Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

Acute Appendicitis During Pregnancy: Different from the Nonpregnant State?

BACKGROUND: Acute appendicitis is the most common nonobstetric indication for surgical intervention during pregnancy. However, the current literature is scarce and composed of relatively small case series. We aimed to compare the presentation, management, and surgical outcomes of presumed acute appendicitis between a contemporary cohort of pregnant women and nonpregnant women of reproductive age. METHODS: The study group included 92 pregnant patients who underwent appendectomy for presumed acute appendicitis at a single tertiary medical center in 2000-2014. Preoperative, operative, and postoperative clinical data were derived from medical records and compared to data for 494 nonpregnant patients of reproductive age who underwent appendectomy in 2004-2007 at the same institution. RESULTS: Median age was 28 years (range 25-33) in the study group and 26 years (range 20-34) in the control group (P = 0.1). There were no between-group differences in mean white blood cell count, patient interval, hospital interval, or operative time. Preoperative abdominal ultrasound was used in a significantly higher proportion of patients in the pregnant group than in the nonpregnant group (73 and 27 %, respectively, P < 0.001) and computed tomography, in a significantly lower proportion of patients (1 vs. 16 %, respectively, P < 0.001) . The two groups had similar rates of negative appendectomy (23 and 22 %, P = 0.9), complicated appendicitis (12 and 11 %, P = 0.9), and overall postoperative complications (15 and 12 %, P = 0.3). CONCLUSIONS: The clinical presentation and outcome of presumed acute appendicitis are similar in pregnant women and nonpregnant women of reproductive age. Therefore, similar perioperative management algorithms may be applied in both patient populations.

The role of the confined water in the dynamic crossover of hydrated lysozyme powders.

Water is of fundamental importance for life since it plays a critical role in biological systems. An organism can only function if its macromolecules and other bioactive molecules are hydrated. However, currently there is a gap in the understanding of how protein interfaces affect water's structure and properties. This work presents combined dielectric and calorimetric measurements of hydrated lysozyme powders with different levels of hydration in a broad temperature interval. We chose lysozyme as a test sample since this globular protein has a well-defined pore with an active hydrophilic center inside. Based on the dielectric and calorimetric tests it was shown that a water quasi-solution, which contains the protein residues, has a glass transition temperature at around 155 ± 3 K. The water confined in the pore of the active center of the lysozyme has its melting temperature at around 186 ± 3 K. Melting of confined water is believed to liberate the internal motions of protein macromolecules.

Surgical Stage I high-grade ovarian cancer: is adjuvant chemotherapy warranted?

OBJECTIVE: To review the results of patients with high-grade Stage I ovarian cancer managed without adjuvant treatment. MATERIALS AND METHODS: A retrospective chart review identified patients with newly diagnosed Stage I high-grade ovarian cancer, who underwent comprehensive surgical staging. RESULTS: Thirty-three patients with FIGO surgical Stage I high-grade ovarian cancer were identified. After a median follow-up of 40 months, nine patients (27%) recurred. The median time to recurrence was 19 months. Of the nine patients with recurrences, four (44%) are alive with disease, three (33%) patients have no evidence of disease, and two have died of disease (22%). The two- and five-year overall survival is 100% and 90%, respectively. CONCLUSIONS: It would appear the recurrence rates of Stage I high risk epithelial ovarian cancer completely staged, without adjuvant treatment are comparable to those of treatment arms reported in the literature. A proportion of these patients can be salvaged at recurrence, yielding a high overall survival.

Survival in women with ovarian cancer with and without microsatellite instability.

PURPOSE OF INVESTIGATION: Microsatellite instability (MSI) is a hallmark of defective mismatch repair and is present in approximately 20% of ovarian cancers. It is not known if the presence of MSI predicts survival in women with epithelial ovarian cancer. MATERIALS AND METHODS: Cases of epithelial ovarian cancer were ascertained from a population-based study in Ontario and tumour samples were tested for MSI, using five MSI markers. Patients were divided into MSI-high and MSI-low/normal, according to National Cancer Institute criteria. The authors compared the prevalence of specific prognostic factors in the two subgroups, including age, grade, stage, and histology. They estimated the hazard ratio for death from ovarian cancer associated with MSI-high and with other prognostic factors using a multi-variate analysis. RESULTS: A total of 418 ovarian cancer patients were included. One hundred and twenty-seven (19.7%) cancers were MSI- high. Subgroup analyses did not reveal any statistically significant differences for pathologic features associated with MSI status. No survival difference was seen according to MSI status. CONCLUSIONS: The presence of MSI in ovarian cancer is not associated with survival.

