Anti-Hypertensive Drugs Moderate the Relationship of Blood Pressure with Alzheimer's Pathologies and Neurodegenerative Markers in Non-Demented Hypertensive Older Adults.

BACKGROUND: We aimed to explore whether the relationships of blood pressures (BPs) with Alzheimer's disease (AD) endophenotypes varied by usage of antihypertensive drugs (AHDs). METHODS: A total of 765 non-demented older adults (mean age: 74.4 years; female: 43.1%) with a self-reported history of hypertension were followed for 6 years. Multiple linear regression and linear-mixed effect models were used to investigate the interaction effects of five categories of AHDs (angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARBs], ß-blocker, calcium channel blockers [CCB], diuretic) with BPs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) on AD core pathology and neurodegenerative markers. RESULTS: After Bonferroni correction, significant interaction effects of BPs with AHDs were observed. Elevated SBP or PP in late-life was associated with higher levels of cerebral Aß burden (diuretic alone/ß-blocker × SBP), higher levels of CSF tau proteins (diuretic × SBP/PP, ARBs/CCB × SBP), and lower volume of entorhinal region (ß-blocker × SBP, diuretic × PP) only among hypertensive patients who received no anti-hypertensive treatments, while these associations became compromised or null for users of specific AHDs except for ACEI. Compared to taking other classes of AHDs, elevated SBP in late-life was associated with lower cerebral Aß burden in diuretic users (padjusted = 0.08) and was associated with higher CSF tau proteins in ACEI alone users (padjusted = 0.03). Longitudinal data validated the above-mentioned interaction effects on changes of cerebral Aß burden (padjusted < 0.05), CSF tau proteins (padjusted < 0.10), and brain atrophy (padjusted < 0.05). CONCLUSIONS: The relationships of late-life BP with AD pathology and neurodegeneration could be modified by anti-hypertensive treatments and varied by AHD classification. These findings provide preliminary evidence for tailored BP management strategy for preventing AD among late-life hypertensive adults.

Clinical outcomes of children with COVID-19 infection in a low-risk centre in Malaysia.

INTRODUCTION: According to WHO, long-COVID or post- COVID-19 condition is defined as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. A systematic review and meta-analyses published in 2022, which mainly focus on the Western population, revealed that the prevalence of long COVID was 25.24%. Literature regarding long-COVID in children in Asia was scarce. The objectives of our study were to assess the long-term effect of COVID-19 infection in children and its correlation to their acute COVID- 19 infection. MATERIALS AND METHODS: This study was conducted in Hospital Kepala Batas (HKB), a district hospital in Penang State, Malaysia, which was the designated regional COVID hospital during the pandemic. It was a retrospective observational study, where children who were admitted from November 2020 to March 2021, and attended follow-up clinics from Jan 2021 to May 2021, were recruited. RESULTS: This study comprised 90 subjects, from 3 months old to 12 years old, mean of 6.5 years old. When comparing asymptomatic and symptomatic children, children with comorbidities were more likely to be symptomatic with a pvalue of 0.045 using the Pearson Chi-square test. All our patients' symptoms resolved upon discharge. During followup at 2-4 months after COVID-19 infection, all children were reported as back to their usual selves. Fifteen patients had recurrent symptoms. Most of their symptoms pointed towards an acute infection. One patient had two episodes of illness, while the rest had one. The most common symptoms were cough, fever and runny nose. The average duration of illness of these 16 episodes was 4.5 days with a standard deviation of 2.48. None of these symptoms lasted more than seven days. None of them required hospital admission. None of them had recurrent COVID-19 infections. Tweleve out of 72 children who had been going to school stopped physical school after COVID-19 infection. Our findings differed from other studies. These could be due to the limitations that we faced. CONCLUSION: Most children who contracted COVID-19 infection recovered fully after acute infection, and most of them recovered fully without long-term sequelae.

Parental control on handphone access and usage among Malaysian children.

