Lymphocyte recovery after bendamustine therapy in patients with mantle cell lymphoma. Results of a retrospective analysis and prognostic impact in the CAR-T era.

Bendamustine in combination with rituximab (BR) or with rituximab and cytarabine (R-BAC) is the standard first-line immunochemotherapy in mantle cell lymphoma (MCL) for elderly patients and patients ineligible for intensive regimens or autologous transplantation. As bendamustine causes prolonged lymphopenia and the literature lacks evidence of its persistence in patients with MCL, this retrospective analysis aims to estimate the lymphocyte recovery time, also in view of potential immunotherapy with CAR-T cells. Data were collected from 44 consecutive MCL patients who received bendamustine (BR or R-BAC) as first-line therapy at the Hematology Unit of Sapienza University Hospital between May 2011 and April 2022. Twenty patients (45%) were treated with R-BAC and 24 (55%) with BR. At baseline, the median lymphocyte count was 1795/µl (range: 370-11730/µL). One month after the end of therapy, it was 450/µl (range: 50-3300/µl) and 3 months after 768/µl (range: 260-1650/µl). After 6 and 9 months, we observed a gradual increase in median lymphocyte count of 900/µl (range: 370-2560/µl and 130-2770/µl, respectively). After 12 months median lymphocyte count was 1256/µl (range: 240-4140/µl). Median lymphocyte count at 1, 3, 6, and 9 months post-treatment was significantly lower than baseline but showed recovery by the 12 months. This finding is crucial for MCL patients considering CAR-T cell therapy, suggesting a minimum 9-month interval between bendamustine administration and leukapheresis.

Gene Expression and Localization of NGF and Its Cognate Receptors NTRK1 and NGFR in the Sex Organs of Male Rabbits.

Experiments were devised to characterize the expression of nerve growth factor, beta polypeptide (NGF), and its cognate receptors neurotrophic tyrosine kinase receptor type 1 (NTRK1) and nerve growth factor receptor (NGFR) in rabbit male sex organs, as well as the concentrations of NGF in both seminal and blood plasma of sexually mature male rabbits. Immunoreactivity and gene expression for NGF and cognate receptors were detected in testis, prostate gland and seminal vesicle. The highest levels of NGF and NTRK1 transcripts were found in the prostate, while intermediate expressions were found in the testis. NGFR transcripts were expressed at the same levels in both testis and prostate and were more abundant than in seminal vesicles. The widespread distribution of NGF in all prostate glandular cells, together with its relative high mRNA abundance, confirms that the prostate of rabbits is the main source of this neurotrophin. In conclusion, the present data suggest that the NGF system is involved in the testicular development and spermatogenesis of rabbits and that NGF may act as a potential ovulation-inducing factor being abundantly present in the seminal plasma.

Dietary fish oil and flaxseed for rabbit does: fatty acids distribution and Δ6-desaturase enzyme expression of different tissues.

Standard feeds are imbalanced in term of n-6/n-3 polyunsaturated fatty acids (PUFA) ratio, with a low proportion of the latter. The reproductive system appears to be strongly affected by administration of n-3 PUFA, and ingredients rich in α-linolenic acid (ALA; i.e. vegetable sources) or EPA and DHA acids (i.e. fish oil) can be included in animal diets to balance PUFA intake. The aim of this study was to evaluate the effect of dietary supplementation with flaxseed (ALA) or fish oil (EPA and DHA) on PUFA metabolism in rabbit does. A total of 60 New Zealand White female rabbits were assigned to three experimental groups: control group, FLAX group fed 10% extruded flaxseed and FISH group fed 3% fish oil. Blood, milk, liver and ovaries were collected from the does to assess the lipid composition; furthermore, FADS2 gene expression was assessed in liver and ovary tissues. Reproductive performance of does was also recorded. The fertility rate and number of weaned rabbits improved with n-3 dietary supplementation: does at first parity showed the lowest reproductive results, but the administration of n-3 reduced the gap between primiparous and multiparous does. Feed consumption and milk production were not affected by the feeding regime. The fatty acid composition of milk, plasma, liver and ovaries were widely influenced by diet, showing higher concentrations of n-3 long-chain PUFA (LCP) in does fed with n-3 enriched diets. FISH diet resulted in the highest n-3 LCP enrichment, whereas in the FLAX group, this increase was lower. Blood and milk showed low levels of LCP, whereas liver and ovaries were the main sites of n-3 LCP synthesis and accumulation. Accordingly, although the liver is the main metabolic centre for LCP synthesis, ovaries also have a prominent role in LCP generation. FADS2 expression in liver and ovary tissue was downregulated by FISH administration. In conclusion, the enrichment of diets with n-3 PUFA could be an effective strategy for improving the reproductive performance of does.

Pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension: short-term functional assessment in a longitudinal study.

AIM: Presently, the surgical treatment choice in chronic thromboembolic pulmonary hypertension (CTEPH) consists in a pulmonary endarterectomy (PEA). The aim of the present study is the functional assessment of patients submitted to PEA both preoperatively and shortly after the intervention. A longitudinal study was developed to study the quality and quantity of functional performance possible in these subjects. METHODS: Twenty-two subjects were assessed immediately prior to PEA and 3 months later in order to obtain quantitative measurements of short-term functional recovery. The functional assessment included the 6-min walk test (6mWT), the measurement of the oxygen percent saturation (HbS%O(2)) and the degree of dyspnea subjectively perceived by each patient. RESULTS: Three months after the surgical intervention, there was a definite increase in the number of meters walked during the 6mWT with respect to preintervention; the difference between the distances walked in the 6mWT (6mWD) in the pre and post-PEA was statistically significant (Paired t-test P<0.001). CONCLUSION: In this study the 6mWT resulted to be a useful tool in the functional evaluation of patients affected by CTEPH and submitted to PEA. The average 6mWD significantly improved already at 3 months after the intervention, thus reaching the minimum limit of the range predicted for the healthy control, but remains lower than the average theoretical value predicted (about 75% of the same).

Global Performance Status Score: A New Tool to Assess Physical Performance in Kidney Transplant Patients.

BACKGROUND: Information on physical performance in renal transplantation is limited because of the shortage of specifically designed evaluation instruments. Therefore, we elaborated and validated the Global Performance Status (GloPerSta) score to provide a new and comprehensive tool, exploring the different components of physical performance in kidney transplant patients. METHODS: We elaborated the GloPerSta score on the basis of the data obtained from a cross-sectional study, in which we evaluated the physical performance of a cohort of kidney transplant patients. The results of these analyses were weighted to describe the different contribution of any single test, via the generation of a structural equation model, resulting in the definition of the GloPerSta. Then, to internally validate this score, we studied its correlation with clinical parameters and quality of life (evaluated as KDQOL-SF, Kidney Disease Quality of Life-Short Form) in the same patient population. RESULTS: We enrolled 132 patients in whom the functional tests revealed a great heterogeneity. GloPerSta allowed the stratification of the patients in 3 different physical performance categories (low: score 0-11; medium: 12-22; high: 23-33). Internal validation showed that GloPerSta was directly and significantly correlated with the quality of life and allograft function, independent of the time from transplantation. CONCLUSIONS: The GloPerSta is a reliable tool to assess physical performance in a kidney transplant population. Its application might be of help in identifying patients needing intensive and personalized rehabilitation programs.

Determinants of quality of life after lung transplant: an Italian collaborative study.

BACKGROUND: With the improvement in survival rates after lung transplantation, concern has arisen about evaluating quality of life (QoL). This multicenter cross-sectional study aimed at describing QoL and identifying factors associated with it. METHODS: We assessed QoL in 129 lung transplant recipients from 5 centres in Italy, during scheduled follow-up visits, using the SF-36, GHQ and St George's respiratory questionnaires (SGRQ). RESULTS: The SF-36 elicited impaired QoL in the physical, but not in the mental domains (PCS = 44; MCS = 53). The GHQ identified 29 patients (23%) with psychological discomfort and the SGRQ scores were significantly better than those of patients with chronic respiratory disease. On multivariate analysis, exertional dyspnea was an independent predictor of the PCS (adjusted delta -6.3 (p < 0.001), while osteoporosis (delta = -3.1), BOS (delta = -4.3), acute rejection (delta = -3.9) and heart and lung transplant (delta = +6.4) were only marginally associated. Dyspnea was also related to a GHQ score > 5. CONCLUSIONS: The study identified exertional dyspnea as the main determinant of QoL as measured both by SF36 (PCS) and GHQ. Other objective measures contributed only to the PCS. Thus, the SF-36 (PCS) and GHQ were useful in identifying patients who needed treatment not only for complications but also psychological support and continued physical rehabilitation.