Conservative management for an entero-adnexal fistula at initial presentation of advanced ovarian carcinoma.

Gastrointestinal fistulae can occur in ovarian cancer patients, usually in the setting of advanced relapsed disease. Treatment typically involves immediate surgery.Here, we describe a case of an abscess resulting from an intestinal fistula as the first manifestation of advanced epithelial ovarian cancer, and we review the current literature on this subject. The patient was successfully treated with a combination of chemotherapy, antibiotics, and delayed surgery. Optimal debulking was achieved without a need for bowel resection.This report is the first of conservative management of a fistula in an ovarian cancer patient in the chemotherapy-naïve setting.

Starry sky pattern of fetal liver sonogram as first sign of twin-twin transfusion syndrome.

'Starry sky' liver is one of the most common sonographic patterns in diffuse liver disease. It is characterized by clearly identified portal venules due to diminished parenchymal echogenicity. In advanced cases of twin-to-twin transfusion syndrome (TTTS), volume overload is considered the key factor in the pathogenesis of cardiac dysfunction of the recipient twin. When right-sided failure occurs, the liver might show signs of edema and, as in acute hepatitis, the appearance of starry sky might develop. We present a case in which the sonographic appearance of starry sky liver, along with right-sided cardiac failure (tricuspid regurgitation), were the first signs of TTTS in monochorionic twins at 20 weeks. A short time later, at 21 weeks, other signs of overload and signs of worsening heart failure were noted, as the typical triphasic waves in the inferior vena cava were replaced by a biphasic flow profile. Twin 2 at that time had relative oligohydramnios. A few days later, relative polyhydramnios and edema of the placental domain of the recipient twin were also noted. To the best of our knowledge, this is the first case report describing this hepatic sonographic pattern as an early sonographic sign of TTTS.

Adenotonsillectomy improves slow-wave activity in children with obstructive sleep apnoea.

The aim of the present study was to estimate slow-wave activity (SWA), a marker of sleep homeostasis, in children with obstructive sleep apnoea (OSA) before and after adenotonsillectomy (AT) compared with untreated OSA children (comparison group). 14 children with OSA (mean ± sd age 6.4 ± 2.5 yrs; apnoea-hypopnoea index (AHI) 10.0 ± 10.3 events·h⁻¹) who underwent AT were consecutively recruited to the study. The comparison group comprised six retrospectively recruited children (age 5.4 ± 2.2 yrs; AHI 9.4 ± 7.6 events·h⁻¹) with OSA that did not undergo treatment. Electroencephalogram (derivation C3/A2) was analysed using spectral and waveform analysis to determine SWA energy and slow-wave slope. The same procedure was repeated 5.4 and 19 months later for the AT and comparison groups, respectively. AT improved respiration without a change in duration of sleep stages. Following AT, >50% elevation of SWA during the first two sleep cycles (p<0.01) and a more physiological decay of SWA across the night (p<0.0001) were noted. The slow-wave slope increased by >30% following AT (p<0.03). No significant changes were found in SWA in the comparison group. Sleep homeostasis is considerably impaired in pre-pubescent children with OSA. AT restores more physiological sleep homeostasis in children with OSA. SWA analysis may provide a useful addition to standard sleep-stage analyses in children with OSA.

Role of growth hormone-releasing hormone in sleep and growth impairments induced by upper airway obstruction in rats.