INTRODUCTION: Parental control for a child's handphone access is important to ensure online safety. This study was to determine parental control on handphone access and the usage amongst Malaysian children. MATERIALS AND METHODS: A cross-sectional survey was conducted electronically between April 2017 and March 2018 among parents with children above 2 years of age, who owned a handphone. The 10-item questionnaire included questions about rules applied to the use of handphones, education on cybersafety, the characteristics and activities of their youngest children who had full-time access to a handphone, and parental perceptions of their children's usage of handphones. A total of 215 parents were included. RESULTS: From this, 92% controlled their children's handphones use by setting rules. The commonest rules were limiting the time of handphone usage (77%) and being aware of whom the child was communicating with (77%). The majority (94%) educated their children on cybersafety, and the commonest discussed topic was not to communicate with strangers (93%). The children's average age of first handphone ownership was 10.6 (SD: 3.6) years, and the use of the handphone averaged 17.4 (SD: 18.5) hours a week. Despite the rules and education provided, only a quarter of parents were confident of their children's capability to manage their own safety when using handphones (27%). CONCLUSION: In summary, Malaysian parents did control their children's handphone usage.

Measles-Mumps-Rubella vaccine for children with egg allergy: Is admission for inpatient vaccination necessary?

INTRODUCTION: Children who develop any hypersensitivity reaction to eggs are routinely referred to hospital for Measles-Mumps-Rubella (MMR) vaccination as inpatients to prevent anaphylaxis. We aimed to study the association between hypersensitivity reactions after egg exposure and similar reactions after MMR immunisation; and examine the necessity of hospital admission for vaccination. METHODS: A prospective observational study was conducted in Paediatric Department in Bukit Mertajam Hospital, Penang, between March and December 2014. Children referred from local polyclinics for inpatient MMR vaccination because of a history of egg allergy were recruited. The children were observed in the ward for post vaccination allergic reactions. Concurrently, a group of children without egg allergy was recruited from those admitted for other illnesses but had recent MMR vaccination at polyclinics. Parents of these children were interviewed and asked if they had observed any reactions post vaccination. In both groups, sociodemographics, medical history and family history of atopy were collected. RESULTS: Eighty-seven subjects were recruited in this study. Fifty-four infants with egg allergy had previous mild allergic reactions after exposure to eggs or egg-related products. They were associated with a family history of egg hypersensitivity, personal history of acute gastroenteritis and upper respiratory tract infections. Two of them developed cutaneous rashes post vaccination during observation, but none developed anaphylactic or anaphylactoid reactions. Two infants among those without egg allergy had post vaccination fever. There was no association between egg allergy and hypersensitivity reactions to MMR vaccine (p=0.632). CONCLUSIONS: MMR vaccine can be safely administered to children with mild egg allergy, hence admission for vaccination in the hospital is not warranted. Risk stratification is required to ensure only infants with severe reactions will be admitted for vaccination.

Amyloid-ß induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer's disease.

Increasing evidence has shown the aberrant expression of inflammasome-related proteins in Alzheimer's disease (AD) brain; these proteins, including NLRP1 inflammasome, are implicated in the execution of inflammatory response and pyroptotic death. Although current data are associated NLRP1 genetic variants with AD, the involvement of NLRP1 inflammasome in AD pathogenesis is still unknown. Using APPswe/PS1dE9 transgenic mice, we found that cerebral NLRP1 levels were upregulated. Our in vitro studies further showed that increased NLRP1-mediated caspase-1-dependent 'pyroptosis' in cultured cortical neurons in response to amyloid-ß. Moreover, we employed direct in vivo infusion of non-viral small-interfering RNA to knockdown NLRP1 or caspase-1 in APPswe/PS1dE9 brain, and discovered that these NLRP1 or caspase-1 deficiency mice resulted in significantly reduced neuronal pyroptosis and reversed cognitive impairments. Taken together, our findings indicate an important role for NLRP1/caspase-1 signaling in AD progression, and point to the modulation of NLRP1 inflammasome as a promising strategy for AD therapy.

Difficulties in diagnosing lesions in the floor of the mouth--report of two rare cases.

This article highlights 2 contrasting lesions of the floor of the mouth, the first being a benign lipoma growth and the latter, an adenoid cystic carcinoma. Both of these lesions appear clinically similar, presenting as a swelling with normal overlying mucosa and otherwise asymptomatic at the time of clinical examination. As the swelling for Case 1 is small and fluctuant, no special investigation was ordered, whereas a computed tomographic scan was ordered for the larger expansile lesion in Case 2. The lesions were excised under local and general anaesthesia respectively and a histology henceforth. Recovery for both cases were uneventful and no recurrence or complication was noted to date when this article was written. The two extreme natures of the lesions manifested in the region serve as a cautionary note to clinicians.

