Learning-induced modulation of SK channels-mediated effect on synaptic transmission

Although small conductance (SK)-mediated calcium-dependent potassium currents are usually mostly thought to modulate neuronal adaptation by suppressing repetitive spike firing, recent evidence suggests that these channels also modulate synaptic transmission. SK2 channels were shown to be activated in dendritic spines following calcium entry via N-methyl-d-aspartate (NMDA) receptor. Such activation of potassium currents terminates the NMDA-dependent postsynaptic potential (PSP). Synaptic potentials in pyramidal neurons in the piriform cortex from olfactory-discrimination-trained rats have enhanced rise time 3 days after learning, and their dendritic spines are significantly smaller at this time. In the present study we examined whether the SK channel-mediated effect on PSPs is modified after learning. The SK channels inhibitor, apamin, that selectively blocks the SK channels-mediated potassium currents enhanced the width of the PSP in neurons from trained rats only. This effect is abolished in the presence of the NMDA-channel blocker, APV. The learning-induced reduction in paired-pulse facilitation was not affected by apamin. Although the effect of the SK channels is increased after learning, the protein expression level of the SK2 channels, the type located in dendritic spines, was decreased after learning. The protein expression level of the SK3 channel, suggested to be located mainly in axon terminals, was not modified by learning. We suggest that the enhanced effect of the SK channels on NMDA-mediated synaptic transmission is the result of the reduction in the spine volume after learning. Moreover, these data indicate that spines are more excitable after learning, and are thus more predisposed to activity-dependent modifications.     

Correlation of CO2 pneumoperitoneal pressures between rodents and humans

Introduction  Many studies have reported on the effects of pneumoperitoneum in a rat model, using a wide range of intra-abdominal pressures. The correlation between pneumoperitoneal pressures in rodents to pressures in humans has not been established. This study evaluates changes in various physiological parameters in different pneumoperitoneum pressures in the rat model with a comparison to known data in humans. Materials and methods  Three groups of eight Wistar rats each were anesthetized, tracheostomized, and mechanically ventilated with fixed tidal volume and respiratory rate. After a stabilization phase, CO₂ pneumoperitoneum was established to 12, 8, and 5 mmHg in the different groups. Changes in blood pressure, heart rate, peak ventilatory pressure, and end-tidal CO₂ (ETCO₂) were recorded throughout the experiment. Results  There were no significant changes in blood pressure and heart rate in all groups. No increase in ETCO₂ was demonstrated following induction of pneumoperitoneum in the 12 and 8 mmHg groups. A statistical significant increase in ETCO₂ occurred only in the 5 mmHg group (39.4 to 41.3 mmHg, p = 0.023). Ventilatory pressures increased after induction of pneumoperitoneum in all groups. The increase reached a maximal level in the 8 and 12 mmHg groups (from 3 to 12 mmHg) and was lower in the 5 mmHg group (from 3 to 7 mmHg) Conclusions  The neglected increase in ETCO₂ in pressures ≥8 mmHg, in the rat correlates to high pressures in humans (above 14–20 mmHg) when CO₂ diffusion through the peritoneum declines due to pressure occlusion of peritoneal capillaries. The maximal ventilatory pressures generated in the rat in intra-abdominal pressures ≥8 mmHg correlate to pressures, which are higher than the standard working pressures in humans. Thus, pneumoperitoneal pressures >8 mmHg in the rat do not simulate routine working pressures employed in humans. A pressure of 5 mmHg is optimal in a rat model to simulate laparoscopy in humans.     

Dry chemistry thin film immunoassay

The authors report the development of a novel thin film multilayer immunoassay technology. The technology is applied to therapeutic drug monitoring and thyroid hormone testing in serum or plasma and can be extended to assays of other low molecular weight analytes. The assay detection range spans five orders of magnitude, from 1 x 10(-3) to 1 x 10(-8) M. The assay element comprises of multilayer coated chip, containing the active reagents in an agarose matrix and a plastic module serving both as a holder and a spreader. The assays are in the fluorescent competitive immunoassay format of the ligand displacement mode and are performed on an automated instrument with random access capability. The assays are fast and reliable and gave very good agreement when compared to reference methods.     