Upper airway obstruction (UAO) can lead to abnormal growth hormone (GH) homeostasis and growth retardation but the mechanisms are unclear. We explored the effect of UAO on hypothalamic GH-releasing hormone (GHRH), which has a role in both sleep and GH regulation. The tracheae of 22-day-old rats were narrowed; UAO and sham-operated animals were sacrificed 16 days post-surgery. To stimulate slow-wave sleep (SWS) and GH secretion, rats were treated with ritanserin (5-HT(2) receptor antagonist). Sleep was measured with a telemetric system. Hypothalamic GHRH, hypothalamic GHRH receptor (GHRHR) and GH receptor, and orexin were analysed using ELISA, real-time PCR and Western blot. UAO decreased hypothalamic GHRH, GHRHR and GH receptor levels, while orexin mRNA increased (p<0.01). In UAO rats, the duration of wakefulness was elevated and the duration of SWS, paradoxical sleep and slow-wave activity was reduced (p<0.001). Ritanserin alleviated these effects, i.e. normalised hypothalamic GHRH content, decreased wake duration, increased duration and depth of SWS, and attenuated growth impairment (p<0.001). Here, we present evidence that growth retardation in UAO is associated with a reduction in hypothalamic GHRH content. Our findings show that abnormalities in the GHRH/GH axis underlie both growth retardation and SWS-disorder UAO.

Lamellar solid-liquid mesophase nucleated by Josephson vortices at the melting of the vortex lattice in Bi2Sr2CaCu2O(8+δ) superconductor.

The local effect of the Josephson vortices on the vortex lattice melting process in Bi2Sr2CaCu2O(8+δ) crystals in the presence of an in-plane field H(ab) is studied by differential magneto-optical imaging. The melting process is found to commence along the Josephson vortex stacks, forming a mesomorphic phase of periodic liquid and solid lamellas, the direction and spacing of which are controlled by H(ab). The reduction of the local melting field H(m) along the Josephson vortex stacks is more than an order of magnitude larger than the reduction of the average bulk H(m) by HH(ab).

Outcomes of diagnosed COVID-19 cancer patients: concerning results of a systematic review.

Since the outbreak of coronavirus disease 2019 (COVID-19), malignancy was shown to be prevalent in COVID-19 patients. This systematic review's searches were conducted in MEDLINE(R), Embase, Web of Science, and Scopos. Considered for inclusion were all reports on outcomes of cancer patients diagnosed with COVID-19. A total of 1099 references were identified through database searching and manual search. Finally, 17 references comprising 88 cancer patients, diagnosed with COVID-19, were included. Prevalence of cancer patients with COVID-19 was shown to range from 0.9% to 3%. The evidence suggested a severe clinical course of 50.6% in COVID-19 diagnosed cancer patients and a mortality rate of 34.5%. Subgroup analysis according to recent anti-cancer treatment showed a similar pattern, with the most concerning results in patients receiving recent immunotherapy/immunosuppressive treatment. COVID-19 morbidity and mortality among cancer patients should be reduced by consideration of testing asymptomatic COVID-19 cancer patients, reduction of hospital visits, and consideration of anti-cancer treatment.

Age-dependent spatial memory loss can be partially restored by immune activation.

Aging is often associated with a decline in hippocampus-dependent spatial memory. Here, we show that functional cell-mediated immunity is required for the maintenance of hippocampus-dependent spatial memory. Sudden imposition of immune compromise in young mice caused spatial memory impairment, whereas immune reconstitution reversed memory deficit in immune-deficient mice. Analysis of hippocampal gene expression suggested that immune-dependent spatial memory performance was associated with the expression of insulin-like growth factor (Igf1) and of genes encoding proteins related to presynaptic activity (Syt10, Cplx2). We further showed that memory loss in aged mice could be attributed to age-related attenuation of the immune response and could be reversed by immune system activation. Homeostatic-driven proliferation of lymphocytes, which expands the existing T cell repertoire, restored spatial memory deficits in aged mice. Thus, our results identify a novel function of the immune system in the maintenance of spatial memory and suggest an original approach for arresting or reversing age-associated memory loss.

Constant rate infusion vs. intermittent bolus administration of IV furosemide in 100 pets with acute left-sided congestive heart failure: A retrospective study.

