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Stanley F Wainapel,1 Stephanie Rand,1 Loren M Fishman,2 Jennifer Halstead-Kenny1 1The Arthur S Abramson Department of Physical Medicine and Rehabilitation, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, 2Department of Rehabilitation and Regenerative Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA Abstract: The frequency with which patients utilize treatments encompassed by the term complementary/alternative medicine (CAM) is well documented. A number of these therapies are beginning to be integrated into contemporary medical practice. This article examines three of them: osteopathic manipulation, yoga, and acupuncture, with a focus on their physiological effects, efficacy in treating medical conditions commonly encountered by practitioners, precautions or contraindications, and ways in which they can be incorporated into clinical practice. Physicians should routinely obtain information about use of CAM as part of their patient history and should consider their role based on physiological effects and clinical research results. Keywords: integrative medicine, osteopathic manipulation, yoga, acupuncture therapy

Wainapel SF, Rand S, Fishman LM, Halstead-Kenny J. Int J Gen Med. 2015;8:361–372.On page 364, left column, line 15, Doctor of Osteopathy should have been Doctor of Osteopathic Medicine. View original article by Wainapel et al.

Context: More than 200 000 000 people suffer from osteoporosis or osteopenia worldwide. An innocuous and inexpensive treatment would be welcome. Study design: Serial controlled repeated measure. Patients: Eighteen serial patients with osteoporosis or osteopenia, average age 68 years. Methods: Qualifying blood and urine tests and dual-energy x-ray absorptiometry (DEXA) scan preceding 10-minute daily yoga. DEXA scan repeated after 2 years. Outcome Measurement: Comparison of pre- and postyoga DEXA scans, injuries. Results: Yoga practitioners gained 0.76 and 0.94 points for spine and hips, respectively, on the T-scale when compared with controls (P = .01). Five patients with osteopenia were reclassified as normal; 2 patients with osteoporosis are now osteopenic. There were no injuries. Conclusion: Yoga appears to be an effective way to build bone mineral density after menopause. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To measure dosage effects of botulinum neurotoxin type B with physical therapy in piriformis syndrome. DESIGN: Prospective study of consecutive patients complaining of buttock pain and sciatica, measuring serial H-reflex tests in flexion, adduction, and internal rotation; visual analog scale; and adverse effects at 0, 2, 4, 8, and 12 wks. We used an electrophysiologic criterion for piriformis syndrome: a 1.86-msec prolongation of the H-reflex with the flexion, adduction, and internal rotation test. Four piriformis syndrome groups were identified. Serial groups were injected once with either 5000, 7500, 10,000, or 12,500 units of botulinum neurotoxin type B in successive months under electromyographic guidance in four separate locations of the affected piriformis muscle, with a 1-mo safety observation period between groups. Patients received physical therapy twice weekly for 3 mos. RESULTS: The flexion, adduction, and internal rotation test and visual analog scale declined significantly, correlating at 72% sensitivity and 77% specificity. A total of 24 of 27 study patients had >/=50% pain relief. Mean visual analog scale score declined from 6.7 to 2.3. A volume of 12,500 units of botulinum neurotoxin type B was superior to 10,000 units at 2 wks postinjection. The most severe adverse effects were dry mouth and dysphagia, approaching 50% of patients at 2 and 4 wks. CONCLUSION: Physical therapy and 12,500 units of botulinum neurotoxin type B seem to be safe and effective treatment for piriformis syndrome. In addition, the flexion, adduction, and internal rotation test seems to be an effective means of diagnosing piriformis syndrome and assessing its clinical improvement. Injection may benefit patients for >3 mos. [ABSTRACT FROM AUTHOR]

In their recent article, Side Plank Pose Exercises for Adolescent Idiopathic Scoliosis Patients, Sarkisova, et. al. found no beneficial effect using the simple poses that Drs. Groessl, Sherman and I found successful in reversing adolescent idiopathic scoliosis (AIS) and degenerative scoliosis (DS). Although they tried to follow our protocol exactly, they did not. They did not distinguish thoracic from lumbar or thoracolumbar from complex (both thoracic and lumbar) curves, affecting the randomization. See Figure 2 in their study. The side plank is only intended to reverse lumbar and thoracolumbar curves, and actually exaggerates thoracic curves, and the thoracic component of complex curves. The vicissitudes of randomization placed 25 lumbar and thoracolumbar curves in the control and non-compliant groups, but no lumbar and only one thoracolumbar in the intervention group that did the side plank. This trial did not prove that the side plank does not reduce lumbar curves: none were tested., (© The Author(s) 2021.)

Osteoporosis is a public health problem affecting individuals globally. Yoga has been found to prevent and reverse bone loss. Yoga may result in better balance, improved posture, and greater range of motion, strength, and coordination, all factors that also mitigate the risk of falls and fractures. A 12-minute, 12-pose yoga regimen is discussed in detail. Once learned, the ongoing use of yoga is safe, without cost, and may be done lifelong., Competing Interests: The author has disclosed no conflicts of interest., (Copyright © 2021 by National Association of Orthopaedic Nurses.)

