Hypertrophic cardiomyopathy and pregnancy.

Women with pre-existing cardiomyopathies have limited cardiovascular reserve. The hemodynamic challenges of pregnancy, labor, and delivery pose unique risks to this group of patients, which can result in clinical decompensation with overt heart failure, arrhythmias, and rarely, maternal death. A multidisciplinary team approach and a controlled delivery are crucial to adequate management of patients with underlying heart disease. Preconception planning and risk assessment are essential and proper counseling should be offered to expectant mothers regarding both the risks that pregnancy poses, and the implications for future offspring. In this paper, we will review the hemodynamic stressors that pregnancy places upon women with hypertrophic cardiomyopathies, risk assessment and discuss what evidence exists regarding the management during pregnancy, labor, and delivery for hypertrophic cardiomyopathy.

Gait variability measurements in lumbar spinal stenosis patients: part A. Comparison with healthy subjects.

The objective of this study is to compare the gait variability of patients with lumbar spinal stenosis (experimental group) with healthy individuals (control group). The hypothesis is that the preoperative gait variability of the experimental group is higher than the control group. The experimental group consisted of 35 adults (18 males, 17 females). The subjects of the experimental group suffered exclusively from spinal stenosis. The patients were determined by MRI scans. A tri-axial accelerometer sensor was used for the gait measurement, and differential entropy algorithm was used to quantify the gait acceleration signal. The Oswestry Low Back Pain Questionnaire was used to determine the condition on the day of the measurement. Receiver operating characteristic (ROC) was utilized to assess the diagnostic value of the method and determine a cut-off value. There is a statistically significant difference between gait variability in the control group and the experimental group. ROC analysis determines a cut-off differential entropy value. The cut-off value has a 97.6% probability of separating patients with spinal stenosis from healthy subjects. The Oswestry Low Back Questionnaire is well correlated with the spectral differential entropy values.

Gait variability measurements in lumbar spinal stenosis patients: part B. Preoperative versus postoperative gait variability.

The objective of this study was to assess the gait variability of lumbar spinal stenosis (LSS) patients and to evaluate its postoperative progression. The hypothesis was that LSS patients' preoperative gait variability in the frequency domain was higher than the corresponding postoperative. A tri-axial accelerometer sensor was used for the gait measurement and a spectral differential entropy algorithm was used to measure the gait variability. Twelve subjects with LSS were measured before and after surgery. Preoperative measurements were performed 2 days before surgery. Postoperative measurements were performed 6 and 12 months after surgery. Preoperative gait variability was higher than the corresponding postoperative. Also, in most cases, gait variability appeared to decrease throughout the year.

Intramural hematoma of the aorta: delayed pericardial tamponade.

Intramural hematoma of the aorta is a fatal disorder that remains poorly characterized. Recently, it has been accepted as a variant form of aortic dissection, where blood accumulates within the aortic media without the presence of an intimal tear. Clinically, it may present somewhat similar to dissection, and although optimal therapy remains controversial, current opinion supports surgery as the preferred method of treatment for intramural hematomas that involve the ascending aorta and aortic arch.

Body mass index (BMI) and parameters of bone formation and resorption in postmenopausal women.

OBJECTIVES: Aim of this study was to evaluate increased body mass index (BMI) as an anthropometric factor, predisposing to lower rates of bone turnover or changes in bone balance after menopause. MATERIAL AND METHODS: For this purpose, we calculated BMI, and measured spinal (BMD(SP)) and femoral bone mineral density (BMD(FN)) and biochemical markers of bone formation (serum osteocalcin (S-OC), serum procollagen type I C propeptide (S-PICP), serum bone-specific alkaline phosphatase (S-B-ALP)) and resorption (urine N- and C-terminal cross-linking telopeptide of type I collagen (U-NTX-I and U-CTX-I), pyridinoline (U-PYD) and deoxypyridinoline (U-DPD)) in 130 healthy postmenopausal women, aged 46-85 years. Bone balance indices were calculated by subtracting z-scores of resorption markers from z-scores of formation markers, to evaluate bone balance. RESULTS: S-PICP ( r = -0.297, P = 0.002), S-OC ( r = -0.173, P = 0.05) and bone balance indices (zPICP-zDPD) and (zPICP-zPYD) were negatively correlated with BMI (r = -0.25, P = 0.01 and r = -0.25, P = 0.01 and r = -0.21, P = 0.037) and with BMD(SP) (r = -0.196, P = 0.032 and r = -0.275 and P = 0.022). Women were grouped according to their BMI, in normals (BMI < 25 kg/m2), overweight (BMI = 25-30 kg/m2, and obese (BMI > 30 kg/m2). Overweight and obese women had approximately 30% lower levels of S-PICP compared to normals (68.11 +/- 24.85 and 66.41 ng/ml versus 97.47 +/- 23.36 ng/ml, respectively; P = 0.0001). zPICP-zDPD, zPICP-zCTX-I and zPICP-zPYD were significantly declined in obese women compared to normals (P = 0.0072, 0.02 and 0.0028). CONCLUSIONS: We conclude that in postmenopausal women, BMI is inversely associated with levels of collagen I formation marker, serum PICP. In obesity formation of collagen I was reduced, in favor of degradation, but since this finding is not followed by simultaneous decrease in bone mineral density, it seems that increased body weight may have different effects on mature estrogen-deficient bone and extraskeletal tissues containing collagen I.

