Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension

Background and purpose:

Voltage-gated potassium (K_v) channels contribute to resting membrane potential in pulmonary artery smooth muscle cells and are down regulated in patients with pulmonary arterial hypertension (PAH) and a contribution from K_v7 channels has been recently proposed. We investigated the effect of the K_v7 channel activator, flupirtine, on PAH in two independent mouse models: PAH induced by hypoxia and spontaneous PAH in mice over-expressing the 5-HT transporter (SERT⁺ mice).

Experimental approach:

Right ventricular pressure was assessed in vivo in mice chronically treated with flupirtine (30 mg·kg⁻¹·day⁻¹). In separate in vitro experiments, pulmonary arteries from untreated mice were mounted in a wire myograph. Relaxations to acute administration of flupirtine and contractions to K_v channel blocking drugs, including the K_v7 channel blocker linopirdine, were measured.

Key results:

In wild-type (WT) mice, hypoxia increased right ventricular pressure, pulmonary vascular remodelling and right ventricular hypertrophy. These effects were attenuated by flupirtine, which also attenuated these indices of PAH in SERT⁺ mice. In the in vitro experiments, flupirtine induced a potent relaxant response in arteries from untreated WT and SERT⁺ mice. The relaxation was fully reversed by linopirdine, which potently contracted mouse pulmonary arteries while other K_v channel blockers did not.

Conclusions and implications:

Flupirtine significantly attenuated development of chronic hypoxia-induced PAH in mice and reversed established PAH in SERT⁺ mice, apparently via K_v7 channel activation. These results provide the first direct evidence that drugs activating K_v7 channels may be of benefit in the treatment of PAH with different aetiologies.     

Assessment of the multidisciplinary education for a major change in clinical practice; a prospective cohort study

Background  

New approaches are often introduced to the neonatal intensive care unit (NICU) and other areas of the health service in either a haphazard or cataclysmic fashion. The needs of staff education are often addressed incompletely or too late. Rarely is education assessed after the introduction of a major change. We changed the basis of our NICU respiratory support. We conducted a major educational and support program before this intervention. This study documented and assessed the educational components of this change in our health service provision.     

The Stimulatory Effects of Topical Application of Radioactive Lantern Mantle Powder on Wound Healing

Some people in different parts of Iran use burned mantles as a wound healing medicine. To perform surface area measurement, twenty rats were divided randomly into two groups of 10 animals each. The 1st group received topical burned radioactive lantern mantle powder at 1st-3rd day after making excision wounds. The 2nd group received non-radioactive lantern mantle powder. For histological study, 36 male rats randomly divided into two groups of 18 animals each. Full thickness excision wound (314±31.4 mm²) was made on the dorsal neck in all animals after inducing general anesthesia. For the first 3 days, cases received topical application of the radioactive lantern mantle powder. Finally, to measure the tensile strength, an incision was made on the dorsal neck of the rats. Surface area measurement of the wounds showed a progressive surface reduction in both groups. Histological study showed a significant statistically difference between cases and controls with respect to fibrinoid necrosis and neutrophilic exudate at the days 3 and 14. Considering the existence of granulation tissue, a significant difference was observed between case and control groups at days 3 and 7. Tensile strength study showed no significant difference between the cases and controls until 30 days after excision.     

Cultural adaptation of birthing services in rural Ayacucho, Peru

Problem

Maternal mortality is particularly high among poor, indigenous women in rural Peru, and the use of facility care is low, partly due to cultural insensitivities of the health care system.

Approach

A culturally appropriate delivery care model was developed in poor and isolated rural communities, and implemented between 1999 and 2001 in cooperation with the Quechua indigenous communities and health professionals. Data on birth location and attendance in one health centre have been collected up to 2007.

Local setting

The international nongovernmental organization, Health Unlimited, and its Peruvian partner organization, Salud Sín Límites Perú, conducted the project in Santillana district in Ayacucho.

Relevant changes

The model involves features such as a rope and bench for vertical delivery position, inclusion of family and traditional birth attendants in the delivery process and use of the Quechua language. The proportion of births delivered in the health facility increased from 6% in 1999 to 83% in 2007 with high satisfaction levels.