Native and oxidized low-density lipoproteins enhance superoxide production from diabetic rat glomeruli.

Oxygen free radicals have been implicated in mediating diabetic complications, and patients with diabetic nephropathy frequently show increased levels of circulating and oxidized low-density lipoproteins (LDL). In the present study, we measured the superoxide production of glomeruli isolated from poorly controlled diabetic (streptozotocin) rats sacrificed 1 week and 1, and 3 months after the induction of diabetes. The animals were stimulated with native and oxidized LDL isolated from normal humans with normolipidemia. The superoxide ion was measured by using a spectrophotometer. The results demonstrated that the poorly controlled diabetic rat glomeruli showed a significantly higher production of superoxide than normal glomeruli under basal conditions, and this production increased further with the progression of diabetes. Stimulation with either LDL or oxidized LDL enhanced superoxide production by diabetic glomeruli, with oxidized LDL being more potent than LDL. Our results suggest that oxidized LDL may play important roles in the pathogenesis of diabetic nephropathy through enhanced generation of oxygen free radicals.

Cryosurgical ablation of soft tissue sarcomas: a phase I trial of feasibility and safety.

BACKGROUND: Cryosurgery is a therapeutic method of treating neoplastic tissue by freezing in situ to achieve devitalization. Cell death results from exposure to severe cold (below -40 degrees C for at least 1 minute) as well as from the process of freezing and thawing, which disrupts cellular integrity. Modern cryosurgical technique involves insertion of hollow probes into the tumor, through which circulating liquid nitrogen and gaseous nitrogen can achieve tissue and tumor freezing and thawing for tumor control. Cryoablation is now a recognized approach to the treatment of various malignant tumors, and it is generally well tolerated. This method has been used only sporadically to date in the treatment of patients with soft tissue sarcomas. METHODS: The purpose of this study was to assess the feasibility and safety of cryosurgical ablation of soft tissue sarcomas utilizing a cryoprobe system. Twelve patients with soft tissue tumors of the extremity were included in this Institutional Review Board-approved protocol. Cryoablation was performed by inserting cryoprobes into the tumors, through which liquid nitrogen and gaseous nitrogen were pumped to achieve two freeze/thaw cycles. The entire process was monitored with intraoperative ultrasonography. All patients had subsequent resection of the residual tumor. Patients were monitored clinically and metabolically for toxicity. RESULTS: Cryoablation was successfully performed on all 12 patients. Complications included peripheral nerve palsy (in 3 patients) and serous wound drainage (in 3 patients). There were no cases of wound infection, deep venous thrombosis, pulmonary embolism, wound dehiscence, skin slough, or metabolic abnormalities. All 3 cases of peripheral nerve palsy showed signs of recovery, 2 within 1 week and 1 within 4 months. CONCLUSIONS: Cryosurgical ablation of soft tissue sarcomas is technically safe and feasible. This method can be used in conjunction with other modalities in the treatment of patients with these tumors. The complications associated with cryoablation of sarcomas are minor or transient, and the procedure is well tolerated by patients. The role of cryosurgery in the management of soft tissue sarcomas needs to be elucidated as more data regarding its safety and effectiveness become available.

Increased renal ANP synthesis, but decreased or unchanged cardiac ANP synthesis in water-deprived and salt-restricted rats.

BACKGROUND: Experiments were performed to examine the effect of water deprivation and salt restriction on ANP synthesis in the kidneys and hearts of normal rats. METHODS: A 4-day water deprivation (WD) and 7-day salt restriction (SR; 0.01% NaCl) were performed in 12 and 14 rats, respectively. Atrial natriuretic peptide (ANP) mRNA expression in the kidney was assessed with reverse transcription-polymerase chain reaction coupled with Southern blot hybridization, while the ANP mRNA in the hearts was measured by Northern blot hybridization. ANP and angiotensin II concentrations in the extracted plasma were measured by radioimmunoassay. The molecular form of renal ANP-like protein was characterized by reverse phase-high-performance liquid chromatography (RP-HPLC). RESULTS: Renal outer and inner medullary ANP mRNA showed a respective 11-fold and ninefold increase in WD rats, and an eightfold and fivefold increase in SR rats as compared to corresponding control groups. Inversely, cardiac atrial ANP mRNA and plasma ANP were decreased in WD rats, whereas they did not change in the SR group. Plasma angiotensin II concentration increased in conjunction with the decrease of urine sodium excretion in both groups. RP-HPLC analysis revealed a 45% extraction of ANP in the WD rat kidneys, whereas only 3% ANP in the control kidneys migrated in a molecular form similar to cardiac atrial proANP. CONCLUSIONS: Our results demonstrate that water deprivation and salt restriction markedly enhance renal ANP mRNA, whereas water deprivation suppresses cardiac atrial ANP mRNA and plasma ANP concentrations. The current study indicates that renal ANP and cardiac atrial ANP appear to be two distinct systems regulated by different mechanisms and possibly exhibiting different intra-renal paracrine and systemic endocrine functions.