Functional outcome of burst fractures of the thoracolumbar spine managed non-operatively, with early ambulation, evaluated using the load sharing classification.

The purpose of this prospective study was to assess the functional outcome of conservative treatment with early ambulation of thoracolumbar burst fractures, using the Load Sharing classification. From 1997 to 2001, 60 consecutive patients with single-level thoracolumbar spinal injury, with no neurological impairment, were classified according to the Load Sharing scoring and were managed non-operatively. A custom-made thoracolumbosacral orthosis was worn by all patients for six months, and early ambulation was recommended. Several radiological parameters were evaluated; the Denis Pain and Work Scale was used to assess the clinical outcome. The average follow-up period was 42 months (range, 24 to 55 months). During this period the spinal canal occupation was significantly reduced. Other radiological parameters, such as Cobb's angle and anterior vertebral body compression, showed loss of fracture reduction, which was not statistically significant. However, the functional outcome was satisfactory in 55 of 60 patients with no complications recorded on completion of treatment. Load Sharing scoring is a reliable and easy-to-use classification for the conservative treatment and prognosis of thoracolumbar spinal fractures. Because of the three characteristics of the fracture site this classification can also predict the structural results of spinal injury, such as posttraumatic kyphosis, as well as the functional outcome in conservatively treated patients.

The influence of tibolone upon serum leptin levels in post-menopausal women.

OBJECTIVE: To estimate serum leptin levels in post-menopausal women, to relate these to the duration of the post-menopausal period, and to body mass index (BMI), and to assess the influence of tibolone on them. METHODS: Fifteen women (age 49-64 years) were included. Three groups were studied; I, those with normal BMI taking tibolone; II, those with a raised BMI taking tibolone, and III, a group with raised BMI not taking tibolone. Blood samples were drawn before and 1, 2, 6, 9 and 12 months after the initiation of tibolone or, in group III, after the start of the study. RESULTS: Serum leptin concentrations were high in all women with abnormal BMI. Long-term tibolone administration did not have any significant effect on serum leptin concentrations. There was no correlation between serum leptin levels and the age and the duration of post-menopausal period. There was a high positive correlation between serum leptin levels and BMI values. CONCLUSIONS: BMI values affect serum leptin concentrations but long-term tibolone administration does not seem to have any effect on serum leptin levels.

Hormone replacement therapy at the threshold of 21st century.

The management of postmenopausal women has become a major focus for the medical profession. The menopause era should progress from a period of "chaos" to an orderly understanding of the many issues related to the menopause and hormone replacement therapy (HRT). Although HRT has beneficial clinical effect and positive benefit/risk ratio, understanding of the side effects and weight gain, and, especially, a fear of cancer limit compliance. New data from long-term, controlled, prospective studies on the effects of different HRT schedules on cancer, cardiovascular disease and osteoporotic fracture risk are needed. HRT should be considered either as for prevention or for individualized care since women experience menopause as individuals, care should be taken not to make inappropriate generalizations. The priority should be the administration of appropriate medication to women with the best result in order to improve health care and quality of life. New therapeutic options will offer substantial medical advancement for the treatment of postmenopausal women.

The effect of testicular seminoma in semen quality.

Although male subfertility has been reported in a variety of malignancies, most notably testicular carcinoma, the literature that refers to semen quality in males with testicular seminoma is very limited. This study was designed to evaluate the effect of testicular seminoma in semen quality and especially in its three main parameters. Semen specimens from 12 men, aged 24-38 years, with testicular seminoma before they underwent orchidectomy and adjuvant radiotherapy to the ipsilateral para-aortic and pelvic lymph nodes, and from 60 fertile men, aged 24-44 years, were studied. The results support the view that testicular seminoma exerts a deleterious effect on spermatogenesis and consequently to the three main parameters of the semen. The mechanism though of the deleterious effect of seminoma on spermatogenesis remains unclear.

