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Biomedical subjects

J E Hall

Publications and source records attributed to J E Hall.

At least 109 records · Page 6Linked to original sources
PubMed1999

Lumbosacral fusion in children and adolescents using the modified sacral bar technique.

Between 1986 and 1995 10 patients who were 9 to 18 years of age underwent posterior spinal fusion and instrumentation to the pelvis for correction of spinal deformity using the modified sacral bar technique at the authors' institution. Etiologies of the spinal deformity included congenital scoliosis, cerebral palsy, myelomeningocele, neurofibromatosis, and postlaminectomy kyphosis. Indications for pelvic instrumentation were progressive scoliosis of the lower lumbar spine, pelvic obliquity greater than 15 degrees, and dysraphic posterior elements. Five of the patients had prior spinal surgery. Five patients had a prior or a planned pelvic osteotomy. Nine of the patients achieved lumbosacral fusion without an additional procedure. Major complications included loss of pelvic fixation in two patients, and a dural leak and a wound infection in another patient with myelomeningocele. Mean scoliotic curve correction was from 71.9 degrees to 34.5 degrees at final followup. Lumbar lordosis essentially was unchanged. Pelvic obliquity was corrected from a mean of 20.5 degrees preoperatively to a mean of 7.6 degrees at final followup. The modified sacral bar technique was selected for fusion to the sacrum because of planned or prior pelvic osteotomies, prior posterior spinal fusion and instrumentation, sacral dysraphism, or local anatomic anomalies. The modified sacral bar technique proved to be an effective technique in these patients.

Adolescent↗
PubMed1999

Spinal fusion in patients with congenital heart disease. Predictors of outcome.

The strong association between congenital heart disease and spinal deformity is well established, but data on the risks and outcome of spinal fusion surgery in patients with congenital heart disease are scarce. The purpose of this study was to identify predictors of perioperative risk and outcome in a large series of children and adolescents with congenital heart disease who underwent spinal fusion for scoliosis or kyphosis. In the authors' retrospective analysis of 74 consecutive patients with congenital heart disease undergoing spinal fusion, there were two deaths (2.7%) and 18 significant complications (24.3%) in the perioperative period. Preoperative cyanosis (arterial oxygen saturation < 90% at rest) with uncorrected or incompletely corrected congenital heart disease was associated with both deaths. Complications occurred in nine of 18 (50%) patients with cyanosis and in 11 of 56 (20%) patients without cyanosis. As judged by multivariate analysis the best predictors of perioperative outcome were the overall physical status of the patient as represented by the American Society of Anesthesiologists' preoperative score and a higher rate of intraoperative blood loss. Seventeen of 43 patients (40%) with an American Society of Anesthesiologists score of 3 or higher experienced complications including two perioperative deaths. Successful spinal fusion and correction were achieved in 97% of patients. Children and adolescents with congenital heart disease can undergo elective spinal fusion with risks that relate to overall cardiac status. Careful assessment of preoperative status by pediatric cardiologists and cardiac anesthesiologists familiar with surgical treatment of patients with congenital heart disease will assist the orthopaedic surgeon in providing the most realistic estimate of risk.

Adolescent↗
PubMed1999

Cardiovascular regulation during insulin infusion into the carotid or vertebral artery in dogs.

OBJECTIVE: To test the hypothesis that insulin increases heart rate and arterial pressure via direct effects on the central nervous system. METHODS AND DESIGN: Insulin was infused into the cerebral circulation of conscious dogs (n = 8) chronically instrumented for continuous infusions and measurement of arterial pressure, cardiac output, heart rate and other hemodynamic variables. In acute experiments, insulin was infused for 30 min into either a carotid or vertebral artery at several rates calculated to increase cerebral circulation insulin concentrations to levels in the physiological or pathophysiological range. It was infused with and without a simultaneous glucose infusion. During long-term experiments, insulin was infused into either a carotid or a vertebral artery for 4 days at 0.4 or 0.2 mU/kg per min, respectively. RESULTS: Insulin infusion alone into the cerebral circulation produced no changes in any measured cardiovascular variable. A simultaneous glucose infusion also produced no changes in cardiovascular dynamics, except at the highest rate of infusion into the carotid artery. The changes seen at the highest rate of infusion are unlikely to be insulin-induced, since similar changes occurred when either glucose or saline was infused in the absence of any insulin infusion. Long-term insulin infusion (4 days) into carotid or vertebral arteries also produced no changes in any measured cardiovascular or renal variable. CONCLUSIONS: These results provide no evidence that insulin, at physiological or pathophysiological concentrations, increases heart rate or arterial pressure by acting directly on the central nervous system, and suggest that sympathetic activation and tachycardia previously observed with systemic hyperinsulinemia may be secondary to peripheral actions of insulin.