The aim of this study was to determine whether the addition of constant rate infusion (CRI) to intermittent intravenous bolus (IVB) administration of furosemide resulted in an improvement in medical outcomes in dogs and cats with acute left-sided congestive heart failure (L-CHF). A total of 76 client-owned dogs and 24 client-owned cats admitted with acute L-CHF were retrospectively divided between an IVB group (43 dogs and 16 cats) and a CRI group (33 dogs and 8 cats). The median furosemide dose used in dogs in the CRI group (median 0.99mg/kg/h; range 0.025-3.73mg/kg/h) was lower than the dose used in dogs in the IVB group (median 1.19mg/kg/h; range 0.027-7.14mg/kg/h; P=0.008). Respiratory rates were lower in the IVB group (P=0.005) and the CRI group (P=0.039) compared to pre-treatment values. The overall short-term mortality was 15%. A trend of longer hospitalisation in the IVB group relative to the CRI group (P=0.07) was shown. Creatinine and total plasma protein concentrations increased more in the CRI group than in the IVB group, suggestive of a higher risk of dehydration and azotaemia. There may be safety profile differences between CRI and IVB, warranting a prospective study using a larger sample size.

Thoracic outlet syndrome: a multidisciplinary problem with a perspective for microsurgical management without rib resection.

BACKGROUND: Thoracic outlet syndrome (TOS) refers to a group of complex symptoms in the upper extremity caused by compression of the brachial plexus, subclavian artery and vein. Different surgical approaches were described for the management of TOS. There is, however, no "gold standard" procedure for this complicated and multidisciplinary problem. OBJECTIVES: This study evaluated the effectiveness of a microsurgical neurovascular decompression in the treatment of TOS. METHODS: 11 patients suffering from TOS (for 1.3 to 15 years after the beginning of the symptoms) were selected for a treatment of the complex symptoms of pain (diffuse or irradiated to the arm and hand), aching or paresthesia in the neck, shoulder, anterior chest, upper extremity and hand. Four of the 11 patients were suffering from signs of vascular compression. Eight patients showed slow progressive neurological deterioration (distribution of the ulnar nerve) with partial muscle atrophy. Patients underwent a microsurgical treatment using a supraclavicular approach followed by brachial plexus neurolysis, scalenectomy and release of the subclavian artery and vein without rib resection. Postoperative results were classified, using Am. J. Surg. (176: 215-218, 1998) scale (4), as good, fair and poor. RESULTS: Surgical results were studied, with a follow-up of 24 to 48 months. Prior to surgery, all patients had partial or severe limitation in physical activities. Post-operative follow-up showed that 9 (82%) of the 11 patients returned to normal everyday physical activities with a complete or significant relief of the symptoms (good results). In 2 patients (18%) the pain decreased and the use of medication was reduced (fair results). Eight of the 11 patients returned to full or partial employment. There were no cases of poor results in the study. CONCLUSION: Microsurgical neurovascular decompression of TOS without a removal of the cervical or first rib using a supraclavicular approach is an effective treatment method for a relief or complete release from symptoms and allows most patients to return to an active normal life.

Combined tibial plateau levelling osteotomy and lateral fabellotibial suture for cranial cruciate ligament rupture with severe rotational instability in dogs.

OBJECTIVE: To report the use of tibial plateau levelling osteotomy and lateral fabellotibial suture in combination for treatment of severe internal tibial rotational stifle instability in cranial cruciate-deficient stifles. METHODS: Twenty-three stifles in 19 dogs were diagnosed with cranial cruciate ligament rupture with severe stifle instability, characterised by marked cranial tibial translation and internal tibial rotation that was evident during orthopaedic examination. A combined tibial plateau levelling osteotomy and lateral fabellotibial suture procedure were performed to stabilise the stifle joint. The surgical complications, short-term lameness scores and owner satisfaction were evaluated. RESULTS: The postoperative complication rate was 21 · 7% with one minor (4 · 3%) and four major (17 · 4%) complications. At short-term follow-up one dog had an intermittent low-grade lameness and two dogs had mild tibial internal rotational instability present on palpation without lameness. Owner's overall satisfaction with the operation and recovery was good (21 · 4%) to excellent (78 · 6%). CLINICAL SIGNIFICANCE: The use of lateral fabellotibial suture in combination with tibial plateau levelling osteotomy was an effective technique for managing cranial cruciate ligament rupture with severe internal tibial rotational stifle instability.