Hetero-domain interactions as a mechanism for the regulation of connexin channels.

Previous studies have shown that chemical regulation of connexin43 (Cx43) depends on the presence of the carboxyl terminal (CT) domain. A particle-receptor (or "ball-and-chain") model has been proposed to explain the mechanism of gating. We tested whether the CT region behaved as a functional domain for other members of the connexin family. The pH sensitivity of wild-type and Ct-truncated connexins was quantified by use of electrophysiological and optical techniques and the Xenopus oocyte system. The CT domain of Cx45 had no role in pH regulation, although a partial role was shown for Cx37 and Cx50. A prominent effect was observed for Cx40 and Cx43. In addition, we found that the CT domain of Cx40 that was expressed as a separate fragment rescued the pH sensitivity of the truncated Cx40 (Cx40tr), which was in agreement with a particle-receptor model. Because Cx40 and Cx43 often colocalize and possibly heteromerize, we tested the pH sensitivity of Cx40tr when coexpressed with the CT domain of Cx43 (hetero-domain interactions). We found that the CT domain of Cx43 enhanced the pH sensitivity of Cx40tr; similarly, the CT domain of Cx40 restored the pH sensitivity of the truncated Cx43. In addition, the CT domain of Cx43 granted insulin sensitivity to the otherwise insulin-insensitive Cx26 or Cx32 channels. These data show that the particle-receptor model is preserved in Cx40 and the regulatory domain of one connexin can specifically interact with a channel formed by another connexin. Hetero-domain interactions could be critical for the regulation of heteromeric channels.

Connexin diversity and gap junction regulation by pHi.

The molecular mechanisms controlling pH-sensitivity of gap junctions formed of two different connexins are yet to be determined. We used a proton-sensitive fluorophore and electrophysiological techniques to correlate changes in intracellular pH (pHi) with electrical coupling between connexin-expressing Xenopus oocytes. The pH sensitivities of alpha 3 (connexin46), alpha 2 (connexin38), and alpha 1 (connexin43) were studied when these proteins were expressed as: 1) nonjunctional hemichannels (for alpha 3 and alpha 2), 2) homotypic gap junctions, and 3) heterotypic gap junctions. We found that alpha 3 hemichannels are sensitive to changes in pHi within a physiological range (pKa = 7.13 +/- 0.03; Hill coefficient = 3.25 +/- 1.73; n = 8; mean +/- SEM); an even more alkaline pKa was obtained for alpha 2 hemichannels (pKa = 7.50 +/- 0.03; Hill coefficient = 3.22 +/- 0.66; n = 13). The pH sensitivity curves of alpha 2 and alpha 3 homotypic junctions were indistinguishable from those recorded from hemichannels of the same connexin. Based on a comparison of pKa values, both alpha 3 and alpha 2 gap junctions were more pHi-dependent than alpha 1. The pH sensitivity of alpha 2-containing heterotypic junctions could not be predicted from the behavior of the two connexons in the pair. When alpha 2 was paired with alpha 3, the pH sensitivity curve was similar to that obtained from alpha 2 homotypic pairs. Yet, pairing alpha 2 with alpha 1 shifted the curve similar to homotypic alpha 1 channels. Pairing alpha 2 with a less pH sensitive mutant of alpha 1 (M257) yielded the same curve as when alpha 1 was used. However, the pH sensitivity curve of alpha 3/alpha 1 channels was similar to alpha 3/alpha 3, while alpha 3/M257 was indistinguishable from alpha 3/alpha 1. Our results could not be consistently predicted by a probabilistic model of two independent gates in series. The data show that dissimilarities in the pH regulation of gap junctions are due to differences in the primary sequence of connexins. Moreover, we found that pH regulation is an intrinsic property of the hemichannels, but pH sensitivity is modified by the interactions between connexons. These interactions should provide a higher level of functional diversity to gap junctions that are formed by more than one connexin.

A particle-receptor model for the insulin-induced closure of connexin43 channels.

