Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

Planned dose of intensity modulated proton beam therapy versus volumetric modulated arch therapy to tooth-bearing regions.

BACKGROUND: Intensity modulated proton beam therapy (IMPT) for head and neck cancer offers dosimetric benefits for the organs at risk when compared to photon-based volumetric modulated arch therapy (VMAT). However, limited data exists about the potential benefits of IMPT for tooth-bearing regions. The aim of this study was to compare the IMPT and VMAT radiation dosimetrics of the tooth-bearing regions in head and neck cancer patients. Also, we aimed to identify prognostic factors for a cumulative radiation dose of ≥40 Gy on the tooth-bearing areas, which is considered the threshold dose for prophylactic dental extractions. METHODS: A total of 121 head and neck cancer patients were included in this retrospective analysis of prospectively collected data. We compared the average Dmean values of IMPT versus VMAT of multiple tooth-bearing regions in the same patients. Multivariate logistic regression analysis was performed for receiving a cumulative radiation dose of ≥40 Gy to the tooth-bearing regions (primary endpoint) in both VMAT and IMPT. RESULTS: A lower Dmean was seen after applying IMPT to the tooth-bearing tumour regions (p < 0.001). Regarding VMAT, oral cavity tumours, T3-T4 tumours, molar regions in the mandible, and regions ipsilateral to the tumour were risk factors for receiving a cumulative radiation dose of ≥40 Gy. CONCLUSIONS: IMPT significantly reduces the radiation dose to the tooth-bearing regions.

Predictive Parameters in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan for Unresectable Liver Metastases from Uveal Melanoma: A Retrospective Pooled Analysis.

PURPOSE: The aim of this study was to identify positive predictors for survival in uveal melanoma (UM) patients treated with percutaneous hepatic perfusion with melphalan (M-PHP), by retrospectively pooling data from three centers. MATERIALS AND METHODS: Retrospective analysis including patients ([Formula: see text] 18 years) treated with M-PHP between February 2014 and December 2019 for unresectable liver-dominant or liver-only metastases from UM. Predictors for OS were assessed using uni- and multivariate analyses. Other study outcome measures were response rate, progression-free survival (PFS), liver progression-free survival (LPFS), overall survival (OS) and complications according to CTCAEv5.0. RESULTS: In total, 101 patients (47.5% males; median age 59.0 years) completed a minimum of one M-PHP. At a median follow-up time of 15.0 months, complete response (CR), partial response (PR), stable disease (SD) and progressive disease were seen in five (5.0%), 55 (54.5%), 30 (29.7%) and 11 (10.9%) patients, respectively, leading to a 89.1% disease control rate. Median PFS, LPFS and OS were 9.0, 11.0 and 20.0 months, respectively. Survival analyses stratified for radiological response demonstrated significant improved survival in patients with CR or PR and SD category. Treatment of the primary tumor with radiotherapy, ≥ 2 M-PHP and lactate dehydrogenase (LDH) < 248 U/L were correlated with improved OS. Thirty-day mortality was 1.1% (n = 2). Most common complication was hematological toxicity (self-limiting in most cases). CONCLUSION: M-PHP is safe and effective in patients with UM liver metastases. Achieving CR, PR or SD is associated with improved survival. Primary tumor treatment with radiotherapy, normal baseline LDH and > 1 M-PHP cycles are associated with improved OS.

Prospective evaluation of percutaneous hepatic perfusion with melphalan as a treatment for unresectable liver metastases from colorectal cancer.