Objective: Assess therapeutic value of specific yoga poses for thoracic and lumbar adolescent idiopathic scoliosis (AIS) taught in office or Internet., Study Design: Nonrandomized control trial: Fifty-six adolescents (mean age 14.0 years; mean Risser 3.0) were recruited from our clinic; 41 did the side-plank, the half-moon and elevated side plank poses as appropriate (treatment group) and 15 did not (controls). Thirty curves were treated in office, 30 via Internet. Curve change was evaluated by blinded serial Cobb angles, and analyzed using Mann-Whitney U, paired t-tests and χ 2 ., Results: Mean lumbar and thoracolumbar Cobb angle change was -9.2 (95% CI = -11.8, -6.6) in the treatment group and 5.4 (95% CI = 1.7, 9.0) in controls. Both treatment group improvement and deterioration in controls were significant (treatment group: paired t-test t = -7.1, df = 40, p = .000; controls: t = 3.2, df = 12, p = .008). Mean thoracic Cobb angle change was -7.1 (95% CI = -13.1, -1.2) in the treatment group and 9.3 (95% CI = 4.5, 14.6) in controls. Both changes were significant (paired t-test t = -3.3, df = 21, p = .022 for treatment group; t = 4.5, df = 5, p = .006 for controls). Nine Internet patients were non-compliant vs. 6 office patients. Office patients improved 1.6 degrees/month or 5.5%/month; Internet patients improved .72 degrees/month or 3.3%/month., Conclusion: These yoga poses show promise for reversing adolescent idiopathic scoliosis. Telemedicine had greater non-compliance and lower efficacy but still produced patient improvement., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Introduction: Piriformis syndrome is entrapment of the sciatic nerve by the piriformis muscle., Methods: In this article we describe a 56-person randomized, double-blind, controlled study involving physical therapy and incobotulinum toxin A or placebo. Inclusion criteria were 3-SD delay of posterior tibial (PT) or fibular (FN) H-reflexes on flexion, adduction, and internal rotation (FAIR) testing, and normal paraspinal electromyographic findings. Outcome measures included adverse side effects, visual analog scale (VAS) findings, and H-reflex delay on the FAIR test., Results: Mean intervention VAS score decreased significantly more compared with placebo at 2, 4, 6, 8, 10, and 12 weeks post-injection (P < 0.0001). FAIR test scores for PT, but not FN, decreased significantly more compared with placebo at 2, 4, 6, and 8 weeks post-injection (PT: P = 0.038, 0.003, 0.003, and 0.046). Adverse effects were minimal. VAS slope and PT FAIR test results varied significantly (P < 0.0001)., Conclusion: Incobotulinum toxin A chemodenervation may be useful for treating piriformis syndrome as identified by the FAIR test. Muscle Nerve 56: 258-263, 2017., (© 2016 Wiley Periodicals, Inc.)

Objective: Assess the effectiveness of selected yoga postures in raising bone mineral density (BMD)., Methods: Ten-year study of 741 Internet-recruited volunteers comparing preyoga BMD changes with postyoga BMD changes., Outcome Measures: Dual-energy x-ray absorptiometric scans. Optional radiographs of hips and spine and bone quality study (7 Tesla)., Results: Bone mineral density improved in spine, hips, and femur of the 227 moderately and fully compliant patients. Monthly gain in BMD was significant in spine (0.0029 g/cm 2 , P = .005) and femur (0.00022 g/cm 2 , P = .053), but in 1 cohort, although mean gain in hip BMD was 50%, large individual differences raised the confidence interval and the gain was not significant for total hip (0.000357 g/cm 2 ). No yoga-related serious injuries were imaged or reported. Bone quality appeared qualitatively improved in yoga practitioners., Conclusion: Yoga appears to raise BMD in the spine and the femur safely.

Background: Non-surgical techniques for treating scoliosis frequently focus on realigning the spine, typically by muscular relaxation or muscular or ligamentous stretching. However, such treatments, which include physical therapeutic, chiropractic, and bracing techniques, are inconsistently supported by current evidence. In this study, we assess the possible benefits of asymmetrical strengthening of truncal muscles on the convex side of the scoliotic curve through a single yoga pose, the side plank pose, in idiopathic and degenerative scoliosis., Methods: Twenty-five patients with idiopathic or degenerative scoliosis and primary curves measuring 6 to 120 degrees by the Cobb method had spinal radiographs and were then taught the side plank pose. After 1 week performing the pose with convexity downward for 10 to 20 seconds, they were instructed to maintain the posture once daily for as long as possible on that one side only. A second series of spinal radiographs was taken 3 to 22 months later. Pre- and post-yoga Cobb measurements were compared., Results: The mean self-reported practice of the yoga pose was 1.5 minutes per day, 6.1 days per week, for a mean follow-up period of 6.8 months. Among all patients, a significant improvement in the Cobb angle of the primary scoliotic curve of 32.0% was found. Among 19 compliant patients, the mean improvement rose to 40.9%. Improvements did not differ significantly among adolescent idiopathic and degenerative subtypes (49.6% and 38.4%, respectively)., Conclusions: Asymmetrically strengthening the convex side of the primary curve with daily practice of the side plank pose held for as long as possible for an average of 6.8 months significantly reduced the angle of primary scoliotic curves. These results warrant further testing.

Peptide analogues targeting various neuropeptide receptors have been used effectively in cancer therapy. A hallmark of adrenocortical tumor formation is the aberrant expression of peptide receptors relating to uncontrolled cell proliferation and hormone overproduction. Our microarray results have also demonstrated a differential expression of neuropeptide hormone receptors in tumor subtypes of human pheochromocytoma. In light of these findings, we performed a comprehensive analysis of relevant receptors in both human adrenomedullary and adrenocortical tumors and tested the antiproliferative effects of peptide analogues targeting these receptors. Specifically, we examined the receptor expression of somatostatin-type-2 receptor, growth hormone-releasing hormone (GHRH) receptor or GHRH receptor splice variant-1 (SV-1) and luteinizing hormone-releasing hormone (LHRH) receptor at the mRNA and protein levels in normal human adrenal tissues, adrenocortical and adrenomedullary tumors, and cell lines. Cytotoxic derivatives of somatostatin AN-238 and, to a lesser extent, AN-162, reduced cell numbers of uninduced and NGF-induced adrenomedullary pheochromocytoma cells and adrenocortical cancer cells. Both the splice variant of GHRH receptor SV-1 and the LHRH receptor were also expressed in adrenocortical cancer cell lines but not in the pheochromocytoma cell line. The GHRH receptor antagonist MZ-4-71 and LHRH antagonist Cetrorelix both significantly reduced cell growth in the adrenocortical cancer cell line. In conclusion, the expression of receptors for somatostatin, GHRH, and LHRH in the normal human adrenal and in adrenal tumors, combined with the growth-inhibitory effects of the antitumor peptide analogues, may make possible improved treatment approaches to adrenal tumors.