Connexin43(Cx43) channels can be regulated by a variety of factors, including low pHi. Structure/function studies from this laboratory have demonstrated that pH gating follows a particle-receptor mechanism, similar to the "ball-and-chain" model of voltage-dependent inactivation of ion channels. The question whether the particle-receptor model is applicable only to pH gating or to other forms of Cx43 regulation as well remains. To address this question, we looked at the uncoupling effects of insulin and of insulin-like growth factor-1 (IGF) on Cx43 channels expressed in Xenopus oocytes. These agonists do not induce changes in pHi. Junctional conductance (Gj) was measured by the dual 2-electrode voltage-clamp technique. Control studies showed that relative Gj did not change spontaneously as a function of time. Continuous exposure of Cx43-expressing oocytes to insulin (10 micro/L) led to a decrease in Gj. After 80 minutes, Gj was 54+/-5% from control (n= 12). Exposure of oocytes to IGF (10 nmol/L) caused an even more pronounced change in Gj (37+/-4% of control, n=6). The time course of the IGF-induced uncoupling was similar to that observed after insulin exposure. The effect of insulin was abolished by truncation of the carboxyl-terminal domain of Cx43 at amino acid 257 (M257). Interestingly, as in the case of pH gating, coexpression of the carboxyl-terminal domain (amino acids 258 to 282) together with M257 rescued the ability of insulin to reduce coupling (Gj, 39+/-12% from control; n=6). Structure/function experiments using various deletion mutants of the carboxyl-terminal domain showed that insulin treatment does not modify Gj if amino acids 261 to 280 are missing from the Cx43 sequence. Our results suggest that a particle-receptor (or ball-and-chain) mechanism, similar to that described for pH gating, also applies to chemical regulation of Cx43 by other factors.

Early afterdepolarization formation in cardiac myocytes: analysis of phase plane patterns, action potential, and membrane currents.

INTRODUCTION: Early afterdepolarizations (EADs) are among the mechanisms proposed to underlie ventricular arrhythmias. Sea anemone toxin, ATXII, known to delay Na inactivation and to induce plateau level voltage oscillations, was used to study the formation of EADs. METHODS AND RESULTS: Action potential and membrane currents were studied in rat ventricular myocytes using whole cell current and voltage clamp techniques. Phase plane trajectories were generated by plotting membrane potential (V) versus the first time derivative of membrane potential (dV/dt). Under current clamp conditions, ATXII (40 nM) consistently prolonged the action potential and induced EADs. The EADs developed at a plateau voltage between -10 and -40 mV. Calcium channel blockers, verapamil 10 microM and cobalt 4 mM, and the sarcoplasmic reticulum modulator, ryanodine (1 microM), did not antagonize ATXII effects on the action potential and EADs. However, Na channel blockers, tetrodotoxin 0.3 microM and lidocaine 40 microM, and rapid stimulation consistently shortened the prolonged action potential and suppressed EADs. Under voltage clamp conditions in the presence of ATXII, a slowly decaying inward current followed the fast inward current during depolarizing pulses. Membrane currents flowing at or later than 100 msec after the test pulse were analyzed. The control isochronal current-voltage (I-V) curves showed no late inward currents. In the presence of ATXII, all the isochronal I-V curves showed an inward current that was more prominent between -40 and 0 mV. The ATXII-induced current at the 100-msec isochrone activated at a potential of approximately -60 mV, peaked at about -20 mV, and reversed at +40 mV consistent with the Na current I-V curve. The isochronal I-V curves obtained after lidocaine superfusion resembled those of the control. The phase plane trajectory of the action potential obtained with ATXII showed an oscillatory behavior corresponding to the EAD range of potential; within this voltage range, the isochronal I-V curves were shown to cross the abscissa three times instead of once. CONCLUSION: These results suggest that, in this experimental model, neither sarcolemmal L-type Ca current nor sarcoplasmic reticulum Ca release plays a significant role in the genesis of ATXII-induced EADs. EADs are generated by a voltage-dependent balance between a markedly prolonged Na inward current and K outward currents within the voltage plateau range of the action potential but not by Ca current reactivation and inactivation.

Danazol influences gonadotropin secretion acting at the hypothalamic level.

OBJECTIVES: The purpose of the study was to determine the influence of danazol on gonadotropin secretion. METHODS: Ten endometriotic patients were treated with danazol for 6 months. To evaluate gonadotropin and estradiol secretion, a gonadotropin-releasing hormone (GnRH) test and a clomiphene citrate (CC) challenge test were carried out in the follicular phase before treatment, during the sixth month of treatment and after the reappearance of the second menses. The same tests were also performed, only once, in the follicular phase of ten normal women. RESULTS: GnRH-stimulated gonadotropin response during danazol treatment was significantly higher than that in the same group of women before and after danazol treatment, as well as in controls. Gonadotropin increase after clomiphene citrate administration during danazol treatment was not significant; moreover, LH response was significantly lower than that in the same group of patients before and after danazol treatment, as well as in controls. CONCLUSIONS: Our results suggest that danazol exerts a suppressive effect on gonadotropin secretion acting at the hypothalamic level.