Lessons learned

Implementing a model of skilled delivery attendance that integrates modern medical and traditional Andean elements is feasible and sustainable. Indigenous women with little formal education do use delivery services if their needs are met. This contradicts common victim-blaming attitudes that ascribe high levels of home births to “cultural preferences” or “ignorance”.     

Treatment disparities for disabled medicare beneficiaries with stage I non-small cell lung cancer

Iezzoni LI, Ngo LH, Li D, Roetzheim RG, Drews RE, McCarthy EP. Treatment disparities for disabled Medicare beneficiaries with stage I non-small cell lung cancer.

Objective

To compare initial treatment and survival of nonelderly adults with and without disabilities newly diagnosed with non-small cell lung cancer.

Design

Retrospective analyses; population-based cohorts.

Setting

Eleven Surveillance, Epidemiology, and End Results cancer registries.

Participants

Persons with disability Medicare entitlement (n=1016) and nondisabled persons (n=8425) ages 21 to 64 years when diagnosed with stage I, pathologically confirmed, first primary non-small cell lung cancer between January 1, 1988, and December 31, 1999.

Interventions

Not applicable.

Main Outcome Measures

Initial cancer treatments (surgery, radiotherapy), survival (through December 31, 2001). Multivariable logistic regression and Cox proportional hazards regression estimated adjusted associations of disability status with treatments and survival.

Results

Persons with disabilities were much more likely to be male, non-Hispanic black, and not currently married. Although 82.2% of nondisabled persons had surgery, 68.5% of disabled persons received operations. Adjusted relative risks (RRs) of receiving surgery were especially low for persons with respiratory disabilities (adjusted RR=.76; 95% confidence interval [CI], .67-.85), nervous system conditions (adjusted RR=.86; 95% CI, .76-.98), and mental health and/or mental retardation disorders (adjusted RR=.92; 95% CI, .86-.99). Persons with disabilities had significantly higher cancer-specific mortality rates (hazard ratio [HR]=1.37; 95% CI, 1.24-1.51) than persons without disabilities. Observed differences in cancer mortality persisted after adjusting for demographic and tumor characteristics (adjusted relative HR=1.23; 95% CI, 1.10-1.39). Further adjustment for surgery use eliminated statistically significant differences in cancer mortality between persons with and without disabilities across disabling conditions.

Conclusions

Persons with disabilities were much less likely than nondisabled Medicare beneficiaries to receive surgery; statistically significant cancer-specific mortality differences disappeared after accounting for these treatment differences. Future research must explore reasons for these findings and whether survival of disabled Medicare beneficiaries with early-stage, non-small cell lung cancer could improve if surgical treatment disparities were eliminated.     

Early renal post-ischaemic tissue damage and dysfunction with contribution of A1-adenosine receptor activation in rat

Aim:   This study investigated the effect of a selective A₁-adenosine receptor (A₁-AR) antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), on the renal dysfunction and histological damage induced by ischaemia/reperfusion at an early stage.
Methods:   Pentobarbital anaesthetised rats were prepared for measuring renal functional variables. Ischaemia was induced by bilateral renal artery clamping for 30 min followed by a 4 h reperfusion period. In DPCPX-treated rats, it was infused (i.v.) at 10 µg/kg per min before and after renal ischaemia. Both kidneys were examined using light and electron microscopy.
Results:   The renal ischaemic challenge resulted in major histological and ultrastructural damages, which were associated with decreased creatinine clearance, absolute potassium-excretion and effective free-water reabsorption, but increased fractional sodium-excretion and urine flow during reperfusion period. In DPCPX-treated rats, the histological and ultrastructural damage to the kidneys was improved along with the decrease in creatinine clearance and increase in fractional sodium-excretion being smaller, but the increase in urine flow being larger than those of the non-treated rats, while absolute potassium-excretion and effective free-water reabsorption were equal to those of the sham-operated rats.
Conclusion:   These findings suggest that endogenous activation of A₁-AR contributes to the early development of renal ischaemia/reperfusion injury.     