Expression of nerve growth factor and its receptors in the uterus of rabbits: functional involvement in prostaglandin synthesis.

The aim of the present study was to evaluate: (1) the presence of nerve growth factor (NGF), neurotrophic tyrosine kinase receptor 1 (NTRK1), and nerve growth factor receptor (NGFR) in the rabbit uterus; and (2) the in vitro effects of NGF on PGF2α and PGE2 synthesis and on the PGE2-9-ketoreductase (PGE2-9-K) activity by the rabbit uterus. Nerve growth factor, NTRK1, and NGFR were immunolocalized in the luminal and glandular epithelium and stroma cells of the endometrium. reverse transcriptase polymerase chain reaction indicated the presence of messenger RNA for NGF, NTRK1, and NGFR in the uterus. Nerve growth factor increased (P < 0.01) in vitro secretions of PGF2α and PGE2 but coincubation with either NTRK1 or oxide nitric synthase (NOS) inhibitors reduced (P < 0.01) PGF2α production and blocked (P < 0.01) PGE2 secretion. Prostaglandins releases were lower (P < 0.01) than control when uterine samples were treated with NGF plus cyclooxygenase inhibitor. However, addition of NGFR inhibitor reduced (P < 0.01) PGF2α secretion less efficiently than NTRK1 or NOS inhibitors but had no effect on PGE2 yield. Nerve growth factor increased (P < 0.01) the activity of PGE2-9-K, whereas coincubation with NTRK1 or NOS inhibitors abolished (P < 0.01) this increase in PGE2-9-K activity. However, cotreatment with either cyclooxygenase or NGFR inhibitors had no effect on PGE2-9-K activity. This is the first study to document the distribution of NGF/NTRK1 and NGFR systems and their effects on prostaglandin synthesis in the rabbit uterus. NGF/NTRK1 increases PGF2α and PGE2 productions by upregulating NOS and PGE2-9-K activities, whereas NGF/NGFR augments only PGF2α secretion, through an intracellular mechanism that is still unknown.

Recovery of deambulation after cardiothoracic surgery: a single center experience.

BACKGROUND: Surgical procedure and postoperative bed rest lead to musculoskeletal system alterations with a possibility of new walking dependence of patients who undergo cardiothoracic surgery, which is sometimes associated with prolonged hospitalization and increased health expenditure. AIM: The aim of this study was to assess the postoperative motor disability in inpatients admitted to the cardiothoracic surgical ward, and the results of customized rehabilitation in terms of recovery of postural changes and walking capacity with respect to the preoperative condition and destination after discharge. DESIGN: A prospective observational study was conducted. SETTING AND POPULATION: Four hundred seventeen inpatients, who had undergone cardiothoracic surgery, were enrolled between March 2011 and January 2012 in a Hospital Unit of Cardiothoracic Surgery. METHODS: A computerized system was used to collect data about ambulation at home, type and number of rehabilitation sessions proposed, ambulation at discharge, destination after discharge from ward of origin. All patients, who give their consent, undergone rehabilitative treatment on the ward of origin with an expert physiotherapist. RESULTS: Three hundred seventy-five inpatients were examined in Cardiac Surgery. One patient (0.26%) refused rehabilitative treatment. Two patients (0.53%) died. At the time of discharge 236 (74.45%) patients had recovered the ability to walk independently. After discharge 87.64% of patients was transferred to a specialist ward for intensive rehabilitation. Forty-two inpatients were enrolled in thoracic surgery. Two patients died whilst in hospital. At the time of discharge, 36 patients (94.73%) were able to walk independently. After discharge 80% of patients returned home. CONCLUSION: In our study, the application of an early and simple rehabilitation program on the ward of origin after surgery has made possible the recovery of ambulation of most inpatients who referred independence at home in a few days, limiting hospitalization and health expenditure. CLINICAL REHABILITATION IMPACT: Data about recovery of ambulation with respect to the preoperative condition and destination after discharge resume the importance of identifying motor impairment after surgery, in order to apply an adequate, early and feasible rehabilitation protocol to inpatients, limiting hospitalization and health expenditure.

Long-term changes in nodular goiter: a 5-year prospective randomized trial of levothyroxine suppressive therapy for benign cold thyroid nodules.