Dielectric Relaxation of Hydration Water in Native Collagen Fibrils.

The dielectric relaxation of hydrated collagen powders was studied over a wide temperature and frequency range. We revealed two mechanisms of dielectric relaxation in hydration water that are driven by the migration of ionic and orientation defects. At high water fractions in powders (h > 0.2), the hydration shell around the collagen triple helixes presents a spatial H-bonded network consisting of structural water bridges and cleft water channels. These two water phases provide the long-range paths for proton hopping and orientation defect migration. At low water fractions (h < 0.2) and in the hydrated collagen samples after the dehydrothermal treatment, the hydration shell presents localized individual water compartments not connected to one another. In these cases, the relaxation mechanism due to proton hopping either disappears or becomes inhibited by the orientation defect migration.

[Does percutaneous nephrolithotripsy (PCNL) affect renal function: assessment with quantitative spect of Tc 99M-DMSA (QDMSA) renal scintigraphy].

PURPOSE: The study aimed to quantitatively investigate the effect of PCNL on global and regional function using quantitative single photon emission computerized tomography (SPECT) measurement of Tc-dimercaptosuccinic acid (DMSA) uptake by the kidneys (QDMSA). METHODS: Seventy nine patients with nephrolithiasis undergoing PCNL were studied by sequential QDMSA examination. There were 42 (53%) males and 37 (47%) females with mean age of 47 +/- 16 years. The initial study was conducted before PCNL procedure and the follow-up studies were performed 1.5-24 months after PCNL. Among 60 of the 79 (76%) patients, in whom PCNL was performed using upper or lower pole access, regional renal function of affected and non-affected pole of operated kidney was calculated separately. RESULTS: There was no statistically significant difference between the uptake of treated kidney before and after PCNL procedure (11.9% +/- 5% vs 11.6% +/- 5%; t = 0.9, p = 0.368). The total renal functional volume of treated kidney was to be slightly decreased from 235cc +/- 62cc to 224cc +/- 59cc (t = 2.7; p = 0.011). The percent of injected dose per ml.. of renal tissue of treated kidney was not affected statistically (0.051 +/- 0.02 vs 0.053 +/- 0.02; t = 0.86, p = 0.296). In the assessment of the regional renal function of treated kidney, a statistically significant decrease in the functional renal volume was revealed at the part which underwent PCNL procedure (91cc +/- 30cc vs 82cc +/- 27cc; t = 2.64, p = 0.013). Regarding percent of injected dose per ml. of renal tissue, no statistically significant difference was found between the part of treated kidney, which underwent PCNL and non-affected area of the same kidney (0.049 +/- 0.02 vs 0.05 +/- 0.02; t = 0.693, p = 0.494). The function of contralateral kidney remained unchanged (13.4% +/- 5.2% vs 13.6% +/- 4.8%; t = 0.68, p = 0.5). Function volume, neither total percent uptake, nor percent of injected dose per ml. of renal tissue were reduced significantly. Further studies with long term follow-up of treated kidney are required.

Testosterone stimulates insulin-like growth factor-I and insulin-like growth factor-I-receptor gene expression in the mandibular condyle--a model of endochondral ossification.