Previous studies have shown that high dose 17beta-estradiol (10 (-5) M) has a G2/M blocking effect in SW-13 human adrenal carcinoma cultures and strongly enhances apoptosis. To examine the differential effects of estrogen alpha and beta-receptors in this system, we incubated SW-13 cells with specific alpha- and beta-estrogen receptor agonists, PPT [4,4',4''-(propyl-[ (1)H]-pyrazole-1,3,5-triyl) trisphenol] and DPN [2,3-bis (4-hydroxyphenyl) propionitrile], respectively (each at 10 (-5) M). Flow cytometry was used to analyze the percentages of cells in various phases of the cell cycle [sub-G1 (apoptosis), G1, S, and G2/M] in each experimental condition. Exposure to 17 beta-estradiol for 48 hours increased apoptosis more than 5-fold (from 3.6+/-0.5 to 20+/-2.2% of cells; p<0.01). The alpha-estrogen agonist PPT had a similar effect, increasing apoptosis to 22+/-1.7% (p<0.01), but the beta-agonist DPN caused no change (3.6+/-0.5 vs. 3.9+/-0.8%). While estrogen and the alpha-estrogen agonist decrease apoptosis in this system, both of these compounds decreased the percentage of cells in G1 (from 59+/-1.4% for control to 34+/-2.3% for estrogen and 40+/-2.0% for PPT; p<0.01 for both agents relative to control); the beta-agonist again had no effect. Estrogen was also found to block the cell cycle in G2/M, increasing it from 15+/-0.4 to 21+/-1.0% of cells (p<0.01), but neither the alpha- nor beta-estrogen agonists had any effect at this point in the cell cycle, indicating that the influence of estrogen was not likely to be either alpha- or beta-receptor mediated. There was no apparent effect of any of these agents on DNA synthesis, as indicated by unchanged percentages of cells in S phase. These studies suggest that induction of apoptosis by estrogen in SW-13 human adrenal cortical carcinoma cultures is mediated by the alpha-receptor, but the G2/M blocking effect of estrogen is not likely to be related to either alpha or beta mechanisms.

The effects of 17 beta-estradiol and progesterone were evaluated separately and in combination, on the growth, survival, and cell cycle dynamics of SW-13 human adrenal carcinoma cells in culture. Both hormones significantly decreased cell survival, with dose response curves at four days demonstrating EC (50)s estimated at 1.2 x 10 (-5) M for 17 beta-estradiol and 4.8 x 10 (-6) M for progesterone. Flow cytometry studies of these cultures indicated a strong G2/M blocking effect of both steroids, either individually or in combination; the effects of progesterone and of both agents together were substantially greater than the effect with 17 beta-estradiol alone. The sub-G1 region of the flow cytometry profile was significantly enhanced by exposure to 17 beta-estradiol and even more by progesterone. Sub-G1 "apoptosis" was confirmed by fragmented and condensed nuclear chromatin staining using a standard DAPI fluorescence assay. The expression of the critical cell cycle regulatory proteins cyclin B1 and D1 were significantly decreased by each hormone, with the influence of progesterone again predominating. These data demonstrate that high doses of 17 beta-estradiol and progesterone have inhibitory and apoptotic effects on SW-13 human adrenal carcinoma cells IN VITRO. The observed effects are associated with declines in cyclin B1 and D1 expression as well as a block in G2/M.

Adrenocortical carcinoma is an uncommon malignancy that is usually fatal within a short time after diagnosis. We have investigated the effects on the growth and survival of SW-13 human adrenal carcinoma cells in culture of some currently used and some potentially new agents in the treatment of adrenal cancer. Established drugs tested were mitotane, cisplatin, etoposide, 5-fluorouracil, and suramin. Other agents studied included adenine arabinofuranoside, cytosine arabinofuranoside, 2-methoxyestradiol, and paclitaxel. The most potent chemotherapeutic agents in this system were paclitaxel and 2-methoxyestradiol, with EC (50) of 1.8x10 (-8) and 3.3x10 (-7) M, respectively. Cytosine arabinofuranoside and cisplatin both had the same EC (50) of 7.0x10 (-7) M, and etoposide 1.1x10 (-6) M. All the other agents tested required much higher doses for effect, including mitotane, the current most commonly used chemotherapy for adrenal cancer, with an EC (50) of 3.3x10 (-4) M. These data suggest that paclitaxel, 2-methoxyestradiol, and cytosine arabinofuranoside should be further evaluated for their potential in the chemotherapy of adrenal carcinoma.

Marine sponges have been shown to produce metabolites with cell growth- and endocrine-altering activities. We tested extracts from two species: the 'brown variable sponge' (Anthosigmella varians) and the 'West Indian bath sponge' (Spongia barbara), for effects on the cell cycle regulatory protein, cyclin B1; cell cycle growth-phase (sub-G1/apoptosis, G1, S, and G2/M); and cell survival in SW-13 human adrenal carcinoma cultures. Polyacrylamide gel electrophoresis studies indicated a 70-90% reduction in cyclin B1 levels by treatment with these agents. Microscopic examination of cultures with DAPI staining showed dense and fragmented DNA fluorescence, characteristic of apoptosis, in both sponge extract-treated cultures but not in controls. Flow cytometry analysis showed a 16-fold increase in the percentage of cells entering apoptosis (sub-G1 phase of cell cycle) by treatment with Anthosigmella varians extract (p <0.01) and a 10-fold increase using Spongia barbara extract (p <0.01) During this same time, the percentage of cells in G2/M was increased 1.6-fold by Anthosigmella varians extract (p <0.01) and 2.0-fold by Spongia barbara extract (p <0.01) Cell growth/survival studies also indicated a time-dependent decline in the percentage confluence of cell cultures exposed to Anthosigmella varians or Spongia barbara extracts. These experiments demonstrate that some species of marine sponges have metabolites which are capable of interfering with the mammalian cell cycle and with the survival of human adrenal carcinoma cells in culture.