We studied for 5 yr a homogeneous group of 83 patients randomly assigned to a levothyroxine (L-T4) suppressive therapy or to a control group to evaluate changes in nodule or thyroid size, appearance of new nodules, and correlations with clinical parameters. In the control group, mean nodule volume increased significantly after 5 yr (2.12 +/- 1.46 vs. 1.46 +/- 0.77 mL), whereas in the treatment group it decreased, although not significantly (1.45 +/- 1.17 mL vs. 1.53 +/- 0.61 mL). Baseline nodule volume was not different in the two groups, but a significant difference was observed at 5 yr. After 5 yr, sonograms detected 12 new nodules in the control group (28.5%) and 3 (7.5%) in the treatment group. Nodule shrinkage was more frequent in patients with complete TSH suppression, but no correlation was found with other parameters. A significant increase in thyroid size was observed in the control group. In conclusion, long term TSH suppression induced volume reduction in only a subgroup of thyroid nodules, but effectively prevented the appearance of new lesions and increases in nodule and thyroid volume. As the changes in the natural history of nodular goiter are related to prolonged TSH suppression, which can induce unfavorable side-effects, L-T4 suppressive therapy should be reserved for small nodules in younger patients.

Percutaneous ultrasound-guided ethanol injection: a new treatment of toxic autonomously functioning thyroid nodules?

Twenty autonomously functioning thyroid nodules were treated with ultrasound-guided percutaneous ethanol injection (PEI) and followed for 12 months. PEI was performed on symptomatic and biochemically proven thyrotoxic patients by injecting 2.0-4.0 mL sterile ethanol and was repeated 3-8 times, depending on nodule size. Serum thyroglobulin increased immediately after PEI, peaked at 6-10 h, and declined thereafter. Free T4 progressed slowly during the first 24 h. Free T3 showed a delayed and not significant increase. By the end of the treatment (4 weeks), PEI had produced clinical improvement and hormonal normalization. Three months later, serum TSH was detectable and responsive to TRH in 17 of the 20 patients. All nodules had a significant shrinkage at ultrasound evaluation. The previous hot thyroid areas manifested hypofunction at technetium-99 m-pertechnetate scintiscan, and the surrounding parenchyma returned to normal function in all but the 3 cases with still suppressed TSH. The histological features of a nodule that had been operated upon and the fine needle aspiration biopsy patterns obtained after PEI showed coagulative necrosis, with scanty follicles, some fibroblasts, but no lymphocytic infiltration. The procedure was generally well tolerated, but in 1 case it induced temporary dysphonia, and in another patient, it caused a transient exacerbation of thyrotoxicosis.

Inhibition of leucocyte and platelet adhesion reduces neointimal hyperplasia after arterial injury.

Restenosis following coronary angioplasty is though to result from migration and proliferation of medial smooth muscle cells. However, the factors that initiate this proliferation are still unknown. In a rabbit model of carotid artery injury, we tested the hypothesis that activated platelets and leucocytes might contribute to the development of neointimal hyperplasia. Following arterial injury, rabbits received either no treatment, R15.7, a monoclonal antibody against the leucocyte CD11/CD18 adhesion complex, aurintricarboxylic acid (ATA), a substance that inhibits platelet glycoprotein Ib-von Willebrand factor interaction, or the combination of R15.7 and ATA. After 21 days, the extent of neointimal hyperplasia was evaluated by planimetry on histological arterial sections. The area of neointima averaged 0.51 +/- 0.07 mm2 in control animals and it was significantly reduced by administration of either R15.7 or ATA alone to 0.12 +/- 0.05 and 0.20 +/- 0.01 mm2, respectively (p < 0.05 vs controls for both groups). The animals that received the combination of R15.7 and ATA showed a further reduction in neointimal hyperplasia, as compared to animals that received ATA alone (p < 0.05 vs ATA alone). These data indicate that platelets and leucocytes play an important role in the pathophysiology of neointimal hyperplasia in this experimental model. Interventions that reduce platelet and leucocyte adhesion to vessel wall might have beneficial effects in reducing restenosis following coronary angioplasty.

[Long-term results of echographically guided percutaneous ethanol injection in the treatment of the autonomous thyroid nodule]. / Risultati a lungo termine dell'iniezione percutanea di etanolo sotto guida ecografica (PEI) nel trattamento del nodulo autonomo tiroideo.