PURPOSE: Percutaneous hepatic perfusion with melphalan (M-PHP) is increasingly used in patients with liver metastases from various primary tumors, yet data on colorectal liver metastases (CRLM) are limited. The aim of this study was to prospectively evaluate the efficacy and safety of M-PHP in patients with CRLM. MATERIALS AND METHODS: Prospective, single-center, single-arm phase II study of M-PHP with hemofiltration in patients with unresectable CRLM. Proven, extrahepatic metastatic disease was one of the exclusion criteria. Primary outcomes were overall response rate (ORR) and best overall response (BOR). Secondary outcomes were overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: A total of 14 M-PHP procedures were performed in eight patients between March 2014 and December 2015. All patients (median age 56 years, ranging from 46 to 68) had received (extensive) systemic chemotherapy before entering the study. The ORR was 25.0%, with two out of eight patients showing partial response as BOR. Median OS was 17.3 months (ranging from 2.6 to 30.9) with a one-year OS of 50.0%. Median PFS and hPFS were 4.4 and 4.5 months, respectively. No serious adverse events occurred. Grade 3/4 hematologic adverse events were observed in the majority of patients, though all were transient and well-manageable. CONCLUSION: M-PHP is a safe procedure with only limited efficacy in patients with unresectable CRLM who already showed progression of disease after receiving one or more systemic treatment regimens.

Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Ocular Melanoma Metastases Confined to the Liver: A Prospective Phase II Study.

BACKGROUND: Ocular melanoma is the most common primary intraocular malignancy and has a very poor prognosis once liver metastases occur. The aim of this study was to prospectively assess the efficacy and safety of percutaneous hepatic perfusion with melphalan (M-PHP) using the new second-generation (GEN 2) hemofiltration system in patients with ocular melanoma metastases confined to the liver. METHODS: Prospective, single-center, single-arm, phase II study including patients with unresectable ocular melanoma metastases confined to the liver. Treatment consisted of two M-PHP procedures at 6-8 weeks interval. Procedures were performed using the CHEMOSAT (GEN 2) system with 3 mg/kg melphalan. Primary endpoints were overall response rate (ORR) and best overall response (BOR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Sixty-four M-PHP procedures were performed in 35 patients between February 2014 and June 2017. The ORR was 72%. BOR was as follows: complete response in 3%, partial response in 69%, stable disease in 13%, and progressive disease in 16%. There was no treatment-related mortality. Fourteen serious adverse events occurred. At a median follow-up of 19.1 months (range 5.6-69.5), median OS was 19.1 months and was significantly longer in responders than in nonresponders (27.5 vs. 11.9 months, p < 0.001). The 1- and 2-year OS was 77% and 43%, respectively. PFS and hPFS were 7.6 and 11.2 months, respectively. CONCLUSIONS: M-PHP using the GEN 2 filter can achieve a high ORR and prolonged survival in patients with liver-only ocular melanoma metastases.

Embolization of variant hepatic arteries in patients undergoing percutaneous hepatic perfusion for unresectable liver metastases from ocular melanoma.

PURPOSE: In patients undergoing percutaneous liver perfusion with melphalan (M-PHP), the presence of variant hepatic arteries (HAs) may require catheter repositioning and thus prolong procedure time. Coil-embolization of variant HAs may enable M-PHP with a single catheter position as occlusion of variant HAs results in redistribution of flow through preexisting intrahepatic arterial collaterals. We aimed to evaluate whether redistribution of flow has any negative effect on therapeutic response in ocular melanoma patients undergoing M-PHP. METHODS: We retrospectively analyzed pretreatment angiograms in all 32 patients that underwent M-PHP between January 2014 and March 2017 for unresectable liver metastases from ocular melanoma. Patients that underwent embolization of a variant left HA (LHA) or middle HA (MHA) during pretreatment angiography followed by at least one technically successful M-PHP were included for further analysis. Redistribution of arterial flow was evaluated on angiography and cone-beam computed tomography (CBCT) images. In each patient, tumor response in liver segments with redistributed blood flow was evaluated using RECIST 1.1 and mRECIST, and then compared with tumor response in segments without flow redistribution. Follow-up scans were reviewed to evaluate progression of liver metastases. RESULTS: A total of 12 patients were included. Replaced LHA embolization resulted in redistribution of flow to segment(s) 2 (n=3), 2 and 3 (n=5), and 2, 3 and 4 (n=2). MHA embolization resulted in redistribution of flow to segment 4 (n=2). Successful redistribution was confirmed by angiography and/or CBCT in all patients. Tumor response was similar for redistributed and non-redistributed liver segments in 8 out of 9 patients (89%) according to RECIST 1.1, and in 7 out of 8 patients (88%) according to mRECIST. In three patients, tumor response was not evaluable according to RECIST 1.1 or mRECIST as metastases were too small to be categorized as target lesions (n=1), or target lesions were confined to non-redistributed segments (n=2). In one patient, tumor response was not evaluable according to mRECIST as target lesions in the redistributed segments were hypovascular. After a median follow-up time of 17.1 months (range, 9.1-38.5 months), hepatic progression was seen in 9 out of 12 patients with a median time to progression of 9.9 months (range, 2.5-17.7 months). Progression of liver metastases was never seen only in the redistributed liver segments. CONCLUSION: Flow redistribution in liver segments by coil-embolization of variant HAs is a feasible technique that does not seem to compromise tumor response in patients undergoing M-PHP.