Puberty is associated with an increase in the plasma concentration of sex steroids, GH, and insulin-like growth factor-I (IGF-I). Gonadal steroid hormones are important for the normal pubertal growth spurt and skeletal growth. The mechanism by which gonadal steroids induce skeletal growth is still not fully understood. To better understand the direct effect sex steroids have on bone growth, we studied an isolated organ culture system of the mandibular condyle, derived from 3.5-5.5-week-old male and female mice. We found that testosterone 10(-6) M, but not estradiol, stimulated thymidine incorporation into the DNA of male-derived condyle. Three days of testosterone treatment doubled the condyle size and increased the chondroprogenitor zone, while maintaining the normal gradient of the developing chondrocytes. Immunohistochemistry and in situ hybridization techniques showed that testosterone stimulated IGF-I and IGF-I-R and their messenger RNAs (mRNAs) mainly in the mature chondrocyte layer. Immunoneutralization of IGF-I in the testosterone-treated condyle caused the disappearance of the chondroblast and young chondrocyte layers, though the progenitor cell layer remained almost unaffected. Overtreatment with testosterone (dose or duration) accelerated condylar ossification. In the presence of testosterone 10(-5) M (high dose), calcification "climbs" up to the chondroprogenitor zone, and most of the condylar chondrocytes are replaced by bone tissue. Similar changes occurred after 7 days of testosterone treatment (long duration) with 10(-6) M. In conclusion, testosterone stimulates growth and local production of IGF-I and IGF-I-R in chondrocyte cell layers of an isolated organ culture of mice mandibular condyle. Part of the effect testosterone has on condylar growth is mediated by IGF-I.

Modulation of insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins in endometrial cancer cells by estradiol.

Insulin-like growth factor I (IGF-I) receptors and membrane-associated IGF-binding proteins (IGFBPs) were examined in Ishikawa endometrial cancer cells. Our findings suggest that about 95% of [125I]IGF-I is bound to membrane-associated IGFBPs rather than to IGF-I receptors. Specifically, [125I]IGF-I binding to cell membranes could be completely displaced by cold IGF-I or IGF-II, but not by insulin, suggesting that binding was primarily due to IGFBPs. This was confirmed by using [125I]des-(1-3)IGF-I as the ligand. Des-(1-3) IGF-I binds with high affinity to IGF-I receptors, but with markedly lower affinity to IGFBPs. [125I]Des-(1-3)IGF-I bound to Ishikawa cells was displaced by IGF-I, IGF-II, and insulin. These results suggest that measuring IGF-I receptor levels using labeled IGF-I may be misleading. Accordingly, we evaluated the differential binding of [125I]IGF-I and [125I]des-(1-3)IGF-I to study the involvement of the IGF system in the stimulation of Ishikawa cell growth by estradiol. IGF-I stimulates Ishikawa cell proliferation, but at low concentrations, and this stimulation is largely dependent on the presence of estradiol. Estradiol caused a 2.5-fold increase in IGF-I receptor levels. Moreover, estradiol reduced soluble IGFBP levels, presumably increasing the availability of IGFs for their receptors. This elevation in IGF-I receptor levels and the decrease in IGFBP levels were accompanied by a 3.5-fold increase in IGF-I receptor messenger RNA and a 2.5-fold decrease in IGFBP messenger RNAs. These experiments suggest that estradiol sensitizes endometrial cancer cells to the effects of IGFs by simultaneously elevating receptor levels and decreasing (potentially inhibitory) IGFBP levels.

Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth.

Caloric imbalance, particularly in critical periods of growth and development, is often the underlying cause of growth abnormalities. Serum levels of leptin are elevated in obesity and are low in malnutrition and malabsorption. The aim of the present study was to determine whether leptin integrates energy levels and growth in vivo, as shown previously in our ex vivo experiments, even in the presence of caloric restriction. In the first part of the study, mice were divided into three groups. Two groups were fed ad libitum and received leptin or vehicle only, and the third group was pair-fed with the group injected with leptin to dissociate leptin's effect on growth from its effect on food consumption. Mice given leptin had a significantly greater tibial length than untreated pair-fed animals and a similar tibial length as control mice fed ad libitum despite their lower weight. In addition, leptin significantly increased the overall size of the epiphyseal growth plate by 11%. On immunohistochemistry and in situ hybridization studies, leptin stimulated both the proliferation and differentiation of tibial growth plate chondrocytes without affecting the overall organization of the plate. There was also a marked increase in the expression and level of IGF-IR. In the second part of the study, two groups of mice were fed only 60% of their normal chow; one was injected with leptin, and the other was injected with vehicle alone. Caloric deprivation by itself reduced serum levels of IGF-I by 70% and the length of the tibia by 5%. Leptin treatment corrected the fasting-induced growth deficiency, but further reduced the level of serum IGF-I. These results indicate that leptin stimulates growth even in the presence of caloric restriction independently of peripheral IGF-I.