Routine pre-contrast CT for liver lesion detection. A re-examination.

OBJECTIVE: Re-examination of routine pre-contrast computed tomography (CT) through liver. MATERIALS AND METHODS: 852 abdominal CTs including pre- and post-contrast images were retrospectively reviewed regarding detection of hepatic lesions. RESULTS: 103 cases demonstrated hepatic abnormalities. More liver lesions were identified post-contrast in 89; equal numbers were seen pre- and post-contrast in 10; more lesions were seen pre-contrast in one case. Tiny calcifications were detected only pre-contrast in three cases. CONCLUSIONS: Routine pre-contrast scanning through liver is not cost-effective.

Increased atrial natriuretic peptide mRNA expression in the kidney of diabetic rats.

To investigate whether renal synthesis of atrial natriuretic peptide (ANP) is influenced in diabetes, we measured renal ANP mRNA levels, urine volume, urinary ANP and sodium excretion rates in streptozotocin (STZ)-induced diabetic rats. By using reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blot analysis, we found that renal cortical and outer medullary ANP mRNA levels in untreated diabetic rats were markedly increased as early as the second day after the onset of hyperglycemia and remained elevated for the entire 42-day study period. Plasma ANP concentrations in untreated diabetic rats were increased on the 42nd day, whereas plasma renin activity were suppressed. The urine volume, urinary ANP and sodium excretion rates in untreated diabetic rats were also significantly elevated on the second day and remained elevated for the entire 42-day study period. Urinary ANP excretion rates were well correlated with urine volume, and urinary sodium excretion rate in normal rats and diabetic rats on days 2, 4, 7, 14 and 42. Our results indicate that renal ANP mRNA expression is enhanced in diabetic rats, and that renal-synthesized ANP as one of regulators to handle water and sodium balance in diabetic rats is worthy of further investigation.

Oxidized low-density lipoprotein stimulates endothelin-1 release and mRNA expression from rat mesangial cells.

Evidence indicates that the glomerular injuries and renal hemodynamic abnormalities in hyperlipidemia are caused by the interaction of low-density lipoprotein (LDL) and oxidized LDL (Ox-LDL) with mesangial cells. Experiments were designed to investigate whether the synthesis of mesangial cell endothelin-1 (ET-1), a potent renal vasoconstrictor and mitogen for mesangial cells, is modulated by LDL and Ox-LDL. Using competitive semi-quantitative reverse transcription polymerase chain reaction (PCR), we report that the expression of cultured rat mesangial cell ET-1 mRNA was increased after treatment with Ox-LDL but not native LDL. Ox-LDL stimulated the release of ET-1 peptide into the culture medium in a time- and concentration-dependent manner. The maximal effect was observed at a concentration of 100 microg/ml, and a higher dose of Ox-LDL was found to be cytotoxic to the mesangial cells. Our results suggest that ET-1 released by Ox-LDL stimulation may be an important pathogenetic factor contributing to the renal hemodynamic alterations and progressive chronic renal diseases induced by hypercholesterolemia.

Increased renal atrial natriuretic peptide synthesis in rats with deoxycorticosterone acetate-salt treatment.