Animals↗
PubMed1999

Integration and regulation of cardiovascular function.

New methods in molecular biology and genetics have made possible many of the dramatic advances in physiological research that have occurred in recent years. For those of us who spend most of our time in the research laboratory, it si sometimes difficult to avoid a research-oriented, reductionist mind-set when discussing physiology with students. This article illustrates, with a few examples, the importance of conveying a "big picture" conceptual framework before discussing the details of cardiovascular physiology. Also, I have chosen examples from cardiac output and blood pressure regulation that show the importance of discussing cardiovascular physiology in terms of feedback control systems and integrating information from other areas, such as renal and endocrine physiology. Finally, I have highlighted the importance of two principles that I believe are often underemphasized in teaching physiology: mass balance and time dependence of physiological control systems.

Cardiac Output↗
PubMed1999

Enhanced vascular reactivity and Ca2+ entry with low-salt diet: effect of obesity.

Salt moderation is often recommended as a nonpharmacological therapy for hypertension, particularly in overweight individuals; however, the effects of low dietary salt on the Ca(2+)-dependent mechanisms of vasoconstriction are unclear. The purpose of this study was to investigate the effect of low salt diet on vascular reactivity and Ca2+ mobilization mechanisms and the modulation of these effects with obesity. Active stress and (45)Ca2+ influx were measured in deendothelialized aortic strips isolated from lean (3.74 kg) and obese (5.51 kg) female rabbits on a normal (0.75%) or low (0.23%) salt (sodium chloride) diet for 18 weeks. Both phenylephrine (Phe, 10(-5) mol/L) and membrane depolarization by 96 mmol/L KCl caused extracellular Ca(2+)-dependent increases in active stress and (45)Ca2+ influx. In lean rabbits, the Phe- and KCl-induced stress and Ca2+ influx were significantly greater with the low-salt versus the normal-salt diet. The Phe-induced Ca2+ influx-stress relationship was significantly greater than that induced by KCl with low-salt diet. In obese rabbits on a normal-salt diet, the Phe- and KCl-induced stress and Ca2+ influx were significantly less than that in lean rabbits but the Ca2+ influx-stress relationship was not significantly altered. Feeding the obese rabbits a low-salt diet was associated not only with significant increases in Phe- and KCl-induced active stress and Ca2+ influx but also with significant enhancement in the Ca2+ influx-stress relationship. In Ca(2+)-free (2 mmol/L EGTA) Krebs solution, stimulation of intracellular Ca2+ release by Phe or caffeine (25 mmol/L) caused a transient contraction that was not significantly different in all groups of rabbits. Thus, with normal salt intake, obesity is associated with a reduction in Ca2+ entry and vascular reactivity. Low-salt diet is associated with an increase in Ca2+ entry and vascular reactivity in both obese and lean rabbits. The enhancement of the Ca2+ influx-stress relationship with low-salt diet, particularly in the obese rabbits, suggests activation of other contractile mechanisms in addition to Ca2+ entry.

Animals↗
PubMed1999

Female reproductive aging is marked by decreased secretion of dimeric inhibin.