Safety of Percutaneous Hepatic Perfusion with Melphalan in Patients with Unresectable Liver Metastases from Ocular Melanoma Using the Delcath Systems' Second-Generation Hemofiltration System: A Prospective Non-randomized Phase II Trial.

PURPOSE: To investigate the safety and toxicity of percutaneous hepatic perfusion with melphalan (M-PHP) with the Delcath Systems' second-generation (GEN 2) filter and compare the outcomes with historical data from studies using the first-generation filter. MATERIALS AND METHODS: A prospective, single-arm, single-center phase II study was carried out including 35 patients with unresectable, histologically confirmed liver metastases from ocular melanoma between February 2014 and June 2017. Main exclusion criteria were extrahepatic disease and age > 75 years. M-PHP was performed with melphalan 3 mg/kg (maximum dose 220 mg). Safety and toxicity were assessed according to the Common Terminology Criteria for Adverse Events version 4.03. RESULTS: A total of 67 M-PHPs were performed in 35 patients (median 2 procedures). Although hematologic grade 3/4 events were seen in the majority of patients (thrombocytopenia 54.5%, leukopenia 75.6%, neutropenia 66.7%, anemia (only grade 3) 18.1%), these were all well manageable or self-limiting. Of the non-hematologic grade 3 events (n = 14), febrile neutropenia (n = 3), pulmonary emboli (n = 2) and post-procedural hemorrhage (n = 2) were most common. A case of sepsis with bacterial pharyngitis was the only non-hematologic grade 4 event. Prior therapy for liver metastases was found to be a predictor of late grade 3/4 neutropenia with an odds ratio of 5.5 (95% CI 1.4-21.7). CONCLUSIONS: M-PHP using the GEN 2 filter has an acceptable safety and toxicity profile, and seems to reduce hematologic toxicity when compared to M-PHP with a first-generation filter. Prior therapy of liver metastases is a possible predictive factor in developing grade 3/4 hematologic toxicity.

Prospective Clinical and Pharmacological Evaluation of the Delcath System's Second-Generation (GEN2) Hemofiltration System in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan.

INTRODUCTION: Percutaneous hepatic perfusion (PHP) with melphalan is an effective treatment for patients with hepatic metastases, but associated with high rates of bone marrow depression. To reduce systemic toxicity, improvements have been made to the filtration system. In pre-clinical studies, the Delcath System's GEN2 filter was superior to the first-generation filters. In this clinical study, we analysed the pharmacokinetics and toxicity of PHP using the new GEN2 filter. METHODS AND MATERIALS: Starting February 2014, two prospective phase II studies were initiated in patients with hepatic metastases from ocular melanoma or colorectal cancer. In 10 PHP procedures performed in the first 7 enrolled patients, blood samples were obtained to determine filter efficiency and systemic drug exposure. PHP was performed with melphalan 3 mg/kg with a maximum of 220 mg. Complications were assessed according to CTCAE v4.03. Response was assessed according to RECIST 1.1. RESULTS: Pharmacokinetic analysis of blood samples showed an overall filter efficiency of 86% (range 71.1-95.5%). The mean filter efficiency decreased from 95.4% 10 min after the start of melphalan infusion to 77.5% at the end of the procedure (p = 0.051). Bone marrow depression was seen after up to 80.0% of 10 procedures, but was self-limiting and mostly asymptomatic. No hypotension-related complications or procedure-related mortality occurred. CONCLUSION: The GEN2 filter has a higher melphalan filter efficiency compared to the first-generation filters and a more consistent performance. PHP with the GEN2 filter appears to have an acceptable safety profile, but this needs further validation in larger studies.