Objectives: To validate an operational definition of piriformis syndrome based on prolongation of the H-reflex with hip flexion, adduction, and internal rotation (FAIR) and to assess efficacy of conservative therapy and surgery to relieve symptoms and reduce disability., Design: Before-after trial of cohorts identified by operational definition., Setting: Outpatient departments of 2 hospitals and 4 physicians' offices. Surgery performed at 3 hospitals., Patients: Consecutive sample of 918 patients (1014 legs) with follow-up on 733., Intervention: Patients with significant (3 standard deviations [SDs]) FAIR tests received injection, physical therapy, and serially reported pain and disability assessments. Forty-three patients (6.47%) had surgery., Main Outcome Measures: Likert pain scale. Subjective estimates of disablement in activities of daily living and instrumental activities of daily living., Results: At 3 SDs, the FAIR test had sensitivity and specificity of.881 and.832, respectively. Seventy-nine percent (514/655) of FAIR test positive (FTP) patients improved 50% or more from injection and physical therapy at a mean follow-up of 10.2 months. Average improvement was 71.1%. Of 385 FTP patients with disability data, mean disability fell from 35.37% prestudy (SD =.2275) to 12.96% poststudy (SD =.1752), a 62.8% improvement. Twenty-eight surgical FTP patients (68.8%) showed 50% or greater improvement; mean improvement was 68% at a mean follow-up of 16 months. Surgery reduced the mean FAIR test to 1.35 +/- 2.17 months postoperatively. FTP patients generally improved 10% to 15% more than others after conservative treatment., Conclusions: The FAIR test correlates well with a working definition of piriformis syndrome and is a better predictor of successful physical therapy and surgery than the working definition. The FAIR test, coupled with injection and physical therapy and/or surgery, appears to be effective means to diagnose and treat piriformis syndrome., (Copyright 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation)

Some species of marine sponge have been shown to produce metabolites with endocrine-altering and cell growth regulatory properties. Since cell division and differentiation are controlled, in part, by the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK/ERK) cascade, we tested extracts (1.0mg/ml) from six shallow water marine species obtained in the Florida Keys for effects on MAPK/ERK(l,2) (sub-variant of EC 2.7.1.37) activity in incubations with SW-13 human adrenal carcinoma cells in culture. In these short-term incubations, extracts from two species, the purple bleeding sponge (Iotrochota birotulata) and the West Indian bath sponge (Spongia barbara), significantly inhibited MAPK/ERK(1,2) activity (to 51 and 44% of control levels, respectively) without altering cell survival. Western blots for phosphorylated and total ERK showed that ERK(2) predominated over ERK(1) by a factor of about 4:1 and that the phosphorylated forms of these isozymes were strongly suppressed by active extracts from both sponges. Another species, the green sponge (Haliclona veridis), whose extract has been shown previously to activate guanylate cyclase and to inhibit adenylate cyclase in a variety of mammalian tissues, was found not to affect MAPK/ERK(1,2) in human adrenal carcinoma cultures but did lyse and kill most of these cultured cells. Extracts from the sheepswool sponge (Hippospongia lachne) and the bleeding sponge (Oligoceras hemorrhages) did not significantly affect either MAPK/ERK(1,2) activity or the survival of attached cells. An extract from the fire sponge (Tedania ignis) did not alter MAPK/ERK(1,2) activity but did modestly decrease cell viability. These studies document for the first time species-specifc effects of marine sponge extracts on the MAPK/ERK(1,2) cascade and on the growth and survival of human adrenal carcinoma cells in culture.

We tested the effects of 17beta-estradiol as well as its catechol- and methoxy-derivatives, two androgens (DHEA and testosterone), a glucocorticoid (cortisol), a mineralocorticoid (aldosterone), and progesterone on the activity of ERK(1,2), a key component of the ERK/MAPK enzyme phosphorylation cascade, in SW-13 human adrenal carcinoma cells. After a 24-hour exposure SW-13 cells incubated with 10(-5) M concentrations of 17beta-estradiol, its 2-hydroxy or its 2-methoxy derivative, all had elevated ERK activities (196%, 159%, and 275%, respectively) relative to control cells (p < 0.01). Incubation with testosterone resulted in 162% of control ERK activity (p < 0.01), whereas incubation with the far weaker androgen DHEA or with cortisol, aldosterone, or progesterone had no significant effects. These findings suggest sex steroid-specific influences in the induction or activation of signal transduction pathways known to play a crucial role in cellular proliferation and differentiation.

Over a 15-year period, our university-based laboratory obtained 125 adrenal tumors, of which 15 (12%) were adrenal cortical carcinomas. Of these, 6 (40% of the carcinomas) occurred in patients with clear clinical manifestations of steroid hormone excess. Adrenal cortical carcinoma cells derived from the surgically resected tumors in 4 of these patients were isolated and established in primary culture. Radiotracer steroid interconversion studies were carried out with these cultures and also on mitochondria isolated from homogenized tissues. Large tumors had the lowest steroidogenic activities per weight, whereas small tumors had more moderately depressed enzyme activities relative to cells from normal glands. In incubations with pregnenolone as substrate, 1 mM metyrapone blocked the synthesis of corticosterone and cortisol and also the formation of aldosterone. Metyrapone inhibition was associated with a concomitant increase in the formation of androgens (androstenedione and testosterone) from pregnenolone. Administration of metyrapone in vivo before surgery in one patient resulted in a similar increase in plasma androstenedione, though plasma testosterone levels were not significantly affected. In cultures of two of four tumors examined, dibutyryl cAMP stimulated 11ss-hydroxylase activity modestly; ACTH also had a significant stimulatory effect in one of these tumors. Unlike results obtained with normal or adenomatous adrenal cortical tissues, mitochondria from carcinomatous cells showed a lack of support of either cholesterol side-chain cleavage enzyme complex or steroid 11ss-hydroxylase activity by Krebs cycle intermediates (10 mM isocitrate, succinate or malate). This finding is consistent with the concept that these carcinomas may tend to function predominantly in an anaerobic manner, rather than through the oxidation of Krebs cycle intermediates.