The increase in serum FSH that accompanies female reproductive aging occurs before changes in estradiol (E2). A decrease in negative feedback from inhibin A (a product of the dominant follicle and corpus luteum) and/or inhibin B (secreted by developing follicles) may explain the rise in FSH with age. To test the hypothesis that decreases in inhibin A or inhibin B occur at an age at which the first increase in follicular phase FSH is evident, daily blood samples were obtained across the menstrual cycle from younger (<35 yr; n = 23) and older (35-46 yr; n = 21) cycling women. These cross-sectional studies were complemented by longitudinal data in 3 women studied at a 10-yr interval. In the early follicular phase, mean inhibin B was lower in older cycling women (88 +/- 7 vs. 112 +/- 10 pg/mL; P < 0.05) and FSH was higher (13.0 +/- 0.5 vs. 11.2 +/- 0.7 IU/L in older vs. younger, respectively; P < 0.04). In the mid- and late follicular phases, inhibin B was also lower in the older women (117 +/- 9 vs. 146 +/- 10 and 85 +/- 8 vs. 117 +/- 11 pg/mL; P < 0.04), whereas E2 was higher (105 +/- 14 vs. 68 +/- 5 and 240 +/- 27 vs. 163 +/- 9 pg/mL; P < 0.02), and no differences in FSH were observed in the two groups at these times. In women studied longitudinally, FSH and inhibin B varied inversely in the follicular phase. In the early luteal phase, mean inhibin B was lower in the older group (64 +/- 6 vs. 94 +/- 12 pg/mL; P < 0.03), and FSH was higher (12.5 +/- 1.0 vs. 9.7 +/- 0.6 IU/L; P < 0.03). In the mid- and late luteal phases, inhibin B was also lower in older subjects (21 +/- 2 vs. 33 +/- 5 and 22 +/- 2 vs. 36 +/- 6 pg/mL; P < 0.02). No difference in inhibin A, E2, or progesterone was observed across the luteal phase, between the two groups. However, in all subjects studied longitudinally, increased age was associated with a decrease in inhibin A, inhibin B, and progesterone in the absence of changes in E2. Our conclusions were: 1) reproductive aging is accompanied by decreases in both inhibin B and inhibin A; 2) the decrease in inhibin B precedes the decrease in inhibin A and occurs in concert with an increase in E2, suggesting that inhibin B negative feedback is the most important factor controlling the earliest increase in FSH with aging; 3) these studies suggest that the decrease in inhibin B is the earliest marker of the decline in follicle number across reproductive aging.

Adult↗
PubMed1999

Disappearance of endogenous luteinizing hormone is prolonged in postmenopausal women.

Pituitary secretion of LH is increased after menopause, but it is not known whether changes in LH clearance also contribute to elevated serum levels. To determine whether the disappearance of endogenous LH is decreased in postmenopausal women (PMW), compared with normal cycling women, GnRH receptor blockade was used to inhibit endogenous secretion of LH and the glycoprotein free alpha-subunit (FAS), and the decline of serum levels was monitored. The NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2, D-3Pal3,Arg5,D-4-p-methoxybenzoyl-2-aminobutyric acid6,D-Ala10]GnRH) was administered s.c., at doses of 5, 15, 50, and 150 microg/kg, to 15 euthyroid PMW in 21 studies. Blood was sampled every 10 min, for 4 h before and 8 h after a single sc injection of the GnRH antagonist, followed by hourly samples, ending at 20 h after injection. Results of the maximally suppressive doses (50 and 150 microg/kg) were compared with those of 24 normal cycling women in the early follicular phase and late follicular phase or early luteal phase, and 8 women at the midcycle surge (MCS), who also received these doses of the GnRH antagonist. The best fit curve describing the decay of hormone serum levels after maximal GnRH receptor blockade was determined by nonlinear regression analysis. The elimination of both LH and FAS, after GnRH receptor blockade, exhibited apparent first-order kinetics characterized by a single exponential phase. No differences were seen in percent suppression or half-lives (t1/2) of LH or FAS, between the 50- and 150-microg/kg antagonist doses, in any of the subject populations; and percent suppression of LH was similar across all groups. The t1/2 of LH was prolonged in PMW (139 +/- 35 min, mean +/- est. SD), in comparison with both the MCS (78 +/- 20 min; P < 0.0005) and other cycle stages (57 +/- 28 min; P < 0.0001). However, the disappearance of FAS was not different in PMW, compared with MCS or other cycle stages (t1/2 = 51 +/- 26, 41 +/- 12, and 41 +/- 19 min, respectively). Our conclusions were: 1) Disappearance of endogenous LH after GnRH receptor blockade is significantly prolonged in PMW, compared with the MCS or other cycle stages; 2) The disappearance of FAS is not altered in PMW, suggesting that differences in the disappearance of LH relate to LH microheterogeneity rather than systemic factors.

Adolescent↗
PubMed1999

Free alpha-subunit is superior to luteinizing hormone as a marker of gonadotropin-releasing hormone despite desensitization at fast pulse frequencies.