Validation and development of MTH1 inhibitors for treatment of cancer.

BACKGROUND: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. MATERIAL AND METHODS: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. RESULTS: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. CONCLUSION: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.

Identification of novel determinants of resistance to lapatinib in ERBB2-amplified cancers.

The gene encoding the receptor tyrosine kinase ERBB2, also known as HER2, is amplified and/or overexpressed in up to 15% of breast cancers. These tumours are characterised by an aggressive phenotype and poor clinical outcome. Although therapies targeted at ERBB2 have proven effective, many patients fail to respond to treatment or become resistant and the reasons for this are still largely unknown. Using a high-throughput functional screen we assessed whether genes found to be recurrently amplified and overexpressed in ERBB2+ve breast cancers mediate resistance to the ERBB2-targeted agent lapatinib. Lapatinib-resistant ERBB2-amplified breast cancer cell lines were screened, in the presence or absence of lapatinib, with an RNA interference library targeting 369 genes recurrently amplified and overexpressed in both ERBB2-amplified breast cancer tumours and cell lines. Small interfering RNAs targeting a number of genes caused sensitivity to lapatinib in this context. The mechanisms of resistance conferred by the identified genes were further investigated and in the case of NIBP (TRAPPC9), lapatinib resistance was found to be mediated through NF-κB signalling. Our results indicate that specific amplified and/ or overexpressed genes found in ERBB2-amplified breast cancer may mediate response to ERBB2-targeting agents.

CT attenuation measurements are valuable to discriminate pledgets used in prosthetic heart valve implantation from paravalvular leakage.

OBJECTIVES: Sutures with polytetrafluorethylene (PTFE) felt pledgets are commonly used in prosthetic heart valve (PHV) implantation. Paravalvular leakage can be difficult to distinguish from PTFE felt pledgets on multislice CT because both present as hyperdense structures. We assessed whether pledgets can be discriminated from contrast-enhanced solutions (blood/saline) on CT images based on attenuation difference in an ex vivo experiment and under in vivo conditions. METHODS: PTFE felt pledgets were sutured to the suture ring of a mechanical PHV and porcine aortic annulus, and immersed and scanned in four different contrast-enhanced (Ultravist®; 300 mg jopromide ml(-1)) saline concentrations (10.0, 12.0, 13.6 and 15.0 mg ml(-1)). Scanning was performed on a 256-slice scanner with eight different scan protocols with various tube voltage (100 kV, 120 kV) and tube current (400 mAs, 600 mAs, 800 mAs, 1000 mAs) settings. Attenuation of the pledgets and surrounding contrast-enhanced saline were measured. Additionally, the attenuation of pledgets and contrast-enhanced blood was measured on electrocardiography (ECG)-gated CTA scans of 19 patients with 22 PHVs. RESULTS: Ex vivo CT attenuation differences between the pledgets and contrast-enhanced solutions were larger by using higher tube voltages. CT attenuation values of the pledgets were higher than contrast-enhanced blood in patients: 420±26 Hounsfield units (mean±SD, range 383-494) and 288±41 Hounsfield units (range 202-367), respectively. CONCLUSIONS: PTFE felt pledgets have consistently higher attenuation than surrounding contrast-enhanced blood. CT attenuation measurements therefore may help to differentiate pledgets from paravalvular leakage, and detect paravalvular leakage in patients with suspected PHV dysfunction.

Illegal treatment of barrows with nandrolone ester: effect on growth, histology and residue levels in urine and hair.