Gap junctional communication disorders have been implicated in the etiology of benign and malignant tumors. Understanding the type, distribution, and frequency of gap junctions in adrenal disorders should provide insight into the role of gap junctions in adrenal carcinogenesis as well as information that may be useful in developing improved diagnosis and treatment of adrenal diseases. Using immunocytochemical techniques, we have characterized and compared alpha1 connexins 43 gap junction protein levels in normal adrenal glands to those in benign and malignant adrenocortical human tumors. In addition, gap junction protein levels were studied in a human adrenal cancer cell line (H295). In both normal and neoplastic adrenal tissues, only alpha1 connexin 43 could be detected, whereas beta1 connexin 32 and beta2 connexin 26 were not found. In the normal adrenal gland, the zona fasciculata was demonstrated to have the highest number of gap junctions per cell (mean +/- SEM, 13.78 +/- 1.93). In contrast, in benign adrenocortical adenomas, the number of gap junctions per cell compared to that detected in normal adrenal glands was significantly reduced (mean +/- SEM, 4.6 +/- 1.17; P < or = 0.05), and the lowest number was found in malignant adrenocortical tumors (1.42 +/- 0.58; P < or = 0.05). Similarly, there were few or no alpha1 connexin 43 gap junctions in the H295 population. There was a progressive decrease in gap junction plaques in adrenocortical cancer cell populations compared to those in normal cell populations. Therefore, analysis of gap junction protein may be helpful for the differential diagnosis of benign and malignant adrenal tumors. The induction of gap junctions in malignant cells may provide a novel therapeutic strategy for adrenal cancer.

The neuronal differentiation of adrenal pheochromocytoma cells from human subjects was studied in vitro for periods of up to 65 days. Changes with time in culture were observed in both intracellular catecholamine content (progressive decreases in epinephrine, norepinephrine, and dopamine, except for a possible transient early increase in the latter) and in morphology (increases in neurite outgrowth) of cells cultured in control medium; supplementation of cultures with nerve growth factor resulted in a substantial increase in neurite formation. The effects on these changes of the presence in the culture medium of various steroids were examined. The addition of 11-oxygenated steroids (aldosterone, corticosterone, cortisol, or dexamethasone) at 10(-5) M concentrations caused at least 2.5-fold increases in mean intracellular dopamine and norepinephrine levels; with dexamethasone, 9-10-fold increases were observed. Intracellular epinephrine content was also enhanced by 11,17-oxygenated steroids (dexamethasone and cortisol), but not by the other 11-oxygenated compounds studied. These two 11,17-oxygenated glucocorticoids also inhibited the morphologic changes seen with extended periods in culture, decreasing the outgrowth of neurite projections and causing cells to attain a vacuolated and granular appearance; the presence of dexamethasone strongly inhibited the morphologic changes induced by nerve growth factor. 11-Deoxy steroid intermediates (pregnenolone, 11-deoxycorticosterone, and 11-deoxycortisol) had little or no effect on catecholamine content or on morphology. Preliminary observations suggest that C-18 and C-19 sex steroid hormones (17 beta-estradiol and testosterone) may have morphologic effects opposite to those of the 11-oxygenated compounds, showing a slight stimulatory influence on the formation of neurite projections, but no significant effect on catecholamine content.

Piriformis syndrome is an often misdiagnosed cause of sciatica, leg, or buttock pain, and disability. The sciatic nerve may be compressed within the buttock by the piriformis muscle, with pain increased by muscular contraction, palpation, or prolonged sitting. A thorough medical history and physical examination are essential to proper diagnosis. Diagnostic testing may be used to differentiate piriformis syndrome from other causes of sciatica, lower extremity weakness, and pain. This article reviews the pathophysiology and management of piriformis syndrome.

Objective: To evaluate whether the combined application of preoperative localization and intraoperative monitoring of intact parathyroid hormone (iPTH) levels could facilitate safe outpatient parathyroidectomy., Design: Consecutive patients, who had no antecedent social or medical conditions mandating hospitalization, were prospectively offered ambulatory parathyroidectomy with a mean follow-up of 7 months (range, 1-25 months)., Setting: Tertiary care referral center, Patients: From 85 patients who had primary hyperparathyroidism with hypercalcemia and elevated iPTH levels, 57 were offered outpatient parathyroidectomy. Nineteen patients were asymptomatic, 3 had hypercalcemic crisis, and the others gave a history of renal stones or had complaints consistent with bone disease., Interventions: Technetium Tc 99m sestamibi scintiscans were used for preoperative localization. Monitoring iPTH levels during parathyroidectomy quantitatively assured the surgeon (G.L.I. only) when all hyperfunctioning glands were excised., Main Outcome Measure: The number of patients without complications and with short operative times who were discharged without hospital admission or overnight stay., Results: The combination of preoperative localization of abnormal parathyroid glands and a decline in circulating iPTH levels predicting postoperative normocalcemia after excision of all hyperfunctioning glands resulted in successful parathyroidectomy in 84 of 85 patients. A decreased operative time (average, 52 minutes) with minimal neck dissection permitted outpatient parathyroidectomy in 42 of 57 eligible patients., Conclusions: The combination of preoperative parathyroid scintiscan localization and iPTH level monitoring during surgery permitted successful parathyroidectomy in an ambulatory setting in half of a consecutive series of patients with primary hyperparathyroidism. The safety, success, and likely cost savings of this approach suggest wider application.

Adrenal cortical mitochondria display an extensive capacity to adapt morphologically to the functional state of the adrenal cortical cell. In the present study, we have used transmission electron microscopy to analyze cortical tissues from 3 normal human adrenal glands (zona fasciculata and zona glomerulosa), and from 8 steroid-secreting adrenal cortical adenomas (3 cortisol-producing, 4 aldosterone-producing, and 1 progesterone-producing tumor), correlating both clinical and biochemical features with cellular ultrastructure. The morphology of mitochondria was related to the enzyme activity and steroid-biosynthetic capacity of each tumor. Cells from aldosterone-producing adenomas demonstrated a large number of elongated tubular mitochondria with characteristic bridging of inner membranes, producing a lamellar-type pattern. Cells from cortisol-producing adenomas showed large round mitochondria with vesicular or tubulovesicular inner membranes surrounded by a characteristic dilated smooth endoplasmic reticulum. A highly unusual progesterone-producing adenoma, in which a deficiency of 21 alpha-hydroxylase activity was demonstrated, showed a peculiar type of enlarged lamellar mitochondria with bright inner matrix and a reduced number of inner membranes. Therefore, the ultrastructural characteristics of adrenal cortical mitochondria appear to be potential markers for the differentiation of steroid-producing adenomas. These studies point to the possibility of a broader use of electron microscopy in the study of adrenal tumors.

