13-trimethyl-12-oxo-10-cyclohexenyl)methyl]-4-methoxybenzoic acid), and three known flavonoids, [3-methylgalangin, 3,7-dimethylgalangin, and (-)-alpinone] have been isolated. The structure of 1 was determined by spectral and chemical methods. Several plant defensive properties of 1 (insecticidal and antifungal) have been evaluated.     

Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain

Objectives: To investigate the relationship between gastric cancer and the intake of specific carotenoids (- carotene, -carotene, lutein, and lycopene) and flavonoids (quercetin, kaempferol, myricetin, and luteolin) using new data on their concentration in foods.Methods: Case-control study carried out in Spain that included 354 cases of gastric cancer and 354 controls, matched by age, gender, area of residence and hospital. Usual food intake was assessed using a dietary history questionnaire.Results: In a multivariate model adjusted for several dietary factors, no association was found between intake of any of the studied carotenoids and the risk of gastric cancer. The adjusted OR of gastric cancer for the highest quartile of total flavonoid intake versus the lowest quartile was 0.44 (95 percent confidence interval [CI]=0.25–0.78; p for trend=0.003). Kaempferol intake was found to be protective (OR=0.48; CI=0.26–0.88; p for trend=0.04) comparing the highest versus the lowest quartile of intake. A trend toward lower risk of stomach cancer with higher intake of quercetin was also found.Conclusions: The results of this study support the hypothesis that the well-established protective effect of fruit and vegetables against gastric cancer could, in part, be due to the presence of flavonoids.     

Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs

It is known that bone mineral density (BMD) is low in men who are hypogonadal. However, the rate and sites of bone loss following testosterone deficiency are not known. The resulting hypogonadism after GnRH analog therapy for the treatment of prostate cancer allows us to examine bone loss and bone resorption immediately after testosterone withdrawal. Therefore, we examined the effects of GnRH analog treatment on bone loss and bone resorption in men with prostate cancer. BMD and serum and urine concentrations of markers of bone turnover were determined in men with prostate cancer and in age-matched controls. Measurements were taken before GnRH therapy and 6 and 12 months after instituting therapy. After 12 months of GnRH therapy, the BMD of the total hip and ultra distal radius decreased significantly (P < 0.001) in men with prostate cancer compared with the controls. The mean bone loss was 3.3% and 5.3%, respectively. The observed reduction in BMD in the spine (2.8%) and the femoral neck (2.3%) did not reach statistical significance. No significant bone loss was observed in the control subjects. The concentration of the urine marker of bone resorption, N-telopeptide, was significantly increased from baseline and from controls at both 6 and 12 months in patients treated with GnRH analog therapy compared with control subjects (P < 0.05). The concentration of a serum marker of bone formation, bone-specific alkaline phosphatase, was not significantly different from baseline or from controls at 6 and 12 months. Thus, the decreased total hip and ultra distal radius BMD and increased urinary N-telopeptide concentration after testosterone withdrawal demonstrate an increase in trabecular bone loss and enhanced bone resorption. These findings demonstrate a significant loss of bone in men with prostate cancer after receiving GnRH therapy and suggest that the total hip and radius are the preferred sites for monitoring bone loss in older men. In addition, markers of bone resorption may be helpful.