The effect of 17ß-19-nortestosterone (17ßNT) treatment of barrows on residue levels and growth was evaluated. Five barrows were treated three times during the fattening period with 17ßNT phenylpropionate (Nandrosol, nandrolone phenylpropionate 50 mg/ml,1 mg/kg body weight). Another five barrows were untreated and five boars (untreated) were kept as positive control. Boars and treated barrows showed a 13 and 9% improvement in growth compared to untreated barrows, with mean final body weights of 121.6, 117.8 and 109.0 kg, respectively. The bulbourethral glands of the treated barrows were three times heavier than untreated barrows. The histology of the prostate and bulbourethral gland of the treated barrows was comparable to the boars, whereas the control barrows showed atrophic glands. Levels of 17ßNT ester in hair from treated barrows were high, whereas boars and untreated barrows did not show levels above LLQ. It is concluded that analysis of hair can detect illegal treatment with 17ßNT ester in barrows. The size of the bulbourethral gland can also be used for screening in the slaughterhouse.

Multiresidue analysis of beta-agonists in bovine and porcine urine, feed and hair using liquid chromatography electrospray ionisation tandem mass spectrometry.

The use of beta-agonists as growth promoters in cattle breeding is forbidden in many countries for reasons of fair trade and consumer protection. In recent years the use of liquid chromatography (LC) tandem mass spectrometry (MS/MS) has been shown to be the method of choice for the control of beta-agonists. In this study an LC-MS/MS multiresidue analysis method is presented for trace analysis of 22 beta-agonists. A truly generic concept has been designed based on mixed-mode solid-phase extraction and positive electrospray ionisation LC-MS/MS operated in the multiple reaction monitoring mode. This method allows application to a wide variety of sample matrices such as urine, feed and hair, following minor modifications to the analysis procedure only. The method features fit-for-purpose sensitivity in urine as shown by CCalpha and CCbeta values of less than 0.2 and less than 0.5 microg/l respectively, for all beta-agonists studied (terbutaline and reproterol, less than 0.3 and less than 1.0 respectively). Similar but semiquantitative application to feed and hair showed CCbeta values of less than 10.0 and less than 5.0 microg/kg, respectively. A further simplification and improvement is demonstrated using Ultra Performance LC (UPLC) and fast-switching MS/MS. The successful validation of this method following the latest EU requirements and its application to real samples demonstrate that a new versatile tool has been achieved for veterinary control of beta-agonists.

Blue five-level frequency-upconversion system in rubidium.

We demonstrate production of continuous coherent blue laser light by using a five-level system in rubidium vapor. Two low-power lasers, at 780 and 776 nm, induce strong atomic coherence in the 5S-5P-5D states. The atoms decay to the 6P excited state, from which stimulated emission produces a coherent blue (420 nm) beam. We have coupled both ground-state hyperfine levels, effecting coherence between four levels. The coherent blue output is enhanced by several mechanisms, including stronger coupling to a larger fraction of the atomic population, operation at a detuning such that the vapor is nominally transparent to the 780 nm pump field, reduced losses owing to optical pumping, and optimal phase matching. We report experimental findings and compare them with results from a semiclassical Maxwell-Bloch model.

Different effort constructs and effort-reward imbalance: effects on employee well-being in ancillary health care workers.

AIMS OF THE STUDY: The present study investigates the relationship between Effort-Reward Imbalance (ERI) and employee well-being, using three different concepts of efforts (i.e. psychological demands, physical demands and emotional demands). BACKGROUND: The ERI model had been used as a theoretical framework, indicating that work stress is related to high efforts (i.e. job demands) and low occupational rewards (e.g. money, esteem and security/career opportunities). The ERI model also predicts that, in overcommitted workers, effects of ERI on employee well-being are stronger compared with their less committed counterparts. METHODS: A cross-sectional survey among 167 ancillary health care workers of two nursing homes was conducted. Multiple univariate logistic regression analyses were used to test the relationship between ERI and employee well-being. RESULTS: Results of the logistic regression analyses showed that employees with both high (psychological, physical and emotional) efforts and low rewards had higher risks of psychosomatic health complaints, physical health symptoms and job dissatisfaction (odds ratios (ORs) ranged from 5.09 to 18.55). Moreover, employees who reported both high efforts and high rewards had elevated risks of physical symptoms and exhaustion (ORs ranged from 6.17 to 9.39). No support was found for the hypothesis on the moderating effect of overcommitment. CONCLUSION: Results show some support for the ERI model; ancillary health care workers with high effort/low reward imbalance had elevated risks of poor employee well-being. In addition, results show that the combination of high efforts and high rewards is important for employee well-being. Finally, some practical implications are discussed to combat work stress in health care work.