Ultrasound-guided percutaneous ethanol injection (PEI) was performed as a therapeutic procedure on twenty-four patients affected by toxic autonomously functioning thyroid nodules (AFTN). After treatment patients were followed up for a mean period of 12 months. PEI induced persistent and complete (clinical and hormonal) disease control in 19/23 cases (82.6%) that completed the procedure, normalization of serum FT4 and FT3 associated with a still suppressed TSH in 2/23 cases (8.6%) and failed to control hyperthyroidism in 2/23 cases (8.6%). After PEI all AFTN became smaller at clinical and US examination with a 60% mean volume decrease. Nodule shrinkage was related to cytological and histological findings of well circumscribed coagulative necrosis, granulomatous inflammation and progressive fibrosis. PEI induced two cases of temporary complications: 1 case of acute worsening of thyrotoxicosis and 1 case of self-resolving vocal cord paresis. No increase of serum autoantibodies (TgAb, TPOAb, TRAb) was detected during the follow-up period.

[Percutaneous treatment under echographic guidance of toxic thyroid nodules. Technique for its performance and preliminary results]. / Trattamento percutaneo sotto guida ecografica dei noduli tossici della tiroide. Tecnica di esecuzione e risultati preliminari.

Six patients affected by toxic thyroid nodules (Plummer disease) were treated by percutaneous ethanol injection (PEI). Treatment was performed injecting under ultrasound guidance 2-4 mL of 95% sterile ethyl alcohol through a spinal needle (22 gauge, 75 mm length). Treatment was performed once-twice weekly and repeated as an outpatient procedure 4-6 times. PEI induced clinical improvement and hormonal control by the end of the treatment (one month) and no complications took place. After PEI all hyperfunctioning thyroid nodules became smaller at clinical and ultrasound examination. Three months after PEI hot areas appeared cold at 99mTc and 1311 scintiscan. Serum levels of FT3, FT4, AbT, AbM, TG reached the normal range and serum TSH levels were significantly increased and responsive to TRH stimulation.

[Combined clinico-thermographic findings for the evaluation of a topical anti-inflammatory agent. Study of cinnoxicam cream]. / Rilievi clinico-termografici integrati per la valutazione di un antiflogistico topico. Studio sul cinnoxicam crema.

In conformity with an integrated clinico-telethermographic protocol, the therapeutic efficacy of cinnoxam cream was evaluated in 20 patients presenting minor rheumatic pathologies or post-traumatic syndromes. The product under examination induced favourable and precocius changes in the clinical and symptomatologic-functional parameters considered.

[Autonomic neuropathy in a diabetic population. Validity of cardiovascular tests and correlations with the complications]. / Neuropatia autonomica in una popolazione diabetica. Validità dei test cardiovascolari e correlazione con le complicanze.

The disfunction of the autonomic system nervous is a frequent finding in diabetes mellitus. Among objective tests proposed for its diagnosis, those assessing cardiovascular reflexes (cardiovascular tests: CVTs) explore the autonomic functionality by means of a group of standardized manoeuvres of relatively easy execution that study the baroreceptorial reflex arc. In our study, CVTs were performed in a population of 207 diabetic patients with no symptoms of autonomic neuropathy. A computerized automatic system (Cardionomic) was utilized. CTVs included: Deep Breathing, Lying to Standing, Valsalva Manoeuvre, Orthostatic Hypotension, Standing to Lying and Cough Test. Diabetic patients were broken down in groups according to: a) age, b) HbA1c levels, c) disease duration. We have then compared the presence of diabetic complications between the group of diabetics positive for cardiovascular disautonomia (CVD+) with another group of diabetics who were negative for cardiovascular disautonomia (DCV-). Our results show a remarkable correlation between autonomic neuropathy and patients age, HbA1c levels and disease duration. Also they show a strong positive correlation between CDV+ and the severity of arteriopathy. We conclude that autonomic neuropathy may play an important role in the pathogenesis of diabetic arteriopathy.

Choosing the best rehabilitation treatment for Bell's palsy.