A pulsatile pattern of GnRH stimulation is essential for normal secretion of luteinizing hormone (LH), while both continuous and fast-frequency GnRH stimulation result in a paradoxical decrease in gonadotrope responsiveness known as desensitization. Under physiological conditions there is striking concordance between the pulsatile secretion of LH and the glycoprotein free alpha-subunit (FAS). The aims of this study were to determine whether the FAS response to GnRH is also decreased at fast frequencies of GnRH stimulation and whether FAS is superior to LH as a marker of GnRH secretory activity at fast-pulse frequencies. The model of GnRH-deficient men was chosen to permit precise control of the dose and frequency of GnRH stimulation of the gonadotrope. The frequency of i.v. administration of GnRH to 5 GnRH-deficient men was progressively increased from every 120 to every 60 min, from 60 to 30 min, and from 30 to 15 min during three 12-h admissions, 1 week apart. The bolus dose of GnRH remained constant and was set at that dose previously shown to produce physiological concentrations and amplitudes of LH secretion and normal testosterone levels. As the frequency of GnRH stimulation was increased, a progressive rise in mean FAS levels was noted (353 +/- 13, 448 +/- 42, 466 +/- 50, and 698 +/- 85 ng/L [mean +/- SEM] for 120, 60, 30, and 15 min intervals; P < 0.005). However, normalization of mean FAS levels to account for the increase in total GnRH delivered with increasing frequencies revealed a progressive decrease in pituitary responsiveness to each GnRH bolus with increasing frequency of stimulation (353 +/- 13, 224 +/- 21, 117 +/- 13, 87 +/- 11 ng/L; P < 0.001). The decrease in normalized mean levels was supported by a decrease in the FAS pulse amplitude with increasing frequency (517 +/- 53, 365 +/- 50, 176 +/- 29 ng/L for 120, 60, and 30 min intervals, respectively; P < 0.005). At interpulse intervals of 120 and 60 min, there was complete concordance of LH and FAS pulses in response to GnRH. However, at the 30-min frequency FAS proved to be a better marker of GnRH with a higher true positive rate and lower number of false positives than LH (P < 0.05). At all frequencies, the number of false positive pulses detected tended to be lower for FAS than for LH (P = 0.06). From these data we conclude that FAS is subject to desensitization in response to increasing frequencies of GnRH administration in GnRH-deficient men, but is superior to LH as a surrogate marker of GnRH pulse generator activity at fast pulse frequencies.

Adult↗
PubMed1999

Inhibin A and inhibin B responses to gonadotropin withdrawal depends on stage of follicle development.

Previous studies demonstrate that inhibin A and B are differentially secreted across the menstrual cycle. To test the hypothesis that the responses of inhibin A and inhibin B to partial gonadotropin withdrawal are influenced by the stage of follicular development, a maximally suppressive dose of the Nal-Glu GnRH antagonist (150 microg/kg) was administered to normal cycling women during the midfollicular (MFP; n = 8), late follicular (LFP; n = 6), and midluteal phase (MLP; n = 5) to assess ovarian responsiveness over a broad range of developmental stages. Administration of the GnRH antagonist resulted in a significant decrease in LH (75 +/- 5%, 63 +/- 3%, and 84 +/- 7%; P < 0.05) and FSH (23 +/- 9%, 32 +/- 5%, and 39 +/- 6%; P < 0.04) during the MFP, LFP, and MLP, respectively. During the MFP, partial withdrawal of gonadotropins resulted in disappearance of the dominant follicle on ultrasound accompanied by a decrease in estradiol (E2; 64.9 +/- 11.4 to 23.9 +/- 3.3 pg/mL; P < 0.02) and inhibin B levels (121.6 +/- 14.8 to 28.4 +/- 4.8 pg/mL; P < 0.002) from baseline to near the limit of detection. Inhibin A was near the limit of detection in this cycle stage (0.8 +/- 0.1 IU/mL). When gonadotropins were withdrawn during the LFP, the size of the dominant follicle remained stationary in four of five subjects, and inhibin B (84.1 +/- 14.1 to 22.2 +/- 3.4 pg/mL; 71 +/- 5%; P < 0.02), inhibin A (4.4 +/- 1.1 to 1.3 +/- 0.5 IU/mL; 71 +/- 7%; P < 0.02), and E2 (236.8 +/- 48.2 to 95.6 +/- 39.0 pg/mL; 61 +/- 12%; P < 0.02) decreased similarly. Time to ovulation was shorter in association with higher inhibin A (r = -0.67; P < 0.02) and E2 (r = -0.79; P < 0.003), but there was no relation to inhibin B. During the MLP, decreased gonadotropin levels resulted in the disappearance of corpus luteum function with a significant decrease in inhibin A (9.0 +/- 0.4 to 0.7 +/- 0.1 IU/mL; 92 +/- 1%; P < 0.0001) in combination with decreased E2 (150.4 +/- 22.9 to 23.8 +/- 4.2 pg/mL; 83 +/- 3%; P < 0.005) and progesterone (12.6 +/- 2.6 to 0.9 +/- 0.2 ng/mL; 92 +/- 2%; P < 0.01). Administration of a GnRH antagonist at precise stages of the menstrual cycle provides further evidence that differential regulation of inhibin A and inhibin B is critically dependent on the stage of follicular development. Inhibin B secretion is exquisitely sensitive to gonadotropin withdrawal during the MFP when inhibin A has not yet risen. Inhibin A and inhibin B decrease equally after GnRH antagonist administration during the LFP. However, before antagonist administration, the positive correlation between estradiol and inhibin A and time to ovulation and the lack of such a correlation with inhibin B suggest that the source of inhibin B secretion is different from that of inhibin A and E2. The decrease in inhibin A secretion after antagonist administration during the luteal phase confirms gonadotropin-dependent secretion of dimeric inhibin A by the corpus luteum.