Interleukin-2-induced lung permeability is mediated by leukotriene B4

Interleukin (IL)-2 therapy leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of the chemoattractant, immunomodulator, and permeability-promoting agent leukotriene (LT) B4 in this setting. Sheep with chronic lung lymph fistulae were given IL-2, 10(5) U/kg as an IV bolus (n = 6). Within 2 hours this led to a significant increase in LTB4 levels in both plasma and lung lymph. The mean pulmonary artery pressure (MPAP) rose while the pulmonary artery wedge pressure was unchanged. Arterial oxygen tension (PaO2) fell. Lung lymph flow (QL) was tripled (P less than 0.05) at 3 hours, coinciding with an increase in the lymph/plasma (L/P) protein ratio (P less than 0.05) resulting in an increase in the lymph protein clearance (P less than 0.05), data documenting increased microvascular permeability to protein. Mild leukopenia and thrombocytopenia (P less than 0.05) occurred. Body temperature rose and shaking chills were common. Pretreatment with the lipoxygenase inhibitor diethylcarbamazine (DEC; n = 6) reduced baseline plasma LTB4 levels and prevented the IL-2-induced increases in LTB4 in plasma and lung lymph (P less than 0.05). In contrast to IL-2 treatment alone, DEC blunted the increase in MPAP and prevented the rises in QL (P less than 0.05), L/P protein ratio (P less than 0.05), and lymph protein clearance (P less than 0.05). DEC also prevented the IL-2-induced leukopenia, the fall in platelet count, and the rise in body temperature (P less than 0.05, respectively). Infusion of IL-2 excipient control (n = 5) did not affect plasma or lymph LTB4 levels but there were mild increases in MPAP (P less than 0.05). The QL also rose but this occurred while the L/P protein ratio fell (P less than 0.05). Body temperature rose moderately. The PaO2, leukocyte, and platelet counts were unaffected. These data indicate that IL-2 administration leads to pulmonary dysfunction manifest by pulmonary hypertension and increased vascular permeability, events associated with LTB4 synthesis and prevented by DEC. Leukotriene B4 appears therefore to mediate the IL-2-induced lung injury.     

Fotemustine and DTIC combination in patients with disseminated malignant melanoma.

Seventeen patients with histologically proven melanoma and measurable metastatic disease received 7-week cycles of fotemustine 100 mg/m2/day on days 1 and 8, and decarbazine (DTIC) 500 mg/m2/day on days 15 and 16, in a prospective open study, to assess the efficacy of fotemustine-DTIC combination. Response rate was 11.7%: one partial response (PR) in brain for 4.5 months, and one PR in brain and lymph nodes for 4 months. There was also one (5.8%) minimal response (MR) in brain, stomach, and lymph nodes for 8 months, and three (17.6%) patients with stable disease. Survival of responders was significantly superior to nonresponders. There was no response in brain without response in extracerebral sites. Toxicity was generally mild and well tolerated by all the patients. Fotemustine-DTIC showed some activity against metastatic melanoma, and should be further evaluated.     

Thawing day 3 embryos and culturing to day 5 may be a better method for frozen embryo transfer

Purpose

Does thawing cleavage embryos and culturing them for transfer as blastocysts improve pregnancy and perinatal outcomes compared to transferring thawed blastocysts?

Methods

Retrospective, observational cohort study performed at two assisted reproductive technology centers, 2014 to 2020. A total of 450 patients with 463 thawed embryo transfer cycles were divided into 2 groups according to the embryonic developmental stage at cryopreservation and transfer: 231 thawed blastocysts (day 5 group) and 232 thawed cleavage embryos that were cultured for 2 days and transferred as blastocysts (day 3–5 group). The two groups were compared for demographics, routine parameters of IVF treatment, pregnancy rates, and perinatal outcomes.

Results

Multivariable logistic regression analysis for ongoing pregnancy and delivery demonstrated that the day 3–5 group had a greater likelihood of achieving ongoing pregnancy and delivery compared to the day 5 group (OR 1.58, 95%CI 1.062–2.361, p?=?0.024). Perinatal outcomes were comparable between the three groups.

Conclusion

Our results support culturing post-thaw cleavage embryos for 2 days and transferring them as blastocysts to increase chances of ongoing pregnancy and delivery.