We performed a comparative study of catecholamine content, tyrosine hydroxylase (TH) activity, and TH mRNA levels in normal human adrenals and various clinical forms of human pheochromocytoma. We studied sporadic, benign intra-adrenal chromaffin tumors and other non-malignant intra-adrenal tumors associated with multiple endocrine neoplasia type 2B (MEN 2B) and von Hippel-Lindau disease along with one extra-adrenal malignant pheochromocytoma. Our findings suggest substantial differences in TH transcriptional rates or the stability of TH mRNA or both may contribute to altered TH expression in human chromaffin cells associated with "normal" adrenal tissues and various forms of pheochromocytoma and distinctive patterns of expression in the different settings in which these tumors arise.

A patient with a markedly elevated serum phosphorus level (23.9 mg/dL) is described, followed by a brief review of severe hyperphosphatemia. Elevated serum phosphorus levels may be artifactual or true. True hyperphosphatemia is usefully subdivided according to (a) whether phosphorus is added to the extracellular fluid from a variety of exogenous or endogenous sources, or (b) whether the urinary excretion of phosphorus is reduced from either decreased glomerular filtration or increased tubular reabsorption. Severe hyperphosphatemia, defined herein as levels of 14 mg/dL or higher, is almost invariably multifactorial--usually resulting from addition of phosphorus to the extracellular fluid together with decreased phosphorus excretion. The hyperphosphatemia of the patient described herein appeared to result from a combination of dietary phosphorus supplementation, acute renal failure, acute pancreatitis, and ischemic bowel disease, complicated by lactic acidosis.

Purpose: To review the effects of heparin and heparinoid compounds on aldosterone physiology and associated induction of hyperkalemia., Materials and Methods: A comprehensive literature search (of human and animal data) was carried out by computer and by using reference citations from primary sources., Results: Heparin and its congeners are predictable, potent inhibitors of aldosterone production. This inhibitory effect is specific for the zona glomerulosa; other corticosteroids are not affected. Aldosterone suppression occurs within a few days of initiation of therapy, is reversible, and is independent of either anticoagulant effect or route of administration. Decreases in aldosterone levels may occur with heparin dosages as low as 5,000 U BID. The most important, but probably not the only mechanism of aldosterone inhibition appears to involve reduction in both the number and affinity of the angiotensin-II receptors in the zona glomerulosa. Prolonged use of heparin causes marked reduction in the width of the adrenal zona glomerulosa., Conclusions: Aldosterone suppression results in natriuresis and less predictably in decreased excretion of potassium. Greater than normal serum potassium levels occur in about 7% of patients, but marked hyperkalemia generally requires the presence of additional factors perturbing potassium balance (in particular, renal insufficiency, diabetes mellitus, or the use of certain medications). Heparin-induced increases in serum potassium need to be better anticipated by clinicians. Serum potassium levels should be monitored periodically in patients being given heparin for 3 or more days, and in patients at relatively high risk for hyperkalemia, the monitoring interval should probably be no greater than 4 days.

This study was undertaken to assess the biomedical and socioeconomic rationale of edema control in disabling chronic venous insufficiency (CVI). In this 15-year retrospective survey (1974 through 1988) edema control was achieved by use of Unna's boot for leg ulcerations and by compressive hosiery for prevention of ulcerations. The study included 2,317 self- or physician-referred patients with disabling CVI, of whom 998 presented with venous stasis ulcers, many with recurrent ulcerations. Two hundred thirty-six patients were seen and treated only once and never returned. They were listed as not healed. Including patients who never returned after the first visit, the overall healing rate was 60.9%. Excluding the nonreturning patients, the overall rate of verified healing was 73.3%. The healing rate was 91% for first ulcers of complaint patients (patients treated at least 12 times in 32 weeks). The Unna's boot, being a functional substitute for the failing muscle pump in CVI, is a noninvasive and ambulatory method of controlling edema and treating ulcers in CVI. It does not interfere with patients' activities, it is inexpensive, and it is adaptable to middle aged and elderly ambulatory populations.

Piriformis syndrome (PS) is defined by a loose cluster of symptoms arising from entrapment of one or both divisions of the sciatic nerve as they pass the sciatic notch. This paper presents a method of using the H-reflex as an aid in the diagnosis of PS. Forcible pressure from the piriformis muscle on the sciatic nerve can be induced by internal rotation of an affected limb in an adducted, flexed position. This pressure is reflected in a delay of the H-reflex. The length of delay seen in 39 legs of 34 patients who met the criteria for PS is compared with that seen in 13 unaffected contralateral limbs and 14 limbs from able-bodied subjects. Mean delay of H-reflex was 2.66 msec for affected legs and .36 msec for the combined control groups (t = 7.45, p less than .001). There were no differences in the H-reflexes themselves between groups. Physical therapy aimed at reducing mechanical impingement was successful in 11 of 12 patients on followup at three to nine months.

The adrenal medulla and tumors derived from it have been shown to be capable of converting radioactive steroid intermediates into glucocorticoid end products in vitro. This capacity for partial steroid synthesis was explored in two large extraadrenal pheochromocytomas and compared to the results of parallel studies with intraadrenal pheochromocytomas and adrenal cortex; in one experiment, all three types of tissue were obtained from a single patient and studied simultaneously. Slice preparations of extraadrenal pheochromocytoma transformed 14C-labeled pregnenolone (3 beta-hydroxypregn-5-en-20-one) into corticosterone and cortisol. Incubations of subcellular fractions demonstrated that, as in the adrenal cortex and intraadrenal chromaffin tissue, delta 5-3 beta-hydroxysteroid dehydrogenase-isomerase, 17 alpha-hydroxylase, and 21-hydroxylase activities in extraadrenal pheochromocytomas were associated with the microsomes and 11 beta-hydroxylase was associated with the mitochondria, where metyrapone was an effective inhibitor, these findings tend to dissociate steroid-metabolizing activity in the adjacent chromaffin tissue perfused by glucocorticoid intermediates in high concentrations.