To investigate the role of renal synthesis of atrial natriuretic peptide (ANP) as a contributor to the water-sodium homeostasis, we studied the effects of electrolyte-water imbalance on renal ANP mRNA levels, plasma ANP concentrations, and urinary ANP excretion rates by using reverse transcription-polymerase chain reaction (PCR) and radioimmunoassay. Male Wistar rates divided into the following three groups: 1) the control group, 2) deoxycorticosterone acetate (DOCA)-salt-treated group, and 3) low-salt-treated group. The urinary sodium excretion rate and urine volume in the DOCA-salt rats were significantly elevated at 2 days and for the 10-day study. The urinary ANP excretion rate in DOCA-salt rats was significantly increased at 2 days after treatment and was well correlated to the urinary sodium excretion rate (r = 0.76, P < 0.01). Plasma ANP levels in the DOCA-salt rats were elevated on the day of death. In contrast, plasma renin activities were markedly suppressed in DOCA-salt rats and increased in low-salt rats. By immunohistochemical study, immunoreactive ANP materials were mainly localized in the proximal and distal cortical tubules of the kidney. With the PCR cloning and sequencing technique, ANP cDNA was cloned from the rat kidney, and the sequences were identical to that of ANP identified in the atria. By semiquantitative PCR technique, the expression of ANP mRNA in the ventricle and renal cortex tissues was significantly enhanced in the DOCA-salt rats. Our results confirm that the rat kidney is a site of ANP synthesis and indicate that renal ANP synthesis is enhanced in a volume-expansion state. We propose that renal synthesized natriuretic peptide participates in the intrarenal regulation of water-electrolyte homeostasis and may contribute to renal adaptation during the mineralocorticoid escape phenomenon.

Increased expression of heparin binding epidermal growth-factor-like growth factor mRNA in the kidney of streptozotocin-induced diabetic rats.

Heparin binding epidermal growth factor (HB-EGF), a new member of the EGF family, is a potent mitogen for smooth muscle cells, fibroblasts, and mesangial cells. To study whether the HB-EGF is involved in the development of diabetic nephropathy, we measured the expression of the HB-EGF gene in the kidney tissues of streptozotocin-induced diabetic rats by Northern blot analysis. The mean kidney weight of diabetic rats without strict blood sugar control was significantly increased as compared to that of the control group. Renal HB-EGF mRNA expression was also increased in diabetic rats without strict blood sugar control at 7 days after induction of diabetes and remained elevated for the entire 3-month study period. Strict insulin treatment abolished the elevation of HB-EGF mRNA expression and kidney growth. As HB-EGF is a mitogen for mesangial cells, our results suggest that HB-EGF may be involved in the development of diabetic nephropathy.

Decrease of renal endothelin 1 content and gene expression in diabetic rats with moderate hyperglycemia.

To investigate the intrarenal endothelin 1 (ET-1) synthesis in streptozocin (STZ) diabetic rats with moderate hyperglycemia, we measured plasma ET-1, renal ET-1 mRNA, and renal tissue ET-1 levels. The renal ET-1 mRNA expression progressively decreased from the 2nd to the 6th week after induction of diabetes by STZ. The renal ET-1 mRNA expression and the renal tissue ET-1 content were significantly reduced in 8 diabetic rats with a mean blood glucose level of 21.0 +/- 0.4 mM as compared with 7 normal rats sacrificed at the 6th week after STZ or citric buffer injection. The reduction of renal ET-1 and mRNA levels was ameliorated in 9 diabetic rats with a mean blood glucose level of 6.9 +/- 0.7 mM after strict glycemic control by insulin treatment. Kidney weight and glomerular filtration rate in moderately hyperglycemic rats were significantly increased as compared with normal rats at the 6th week after STZ injection. The mean plasma ET-1 levels in moderately hyperglycemic diabetic rats were not different from those of the other two groups. This study demonstrates that moderate hyperglycemia in diabetic rats is associated with a reduction in renal ET-1 synthesis. Whether decreased renal ET-1 synthesis is an adaptive phenomenon of a renal hemodynamic change during the early stage of diabetes is worthy of further investigation.