     

Comparison of the effects of adenosine and nifedipine in pulmonary hypertension.

The hemodynamic effects of intravenously administered adenosine, a potent vasodilator, were examined in 15 patients with pulmonary hypertension. All patients were given adenosine, 50 micrograms/kg per min, increased by 50 micrograms/kg per min at 2 min intervals to a maximum of 500 micrograms/kg per min or until the development of untoward side effects. The patients were then given oral nifedipine, 20 mg every hour, until a greater than or equal to 20% decrease in pulmonary vascular resistance or systemic hypotension occurred. The administration of maximal doses of adenosine, 256 +/- 46 micrograms/kg per min, produced a 2.4% reduction in pulmonary artery pressure (p = NS), a 37% decrease in pulmonary vascular resistance (p less than 0.001) and a 57% increase in cardiac index (p less than 0.001). The administration of maximally effective doses of nifedipine (91 +/- 36 mg) produced a 15% reduction in the mean pulmonary artery pressure (p less than 0.05), a 24% decrease in pulmonary vascular resistance (p less than 0.01) and an 8% increase in cardiac index (p = NS). There was a significant correlation (r = 0.714, p = 0.01) between the reduction in pulmonary vascular resistance that resulted from adenosine administration and that achieved with the administration of nifedipine. Six patients had substantial reductions in pulmonary vascular resistance with adenosine but not with nifedipine. Thus, adenosine is an effective vasodilator in patients with pulmonary hypertension and can be used for safe and rapid assessment of vasodilator reserve in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of body posture on exercise- and hyperventilation-induced asthma

Recent studies have shown that swimming is of relatively low asthmogenicity, even under conditions of high respiratory heat (and/or water) loss (RHL). It has been suggested that the horizontal body position may contribute to swimming's low asthmogenicity. We studied the effects of upright and prone body postures on pulmonary function following exercise (EIA) and after nonexercise hyperventilation (HIA). Twelve asthmatic boys (aged 12 to 16 years) underwent two 8-min exercise sessions of shoulder flexion-extension and two 8-min isocapnic hyperventilation treatments, in a counterbalanced order, either while lying prone or standing upright. All tests were carried out in a climatic chamber at 10 +/- 1 degree C and 31 +/- 2 percent relative humidity. Minute ventilation (VE) was kept constant at a predetermined individual level during all treatments. No differences were observed in pulmonary functions between the prone and upright postures following either exercise (FEV1 = -20.5 +/- 18.7 percent vs -22.2 +/- 18.7 percent, respectively) or hyperventilation (FEV1 = -29.6 +/- 19.0 percent vs -29.7 +/- 20.2 percent). We conclude that body posture on land has no meaningful effect on the severity of bronchoconstriction in asthmatic children; however, in view of some conceivable physiologic benefits of the prone position in water, an interactive effect on swimming-induced asthma (SIA) of body posture and water immersion cannot be ruled out.     

Metastatic disease of the cavernous sinus: contribution of computed tomography and magnetic resonance imaging to diagnosis

The clinical presentation of metastatic disease to the cavernous sinus includes ophthalmoplegia, pain and sensory deficit along the optic or maxillary branches of the trigeminal nerve. The role of a CT scan and magnetic resonance imaging in the diagnosis is discussed. It was found that magnetic resonance imaging is superior to CT scan in demonstrating the cavernous sinus and pontine borders, especially in lymphomatous involvement of these structures.     

Cisplatin-related Lhermitte's sign.

The sensation of a sudden electrical impulse travelling along the spine to the legs and feet on flexion of the neck has been known as Lhermitte's sign. Lhermitte's sign, as part of cisplatin-related neurotoxicity, was observed in four patients, with ovarian or lung cancer, simultaneously with peripheral neuropathy, after a dose of 375-700 mg/m2. The dose intensity (DI) of cisplatin in our patients ranged from 12.5 to 26.9 mg/m2/week. No direct relationship was found between DI and the timing of Lhermitte's sign. Other relevant causes for this sign were ruled out. The mechanism responsible for the development of Lhermitte's sign is unclear. Interruption of treatment with cisplatin may not prevent the appearance of Lhermitte's sign. In most of the reported cases in the literature this sign developed after the end of cisplatin courses.