Hormonal patterns in breeding and nonbreeding kestrels, Falco tinnunculus: field and laboratory studies.

Plasma levels of luteinizing hormone (LH), androgens, and corticosterone (B) were measured in breeding and nonbreeding kestrels, both in the field and in captivity under different food conditions. LH levels in breeding males were elevated from courtship through incubation and androgen concentration peaked during courtship and laying. Seasonal changes in LH and androgens were similar in breeding and nonbreeding males, although androgens declined sharply after laying in breeding males. Egg laying was characterized by marked increases in both female body mass and plasma concentrations of LH and B. In both breeding and nonbreeding females LH and B increased during pair formation and courtship (March-April), although maximum levels were lower in nonbreeders. Two marked differences were found between free-living and captive (paired) birds. First, during winter plasma levels of LH were basal in free-living birds, while significantly elevated in both captive males and females. Second, during courtship androgen levels in breeding males were three-fold higher in the field than in captivity, probably as a result of intermale aggression under natural conditions. Females breeding early, late, or not at all had similar LH concentrations on arrival and during early courtship. Before breeding there were also no differences in LH (males and females) or in androgen levels (males) between pairs fed ad libitum and pairs temporary food rationed. However, captive females with experimentally reduced food intake showed low levels of B until their rations were increased. Nonbreeders showed hormonal changes similar to breeders, except for those changes in females that were associated with laying. These results suggest that at the start of the breeding season both nonbreeding and breeding kestrels have functional reproductive systems. That some breed early, late, or not at all is primarily an effect of food availability and is not due to hormonal modulation of the reproductive cycle.

Photoperiodic control of reproduction and molt in the kestrel, Falco tinnunculus.

An adaptive decline in average clutch size with progressive date of laying is characteristic of most bird species with a single clutch of variable size per year. The effect of photoperiod on timing of laying, clutch size, and subsequent molt was investigated in kestrel pairs breeding and raising their young in captivity. In natural daylight (nLD), clutch size, under ad libitum feeding, showed the same decline with date as in nature. Birds breeding later also started molt later and molted faster (more feathers simultaneously), so that all birds completed molt more or less at the same time. Constant long days (LD 17.5:6.5 and LD 13:11) from December 1 onward advanced both reproduction and molt. The LD 17.5:6.5 group developed the reproductive system faster, had a shorter courtship period, and laid eggs earlier than the LD 13:11 group. In both photoperiods there was a decrease in clutch size with progressive laying date, similar to that in nLD. Molt started in both groups at about the end of the laying period and slowed down in the longer photoperiod, especially in males. Plasma luteinizing hormone (LH) changes in the two photoperiods were different for males and females. Males showed the expected slower LH response in the shorter photoperiod, but the initial LH response by females was the same in both photoperiods. Data on LH, reproductive behavior, and body mass suggest that females have a wider annual reproductive window than males. Data on time of laying and number of eggs suggest that clutch size in the kestrel is determined by laying date itself, following an endogenous rhythm that is phase-locked to the reproductive cycle.

Neurological sequelae in high- and low-optimality obstetrics.

Neonatal neurological findings and the results of a neurological follow-up examination at 4 years of age were compared in two groups of subjects. The first group contained 39 children with an extremely low obstetrical optimality score, the second one contained 38 children with an extremely high obstetrical optimality score. More children were neurologically deviant in the first group than in the second one, both shortly after birth and at 4 years. The predictive power of the neonatal neurological examination was less in the low-optimality group, probably due to false-negative diagnoses in preterm infants.