The Timing of Calcium Measurements in Helping to Predict Temporary and Permanent Hypocalcaemia in Patients Having Completion and Total Thyroidectomies

INTRODUCTION

Postoperative hypocalaemia commonly occurs after extensive thyroid surgery and may require calcium and/or vitamin D supplements to alleviate or prevent the symptoms. In this study, we determined the risk factors for developing hypocalcaemia and whether early serum calcium levels can predict the development of or differentiate between temporary or permanent hypocalcaemia.

PATIENTS AND METHODS

A total of 162 patients who either had a completion or total thyroidectomy formed the basis of this prospective study. Serial serum calcium measurements were recorded as well as details of the operation, pathology, indications for surgery, number of parathyroids identified at operation and any complications.

RESULTS

Eighty-four (52%) patients did not develop hypocalcaemia but 69 (43%) were found to have temporary hypocalcaemia and 9 (5%) had permanent hypocalcaemia. Hypocalcaemia was more common after total than completion thyroidectomies and the identification of parathyroids at operation appears to have a significant adverse effect on outcome. The calcium levels measured on day 1 postoperatively and the slope (serum calcium levels of day 1 postoperative minus day of operation) were statistically significant in predicting the development of hypocalcaemia and possibly to differentiate between temporary or permanent hypocalcaemia.

DISCUSSION

Although almost half the patients having extensive thyroid surgery developed hypocalcaemia (as defined by any postoperative corrected serum calcium level of < 2.12 mmol/l) only 24% had a serum calcium of < 2.12 mmol/l associated with clinical symptoms of hypocalcaemia or a calcium level of < 2.0 mmol/l. Only 5% had persistent hypocalcaemia defined as requiring exogenous supplements at 6 months'' postoperatively. Patients having a completion thyroidectomy appear to be less likely to develop hypocalcaemia perhaps as a result of any iatrogenic effects on the parathyroids at the first operation being reversed before the second operation. Identification and, therefore, exposure of parathyroids at operation may have an adverse effect on the blood supply to the glands affecting their function.

CONCLUSIONS

Serum calcium levels measured 6 hours'' post-surgery and on day 1 postoperatively can be useful in predicting if the patient will develop hypocalcaemia and the slope may indicate whether the hypocalcaemia will be temporary or permanent. Patients with toxic goitres and those having a one-stage total thyroidectomy are most at risk of developing hypocalcaemia.     

Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer

Cytochrome P4502E1 (CYP2E1) is involved in the metabolic activation of carcinogenic N-nitrosoamines. We therefore assessed the genotype frequencies of PstI or RsaI CYP2E1 restriction fragment length polymorphisms and another susceptibility marker, mutagen sensitivity, in 137 lung cancer cases (92 African American and 45 Mexican American) and 206 controls (114 African American and 92 Mexican American) identified in a molecular epidemiological study of lung cancer. The CYP2E1 c1/c1 genotype was found in 86.7% of Mexican American cases, 70.6% of Mexican American controls, 89.1% of African American cases and 86.8% of African American controls. By multivariate analysis, this genotype was found to be associated with a 14.0-fold increased risk of lung cancer in Mexican Americans but not in African Americans; a 9.9- fold increased risk of lung cancer in Mexican American former smokers, but not in non-smokers or current smokers; a 15-fold increased risk of lung cancer in Mexican American males, but not in females. Patients with the susceptible genotype appeared to have developed cancer at an earlier age and with lower cigarette pack-year of exposure than did patients with the c1/c2 or c2/c2 genotypes. Stratified analysis suggested a greater than multiplicative interaction between cigarette smoking and CYP2E1 c1/c1 genotype, although not statistically significant. The odds ratios (ORs) for the CYP2E1 c1/c1 genotype, cigarette smoking and both risk factors combined were 1.3, 6.7 and 16.3, respectively. The association between CYP2E1 c1/c1 genotype and pack-years of smoking followed the same pattern. The interaction between mutagen sensitivity and CYP2E1 c1/c1 genotype was especially strong in former smokers (the ORs for the CYP2E1 c1/c1 genotype, mutagen sensitivity and both risk factors combined were 3.9, 5.4 and 23.0, respectively). Therefore, the data suggest that individuals who lack a c2 allele might be at higher risk for developing lung cancer.