Induction of heparin-binding epidermal growth factor-like growth factor mRNA by protein kinase C activators.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent smooth muscle cell mitogen of macrophage origin. To determine whether the HB-EGF gene is transcribed and regulated in mesangial cells, we measured HB-EGF mRNA levels in cultured rat mesangial cells by RNA blot analysis. A 2.5-kb HB-EGF mRNA was detected in unstimulated mesangial cells. The protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) increased HB-EGF mRNA levels by 15-fold in mesangial cells, and this induction of HB-EGF mRNA by TPA was both time- and dose-dependent. HB-EGF mRNA could also be stimulated by 10% fetal calf serum, ionomycin, thrombin, and endothelin-1. Staurosporine, a protein kinase C inhibitor, abolished the induction of HB-EGF mRNA by TPA and serum. To determine whether HB-EGF is mitogenic for mesangial cells, we transfected COS cells with HB-EGF expression plasmids. Culture medium from COS cells transfected with these plasmids increased 3H-thymidine incorporation in mesangial cells in a dose-dependent manner. To our knowledge, this is the first report that HB-EGF is expressed in renal cells. This inducible transcription of HB-EGF suggests that it may have an autocrine role in mesangial cell proliferation in kidney disease.

Regulation of heparin binding-epidermal growth factor like growth factor gene expression by LDL and oxidized-LDL in rat mesangial cells.

The present study was to determine whether low-density lipoprotein (LDL) and oxidized LDL (Ox-LDL) modulate the heparin binding-epidermal growth factor like growth factor (HB-EGF) gene expression in rat mesangial cells (RMC). Using Northern blot analysis, LDL and Ox-LDL stimulated the expression of RMC HB-EGF mRNA in a time- and concentration-dependent manner, and the stimulatory effect of Ox-LDL lasted longer than LDL. In addition, a protein kinase C (PKC) inhibitor-staurosporine and a PKC-depletion condition abolished both of the stimulatory activities of LDL and Ox-LDL, while H-8 (a protein kinase A inhibitor) and cAMP-antagonist (cyclic adenosine-3':5'-monophosphothioate) had little effect. Our data indicate that LDL and Ox-LDL enhance HB-EGF gene expression and both via the PKC pathway in RMC. As HB-EGF is a mitogen for RMC, our results suggest that lipoproteins may regulate RMC function by inducing HB-EGF gene expression and thus contribute to glomerular injury.

Characterization and cloning of enterotoxin genes of Salmonella typhimurium.

Five of fifty five strains of Salmonella typhimurium of human origin was hybridized with both the LT-A and LT-B gene of Escherichia coli. The remarkably erythromatous and indurated response on rabbit skin and significant elongation of Chinese Hamster Ovary (CHO) cells indicated the production of enterotoxin of these isolates. The Salmonella enterotoxin is heat-labile and is not a secretory product. The LT gene of E. coli was used to analyze the chromosome and plasmid DNA from Salmonella typhimurium strains for toxin gene sequences. Southern blot analysis demonstrated that the toxin gene was located on the plasmid but not on the chromosome. Restriction enzymes BamHI, EcoRI, HindIII and PstI were used to analyze the DNA isolated from salmonella strains Nos.22, 52, 55 and 59. Three DNA fragments with size of 5.2 Kb of strain 22, 5.0 Kb of strain 52 and 8.6 Kb of strain 59 were identified as containing the enterotoxin gene. Plasmid pUC19 was used as the vector to clone these DNA fragments in E. coli. The rabbit skin permeability test indicated that Salmonella enterotoxin could be synthesized at readily detectable levels in these transformed E. coli.

Randomized sequential hormonal therapy vs adrenalectomy for metastatic breast carcinoma.

One hundred sixty-one postmenopausal and 65 premenopausal women, a total of 226 patients with metastatic breast carcinoma, were included in this randomized study to evaluate the merits of adrenalectomy as the primary mode of therapy as compared to the customary sequential hormonal manipulation. The 145 evaluable postmenopausal patients were randomized as follows: (1) primary additive hormone therapy first followed by adrenalectomy and (2) primary adrenalectomy followed by chemotherapy and/or additive hormone therapy. When 76 patients in group 1 were compared with 70 patients in group 2 regarding their survival time, there was no essential difference, but the response rate was 20% vs 38.6%, a significant difference. The 55 evaluable premenopausal women were randomized into two groups: (1) oophorectomy followed by adrenalectomy; (2) adrenalectomy-oophorectomy as primary mode of therapy. The response rate in group 1 was 17.4% as compared with 41.9% in group 2, but again there was no difference in the survival time among these two groups. When sequential hormonal manipulation was utilized, only one-third of these patients were subjected to adrenalectomy because of their rapidly deteriorating condition. Adrenalectomy performed as a secondary procedure showed a lower response rate but the total survival time was comparable with primary adrenalectomy patients.