Adult↗
PubMed1999

Neuroendocrine abnormalities in hypothalamic amenorrhea: spectrum, stability, and response to neurotransmitter modulation.

UNLABELLED: To characterize the neuroendocrine patterns of abnormal GnRH secretion in hypothalamic amenorrhea (HA), 49 women with primary and secondary HA underwent frequent sampling of LH in a total of 72 baseline studies over 12-24 h. A subset of women participated in more than one study to address 1) the variability of LH pulse patterns over time; and 2) the impact of modulating opioid, dopaminergic, and adrenergic tone on LH secretory patterns. The frequency and amplitude of LH secretion was compared with that seen in the early follicular phase (EFP) of normally cycling women. The spectrum of abnormalities of LH pulses was 8% apulsatile, 27% low frequency/low amplitude, 8% low amplitude/normal frequency, 43% low frequency/normal amplitude, 14% normal frequency/normal amplitude. Of patients studied overnight, 45% demonstrated a pubertal pattern of augmented LH secretion during sleep. Of patients studied repeatedly, 75% demonstrated at least 2 different patterns of LH secretion, and 33% reverted at least once to a normal pattern of secretion. An increase in LH pulse frequency was seen in 12 of 15 subjects in response to naloxone (opioid receptor antagonist). Clonidine (alpha-2 adrenergic agonist) was associated with a decrease in mean LH in 3 of 3 subjects. An increase in LH pulse frequency was seen in 4 of 8 subjects in response to metoclopramide (dopamine receptor antagonist), but the response was not statistically significant. Baseline abnormalities in LH secretion did not appear to influence response to neurotransmitter modulation. CONCLUSIONS: 1) HA represents a spectrum of disordered GnRH secretion that can vary over time; 2) LH pulse patterns at baseline do not appear to influence the ability to respond to neurotransmitter modulation; 3) Opioid and adrenergic tone appear to influence the hypothalamic GnRH pulse generator in some individuals with HA.

Adolescent↗
PubMed1999

Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney.

The renin-angiotensin system (RAS) is one of the body's most powerful regulators of arterial pressure and body fluid volumes. Although the acute effects of angiotensin II (AngII), the primary active component of the RAS, on arterial pressure are mediated primarily by peripheral vasoconstriction, its chronic BP effects are closely intertwined with volume homeostasis, particularly with intrarenal actions that influence pressure natriuresis. AngII shifts pressure natriuresis toward higher BP primarily by increasing tubular reabsorption rather than decreasing GFR. In fact, activation of the RAS can serve as an important means of preventing decreases in GFR during volume depletion or circulatory depression. However, with prolonged excess AngII formation, particularly in association with hypertension or overperfusion of the kidney, AngII can contribute to glomerular injury and a gradual loss of nephron function through its hemodynamic actions. The multiple effects of AngII to increase tubular reabsorption provide a powerful mechanism to protect against volume depletion and low BP. However, when AngII levels are inappropriately elevated, this necessitates increased arterial pressure to maintain sodium and water balance. Blockade of the RAS has proved to be a powerful therapeutic tool for lowering BP and improving kidney function in disorders such as hypertension, congestive heart failure, and chronic renal disease.