BACKGROUND: It is useful to perform neurophysiologic electromyography and electroneurography (EMG/ENG) on patients with peripheral facial palsy during the acute phase of paralysis in order to assess the severity of their nerve lesion and thus plan rehabilitation treatment and evaluate its results. AIM: To evaluate the motor recovery of patients with Bell's palsy with respect to the severity of their neurological lesion and to compare the results of two different rehabilitation treatments, with electromyographic biofeedback (EMG-BFB) and mirror visual biofeedback (mirror-BFB), in patients with Bell's palsy and neurophysiologic pattern of axonotmesis. STUDY DESIGN: Cohort study on retrospective clinical records. POPULATION: 102 patients with Bell's facial palsy were clinically assessed according to the House scale both during the acute phase of paralysis and 12 months after onset. METHODS: All patients underwent EMG/ENG examination 3-4 weeks after the onset of paralysis; 29 patients had an EMG pattern of neurapraxia and were not given rehabilitation treatment; 73 patients who presented with signs of denervation had an EMG pattern of axonotmesis. The group, which was homogenous in terms of lesion severity, was divided into two parts: 38 patients were treated with electromyographic biofeedback (EMG-BFB) and 35 were treated with mirror visual feedback (mirror-BFB). RESULTS: All 29 patients with neurapraxia made a full spontaneous recovery; Although the 73 patients with axonotmesis received different types of rehabilitation treatment, they obtained similar results regarding quality of recovery, development of synkinesis, rehabilitation timing and resources used. CONCLUSION AND CLINICAL REHABILITATION IMPACT: Rehabilitation treatment is not necessary for patients with neurapraxia. The two biofeedback methods used to treat patients with axonotmesis resulted in similar rehabilitation outcomes.

Prevalence and incidence of scoliosis in Turner syndrome: a study in 49 girls followed-up for 4 years.

BACKGROUND: Turner syndrome (TS) is a sex chromosome abnormality in females characterized by gonadal dysgenesis, short stature and skeletal malformations like kyphosis and scoliosis. AIM: To evaluate the prevalence of scoliosis and its incidence over 4 year follow-up. DESIGN: Consists in two parts: cross sectional study and longitudinal study. SETTING: Outpatient. POPULATION: Forty-nine TS assessed at the Pediatric Outpatients Clinic. METHODS: Clinical and radiological evaluation of spine. RESULTS: Cross sectional study: at baseline an high prevalence of minor scoliosis was observed (59%, 95% CI 44-73). The prevalence increased with age (trend test P=0.01). Patients with scoliosis were more frequently on GH therapy (69% vs. 35%, P=0.023). At multivariable analysis (including age, height and GH therapy), height was the only independent correlate of scoliosis. Longitudinal study: of the 20 cases without scoliosis at baseline, 9 were diagnosed with new scoliosis (classified as minor ) after 4 years (incidence of 45% , 95% CI 23-68). We didn't found any predictor of new scoliosis; patients who developed scoliosis 4 years later were older and taller at baseline. CONCLUSION: TS have a higher risk to develop scoliosis and the age at risk is protracted further with respect to normal subjects. This risk appears influenced by the height of the patient and, indirectly, by the GH therapy. Clinical rehabilitation impact. In TS is necessary a prolonged time of observation (until age twenty) for identifying scoliosis and beginning a rehabilitation program.

[Premature pubarche]. / Il pubarca prematuro.

Premature adrenarche refers to the appearance of public hair before age 8 years in girls and 9 years in boys, without other signs of puberty or virilization. Growth velocity may be increased and slightly advanced bone maturation is often present and is usually well correlated with the height age. The transient acceleraration of growth and of bone maturation have no negative effects on the onset and progression of puberty, and on final height. The diagnosis is based on the exclusion of the different forms of hyperandrogenism such as precocious puberty, late-onset congenital adrenal hyperplasia, virilizing tumors, glucocorticoid resistance, and Cushing syndrome. Once the diagnosis is made, no treatment is needed. However, a long-term follow-up of these patients is warranted. Recent data, in fact, indicate that girls with premature adrenarche may not have a benign outcome. Postpubertal girls with premature adrenarche during childhood have an increased frequency of functional ovarian hyperandrogenism. Furthermore, hyperinsulinemia is a common feature in adolescent patients with premature adrenarche and functional ovarian hyperandrogenism, and appears to be directly realted to the degree of androgen excess. Although the mechanisms interlinking the triad of premature pubarche, hyperinsulinemia and ovarian hyperandrogenism remain enigmatic, this frequent concurrence may result, at least in part, from a common early origin rather than from a direct interrelationship later in life.