Cortisol, corticosterone, epinephrine and norepinephrine have been identified for the first time in two adrenal cysts removed from patients without endocrine dysfunction. Total concentrations of corticosteroids and catecholamines in both capsule and fluid of these cysts were higher than in plasma of normal subjects but lower than in human adrenal tissue. The cysts contained preformed cholesterol in concentrations similar to normal adrenal parenchyma. Contrary to adrenal tissue, however, homogenates of cyst components failed to utilize [4-14C] cholesterol for steroid formation. The data presented suggest that hormones in adrenal cysts probably arise by passive diffusion from the surrounding gland and that the endocrine status of patients bearing adrenal cysts is determined by the adjacent non-cystic tissue.

Histochemical assays, hormonal quantitation, and steroid biosynthetic studies were carried out with adrenal glands obtained from four stranded whales of two different species (Kogia breviceps and Mesoplodon europaeus), and selected comparisons were made with the results of similar studies of adrenals from terrestrial mammals (man, beef, rat). Histochemical chemical assays of the whale glands for succinic dehydrogenase activity (SDA) showed an intense SDA-positive reaction in the peripheral cortex, and an SDA-negative central medulla, a pattern similar to that found in terrestrial mammals; the whale adrenals, however, demonstrated a markedly pseudolobulated appearance because of a festooned corticomedullary junction. On radioimmunoassay of preformed cortical steroid hormones, corticosterone (B) exceeded cortisol (F) levels by a factor of 3 in the whale adrenals and aldosterone (Aldo) concentrations were 20-100 times lower than in the terrestrial mammals studied. HPLC determinations of preformed medullary catecholamines showed that, contrary to the findings in the terrestrial mammals studied, norepinephrine predominated over epinephrine and the levels of dopamine were much higher in the whale adrenals. In vitro, surviving sections of whale adrenals elaborated B from endogenous substrates, but not F or Aldo. Incubations of subcellular fractions of the whale adrenals with 14C-labeled precursors resulted in the isolation of several steroid intermediates (pregnenolone, progesterone, deoxycorticosterone) as well as the glucocorticoid end-product B, but again without evidence of the formation of either F or Aldo. In keeping with studies in terrestrial mammals, the enzymatic reactions involved in the conversion of [14C]cholesterol to B occurred under aerobic conditions, required the presence of an exogenous NADPH-generating system, and had identical subcellular localization in the whale adrenals. The process of steroid biosynthesis thus appears generally similar in aquatic and terrestrial mammals. It is possible that some of the unusual findings in the whale adrenals studies here may be related to the profound stress of stranding experienced by these marine mammals.

The possibility of bilateral, extra-adrenal, and malignant tumors has dictated a thorough abdominal exploration through an anterior incision in the management of patients with pheochromocytomas. Careful visualization or palpation of the sites known to harbor secondary tumors is still recommended by many surgeons. The present study contrasts the results and morbidity of the retroperitoneal approach with that of the intraperitoneal operative approach for resection of pheochromocytoma. In the last 14 years, 37 patients had successful total resections of their pheochromocytomas, excluding one patient with metastasis to the liver at the time of surgery who died 10 years after operation. After preoperative localization of their tumors, 17 patients were explored anteriorly and 20 underwent resection using a lateral approach. Thirty-one patients have been followed from 2 to 141 (average 56) months. All patients have either returned to a normotensive state on no medication (27 patients) or, while requiring medication (9 patients), have had normal urinary metanephrine/catecholamine levels, except for the one patient with metatastic disease. There were substantial differences in morbidity rates between the two groups, however. Four patients (20%) had minor postoperative complications, following retroperitoneal resection that included pleural effusion, urinary retention, pulmonary congestion, and fever. Nine patients (53%) had complications when the anterior approach was used, including splenectomy in two, pneumonia, and postoperative fever. Postoperative hospital stay averaged 9.8 days (range, 4 to 21 days) for the anterior group and 6.1 days (range, 4 to 12 days) when a lateral approach was used (p = 0.002). Our data suggest that, with accurate unilateral localization, the flank, retroperitoneal approach for resection of pheochromocytoma can be used successfully with less morbidity.

The changes in plasma renin activity (PRA) and plasma aldosterone concentration (PA) in response to postural stimuli were evaluated in 12 patients with stable diabetes mellitus and in five volunteers. Seven diabetic patients had hyperkalemia, and several had renal insufficiency and neurological complications. Five diabetics and had normal serum potassium concentration, a mean creatinine clearance within the normal range, and few complications. PRA and PA were measured in these patients and in the control subjects, all of whom were receiving a diet containing 10 mEq of sodium and 50 mEq of potassium while they were in a supine position, after they were tilted to a 90 degrees position, and after upright posture for two hours. The results indicate that impaired responsiveness of PRA and PA may occur in patients with complicated and those with uncomplicated diabetes and may be responsible in part for a relatively high prevalence of hyperkalemia especially in those diabetic patients with reduced renal function.

In a patient with pituitary ACTH-dependent adrenal hyperplasia (AH), the standard oral metyrapone test resulted in a decrease in "apparent 11beta-hydroxylase activity" (-48%) accompanied by an increase in "apparent cholesterol cleavage activity" (+318%). When incubated adrenal mitochondria from this patient were studied, metyrapone inhibited both 11beta-hydroxylation of labeled 11-deoxycorticosterone and cleavage of labeled cholesterol, although at 0.1 and 1.0 mM metyrapone concentrations, depression of cholesterol cleavage (23 and 54%, respectively) was less than that of 11beta-hydroxylation (62 and 84%, respectively). The inhibition of cholesterol cleavage by metyrapone (26 and 62%, at 0.1 and 1.0 mM concentrations, respectively) was also demonstrable in adrenal mitochondria from a patient with hypercorticism resulting from an ACTH-independent adrenal adenoman (AA). Metyrapone administration to AA resulted in a significant depression of both 11beta-hydroxylase (-62%) and cholesterol cleavage (-36%) "apparent activities"; when metyrapone and ACTH were given together to this patient, however, only 11beta-hydroxylase "apparent activity" diminished (-26%), while cholesterol cleavage "apparent activity" was greatly augmented (+231%), thereby simulating the results of the standard metyrapone test in AH. These data demonstrate that metyrapone inhibits both mitochondrial reactions involved in cortisol synthesis--initial cholesterol cleavage and final 11beta-hydroxylation; these effects probably result from interference by this agent with the interaction between substrate and related cytochrome P - 450. Since ACTH has a major stimulatory effect on cholesterol cleavage but not on 11beta-hydroxylation, the outcome of metyrapone administration is thus determined by whether a change in ACTH level ensues: while 11beta-hydroxylation is inhibited by metyrapone under any circumstances, total steroid output rises when a compensatory ACTH increase overcomes metyrapone inhibition of cholesterol conversion into pregnenolone and falls when metyrapone inhibition of this reaction is unopposed.