Angiotensin II↗
PubMed1999

Surgical correction of acetabular dysplasia in the adult. A Boston experience.

Acetabular redirection surgery is the mainstay of treatment for the symptomatic, dysplastic hip. The authors' experience with the Salter innominate osteotomy, Wagner spherical acetabular osteotomy and the modified Bernese periacetabular osteotomy shows that major acetabular redirection surgery can reliably improve the structure of the dysplastic hip and delay or prevent secondary osteoarthrosis. The limited correction achieved by the Salter innominate osteotomy suggests this procedure generally should be reserved for younger patients with mild dysplasia. The modified Bernese periacetabular osteotomy is the authors' current preferred method of treating acetabular dysplasia, even in the presence of mild to moderate secondary osteoarthrosis.

Acetabulum↗
PubMed1999

Occipitocervical fusions in children. Retrospective analysis and technical considerations.

This report presents a retrospective analysis of the authors' experience with occipitocervical fusions in children and adolescents during the last 2 decades. A description of an operative technique devised by the senior author (JEH), and a comparison of the results using this and other methods of fusion are given. Twenty-three patients underwent occipitocervical fusion. Fifteen of the patients were operated on using the authors' technique. To achieve stable fixation of the distal cervical vertebra a threaded Kirschner wire was passed transversely through the spinous process; occipital fixation was achieved by the traditional method of wiring corticocancellous bone graft to the skull through burr holes. The occipital wires then were wrapped around the Kirschner wire and the graft was cradled in the resulting nest. Halo immobilization was used in 10 patients for an average of 12.5 weeks (range, 6-24 weeks). Twenty-two patients achieved successful fusion at an average followup of 5.8 years (range, 1-14.33 years). Several complications, including transient quadriplegia in one patient, pseudarthrosis in two (one of which persists), hardware fixation failure in one, unintended distal extension of the fusion, pneumonia, wound infection, halo pin infection, skin breakdown under the halo vest, hydrocephalus, cerebrospinal fluid leak, and traumatic fusion fracture were encountered. Results using the technique described herein are comparable with or better than the results reported in the previous literature, and the results of the patients in this series in whom the technique was not used.

Adolescent↗
PubMed1999

Physiologic and genetic insights into the pathophysiology and management of hypogonadotropic hypogonadism.

Initiation and maintenance of reproductive capacity is contingent upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. While GnRH deficiency manifests itself clinically as hypogonadism, the time of onset of the defect in GnRH secretion (i.e. before or after the onset of puberty) determines the clinical presentation that is further modified by the severity of the defect. GnRH deficiency can be associated with structural lesions that interfere with the normal pattern of GnRH secretion through compression or destruction of critical areas of the median eminence of the hypothalamus. Idiopathic hypogonadotropic hypogonadism (IHH) has been described and is characterized by isolated GnRH deficiency in the absence of a hypothalamic or pituitary lesion. Typically, patients with hypogonadotropic hypogonadism and anosmia have been given the diagnosis of Kallmann's syndrome and those with normal olfaction, IHH. However, both entities can be present in the same family, demonstrating variability in phenotypic expression and raising questions about the usefulness of this distinction. GnRH deficiency may be inherited via autosomal dominant, autosomal recessive and X-linked modes of inheritance. Specific defects in a number of genes have now been found in association with GnRH deficiency in the human and including the KAL gene, the DAX gene and the GnRH receptor gene, but not the gene encoding GnRH itself. While these mutations account for only a small fraction of cases, genetic studies not only provide promise for future treatment, but also insights into the complexity of the GnRH neuronal system. The treatment of GnRH deficiency is highly successful whether designed for steroid hormone replacement or for fertility. The challenge in the treatment of these abnormalities is in the early and accurate diagnosis and the use of replacement therapies that are as close to physiologic as possible.