Calcium requirement in elderly Japanese women.

In order to evaluate calcium requirements (RC) in Japanese elderly women, a calcium balance study was carried out in 9 osteoporotics (73.9 +/- 2.7 years old, mean +/- SE) and 9 normal elderly women (67.0 +/- 2.5 years old). Diet containing 700 mg/day of calcium were given for at least 1 week. Then, diets containing approximately 700 mg/day (722.5 +/- 91.9 mg/day) of calcium in the 1st week and 1,474 mg/day of calcium in the 2nd week were served. The amount of calcium intake to maintain zero balance, defined as daily RC, was 550.4 +/- 50.0 and 648.8 +/- 44.7 mg/day in normal and osteoporotic subjects, respectively. There was no statistically significant difference between these two groups. Although the recommended daily allowance (RDA) for the adult Japanese is 600 mg/day, our study suggests that RDA in the elderly Japanese should be 847 mg.

Effect of dietary magnesium on development of atherosclerosis in cholesterol-fed rabbits.

The effect of dietary magnesium (Mg) on the development of atherosclerosis in cholesterol-fed rabbits was investigated. Male New Zealand White rabbits (n = 31) were placed on five kinds of diets: regular, 1% cholesterol, and 1% cholesterol diets supplemented with either 300, 600, or 900 mg (as Mg) of Mg sulfate. The regular and 1% cholesterol diets contained 400 mg of Mg per 100 g. Each rabbit received 100 g daily of the appropriate diet. Additional Mg was well tolerated and did not affect blood pressure or body weight. The rabbits were sacrificed after 10 weeks, and the oil red O-positive atherosclerotic area that covered the aortic intima and the cholesterol content of the aorta was measured. Additional Mg decreased both the area of the aortic lesions and the cholesterol content of the aortas in a dose-dependent manner. The 1% cholesterol diet significantly increased plasma cholesterol and triglyceride concentrations and decreased high density lipoprotein (HDL) cholesterol concentration. Additional Mg had no further effect on cholesterol and HDL cholesterol concentrations, but it slightly decreased the rise in triglyceride concentration. These results indicate that dietary Mg prevents the development of atherosclerosis in cholesterol-fed rabbits by inhibiting lipid accumulation in the aortic wall.

Inhibition by aspirin of the stimulated PGI2 synthesis after administration of kallikrein to hypertensive patients (new aspects of chemical pathogeny concerning the messenger systems: A and C).

The vascular smooth muscle cells belong to the category of "bidirectionally controlled cells", which can be activated (leading to contraction) by some first-messengers (such as Catecholamine-alpha 1, or Angiotensin II) in connection with a recently discovered intracellular second-messenger system-C (sms-C), namely, Diacylglycerol-dependent Protein Kinase-C + Calcium mobilization. On the other hand, these cells can be inhibited (leading to relaxation) by other first-messengers (such as Catecholamine-beta or PGI2) related to the classical "second-messenger system-A" (sms-A), namely: Ns--Adenylate Cyclase--cAMP--Protein Kinase-A. It is also known that kallikrein (via kinins) can stimulate PGI2 synthesis, and implicitly sms-A, relaxing the vascular tone by counteracting the opposite pressor effect of sms-C. In the four h samples of urine, collected before and after administration of kallikrein (i.m., 40 IU) to six hypertensive patients, we measured (RIA): 6-keto-PGF1 alpha, the stable metabolite of PGI2. The results 5.86 +/- 1.25 vs 9.94 +/- 0.6 pg/mL +/- SEM (p less than 0.05) indicate a rise in PGI2 synthesis. However, no such effect was obtained when the same patients were given aspirin (4 g in divided doses) one day before repeating the above test: 5.59 +/- 1.97 vs 6.85 +/- 1.28 (NS). We may conclude that administration of kallikrein can stimulate PGI2 synthesis, which, in turn, can be blocked by relatively high (= nocive) doses of aspirin. Some new aspects of chemical physiology, pathogeny and systematization of the two major messenger systems, MS-A and MS-C, are discussed.