In the presence of ethanol, corticosterone and dexamethasone inhibit choline acetyltransferase and acetyl-cholinesterase activities in cultured fetal brain cells of the rat. These results suggest that corticosteroids may have an important influence on the activity of cholinergic enzymes in the fetal brain may antagonize the effects of ethanol in this setting.

Homogenates from four adrenal pheochromocytomas converted 4-14C-labeled pregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone into androstenedione and testosterone. In addition to these androgens, labeled pregnane substrates were also transformed into corticosteroids, as previously reported, and this conversion occurred in even higher yield. The formation of labeled metabolites of either pathway was greater in homogenates from intraadrenal pheochromocytomas than in those derived from an extraadrenal tumor, but less than in preparations of hyperplastic adrenal cortex. Incubations of subcellular fractions isolated from an adrenal pheochromocytoma showed that the enzyme activities involved in androgen formation from the radioactive substrates studied were associated with the microsomes and required exogenous cofactors. In contrast to adrenocortical tissue, chromaffin cell preparations uniformly failed to convert substrate [4-14C] cholesterol into either androgens or corticosteroids. The data available demonstrate the presence in chromaffin tissue of all of the enzyme activities required for the biosynthesis of androgens and corticosteroids except for those involved in the side-chain scission of cholesterol.

The effects of adrenocorticotropic hormone (ACTH), cyclic AMP (cAMP), NADPH, Krebs cycle intermediates (KCl), and metyrapone on the two key mitochondrial reactions in the biosynthesis of glucocorticoids--11 beta-hydroxylation and cholesterol cleavage--were studied in preparations from the adrenal glands of stranded whales (Kogia breviceps and Mesoplodon europaeus) and some terrestrial mammals. ACTH (30 pM) and cAMP (1.0 mM) enhanced the 11 beta-hydroxylation of [11-3H]deoxycorticosterone ([3H]DOC) in monolayer cultures of whale adrenal cells during a 4-hr incubation period. Mitochondria from whale and beef adrenals responded in a similar dose-related fashion to NADPH generated by the addition of increasing amounts of NADP (0-0.6 mM) to the in vitro system: at each level of NADPH, 11 beta-hydroxylation of [14C]DOC was several-fold greater than the cleavage of [14C]cholesterol. Metyrapone interfered in a dose-related manner with both the 11 beta-hydroxylation of [14C]DOC and the cleavage of [14C]cholesterol by mitochondria from whale and beef adrenals; inhibition of 11 beta-hydroxylation exceeded 60% at 0.1 mM metyrapone and was virtually complete at 1.0 mM in both species, while inhibition of [14C]cholesterol cleavage averaged 25% at 0.1 mM metyrapone and 50% at 1.0 mM. The effect of exogenous NADPH in supporting the 11 beta-hydroxylation of [14C]DOC could be maintained in beef and rat adrenal mitochondria to the extent of 70-100% by substitution with any of the KCl. This phenomenon was not found in similar whale studies where the KCl were all ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum cholesterol-binding reserve (SCBR), the capacity of a serum sample to solubilize additional cholesterol in excess of its cholesterol content, was measured in 43 white male patients with maturity-onset diabetes in the age range of 35--59 years who were under treatment with insulin. The values were compared with those of 194 nondiabetic controls of the same race, sex, and age range. The mean +/- S.D. of SCBR of patients (71.9 +/- 29.3 mg./dl.) was lower than that of controls (88.9 +/- 30.9 mg./dl.) (p less than 0.001). Age in the range of 35 to 59 years had no correlation with SCBR in either patients or controls. SCBR was positively correlated with serum levels of cholesterol (SC) and triglycerides (TG) in both patients and controls. After adjustment for SC and TG, the difference in SCBR between patients and controls persisted (p less than 0.001). In 15 of 20 (75 per cent) patient-control pairs matched for SC and TG to within 5 per cent, the patient had lower SCBR (paired t-test, p less than 0.002). In 16 patients without elevation of serum lipid levels (SC below 250 and TG below 150 mg./dl.), the mean +/- S.D. of SCBR (59.1 +/- 17.7 mg./dl.) was lower than that of 49 controls having serum lipids in the same range (77.4 +/- 31.7 mg./dl.) (p less than 0.03). These results indicate an association of decreased SCBR with diabetes and are consistent with the hypothesis that low SCBR is associated with accelerated atherosclerosis and enhanced risk for coronary heart disease.

During a 15-year period, 24 patients were treated operatively for pheochromocytoma at this medical center. In this group a father and three daughters were recognized to have the familial variety of this disease. Malignant hypertension, which began at an early age, was the most prominent characteristic. Operative treatment of the three sisters occurred at the ages of 9, 15, and 17 years. All pheochromocytomas were bilateral and were confined to the adrenal glands except for hepatic extension in the father. In contrast to most recent reports of familial pheochromocytoma, there was no evidence of multiple endocrine adenomatosis in this family. Total adrenalectomy was performed in only the youngest patient and, although normotensive, she requires close observation and steroid replacement. Three patients underwent a controversial partial adrenalectomy after excision of bilateral tumors. The father has remained hypertensive for 8 years and has evidence of a residual tumor in the liver. The two daughters who have had subtotal adrenalectomies remain normotensive, require no medication, and have normal urine catecholamine values 7 and 3 years after operation. These results show that removal of bilateral pheochromocytomas without total adrenalectomy may allow normal adrenal function free of recurrence for several years in patients without multiple endocrine adenomatosis.