Adolescent↗
PubMed1998

Reproductive correlates of chronic fatigue syndrome.

A case-control study was conducted to determine whether menstrual and gynecologic abnormalities precede the onset of chronic fatigue syndrome (CFS) in women with this disorder to a greater extent than that observed among healthy controls. We identified 150 women who met the 1988 Centers for Disease Control criteria for CFS from the Brigham and Women's Hospital Cooperative CFS Research Center. A comparison group of 149 women being seen for nongynecologic conditions were selected from the waiting area of the Brigham and Women's Hospital Internal Medicine outpatient department. Women with and without CFS completed self-administered questionnaires on menstrual, reproductive, and medical history. Women with CFS reported increased gynecologic complications and a lower incidence of premenstrual symptomatology. After adjustment for age, a somewhat greater number of cases compared with controls self-reported irregular cycles, periods of amenorrhea, and sporadic bleeding between menstrual periods. Factors suggestive of abnormal ovarian function--such as a history of polycystic ovarian syndrome, hirsutism, and ovarian cysts--were reported more often in CFS cases compared with controls. Frequent anovulatory cycles due to ovarian hyperandrogenism (PCOS) or hyperprolactinemia may increase risk for CFS through loss of the potential immunomodulatory effects of progesterone in the presence of continued estrogen production. We hypothesize that frequent anovulatory cycles due to PCOS and/or hyperprolactinemia may explain the increased reporting of gynecologic complications and the lower reported premenstrual symptomatology observed in women with CFS.

Adult↗
PubMed1998

Extended aromatic furan amidino derivatives as anti-Pneumocystis carinii agents.

The syntheses of nine new derivatives of 2, 5-bis[4-(N-alkylamidino)phenyl]furans with extended aromatic systems are reported. The interaction of these dicationic furans with poly(dA)poly(dT) and with the duplex oligomers d(CGCGAATTCGCG)2 and d(GCGAATTCGC)2 was determined by Tm measurement, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At a screening dose of 10 micromol/kg, 4 of the 12 amidino furans described here are more active than the parent compound 1. In general, extension of the aromatic system in the absence of a substitution of the amidino nitrogens resulted in higher affinity for DNA than the parent compound as judged by the larger DeltaTm values and suggests enhanced van der Waals interactions in the amidino furan-DNA complex. Three of the compounds, 3, 5, and 11, yield cysts counts of less than 0.1% of control when administered at a dosage of 10 micromol/kg. Compound 3, which does not have an extended aromatic system, is the most active derivative. Although a direct correlation between anti-P. carinii activity and DNA binding affinity was not observed, all compounds which have significant activity have large DeltaTm values.

Amidines↗
PubMed1998

1,5-Bis(4-amidinophenoxy)pentane (pentamidine) is a potent inhibitor of [3H]idazoxan binding to imidazoline I2 binding sites.

The aromatic diamidine 1,5-bis(4-amidinophenoxy)pentane (pentamidine) is used for treatment and prophylaxis of Pneumocystis carinii pneumonia in patients with Acquired Immune Deficiency Syndrome. Clinical use of pentamidine has been restricted by significant toxicity, that includes hypotension, and hypoglycemia. Although clinical toxicity is well described, the mechanisms are still poorly understood. Competitive binding analyses using [3H]idazoxan as the radioligand, and cirazoline to define non-specific binding, demonstrate that pentamidine binds to an imidazoline I2 binding site on rat liver membranes with a Ki of 1.4+/-0.22 nM. The Ki indicates that pentamidine inhibits radioligand binding at imidazoline I2 sites with an affinity approximating the most potent known ligands and may be related to pentamidine toxicity. Moreover, pentamidine analogs inhibit radioligand binding with a range of affinities that vary according to their structure. Two candidate drugs, Compounds 5 and 6, are more active than pentamidine in the corticosteroid-suppressed rat model of P. carinii pneumonia, yet have different affinities for the imidazoline I2 site (Ki 5 = 50.1+/-1.06 nM and Ki 6 = approximately 3500 nM). Affinity for this site does not correlate with antimicrobial activity (r = 0.60; p = 0.09) or the calculated log of the octanol:water partition coefficient (ClogP) (r = -0.38; p = 0.22).

Animals↗