Stanley Cobb, the Rockefeller Foundation and the evolution of American psychiatry.

Stanley Cobb founded the Harvard Departments of Neurology (1925) and Psychiatry (1934) with Rockefeller Foundation funding. Cobb was an important transitional figure in both neurology and psychiatry. He and his friend Alan Gregg were the most visible parts of the Rockefeller Foundation psychiatry project, which prepared American psychiatry for the rapid growth of psychiatric research after World War II. Edward Shorter called him the founder of American biological psychiatry, but this misunderstands Cobb and the Hegelian evolution of twentieth-century American psychiatry. I review the major role of the Rockefeller Foundation in the evolution of American academic psychiatry and the disappearance of Cobb's teaching and that of his mentor Adolf Meyer, a founding father of American academic psychiatry.

An examination of nucleotypic effects in diploid and polyploid cotton.

Nucleotypic effects are phenotypic changes related to the total nuclear DNA amount per cell. These effects are commonly observed among and within genera for certain cell types, and the generality of the positive correlation between genome size and cell size has been well established. However, there are few studies of nucleotypic effects which incorporate into the analysis both ploidy level and genome size (given as Mbp determined by 2C values). To test the hypothesis that cell size scales with genome size and ploidy, we measured the guard cell length, epidermal pavement cell surface area, and pollen grain diameter using individuals of multiple species and accessions of the cotton genus (Gossypium), in which different species exhibit three-fold variation in genome size. We measured cell sizes using calibrated microscopic image analysis. Significant relationships were found between genome size and cell size, with stronger correlations between guard cell length and genome size than with epidermal pavement cell surface area. We also found a relationship between pollen grain diameter and genome size. These results indicate that nucleotypic effects occur within Gossypium, scale with ploidy level, and are stronger in less variable cell types.

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans.

In this review, a companion piece to our recent examination of choroid plexus (CP), the organ that secretes the cerebrospinal fluid (CSF), we focus on recent information in the context of reliable older data concerning the composition and functions of adult human CSF. To accomplish this, we define CSF, examine the methodology employed in studying the CSF focusing on ideal or near ideal experiments and discuss the pros and cons of several widely used analogical descriptions of the CSF including: the CSF as the "third circulation," the CSF as a "nourishing liquor," the similarities of the CSF/choroid plexus to the glomerular filtrate/kidney and finally the CSF circulation as part of the "glymphatic system." We also consider the close interrelationship between the CSF and extracellular space of brain through gap junctions and the paucity of data suggesting that the cerebral capillaries secrete a CSF-like fluid. Recently human CSF has been shown to be in dynamic flux with heart-beat, posture and especially respiration. Functionally, the CSF provides buoyancy, nourishment (e.g., vitamins) and endogenous waste product removal for the brain by bulk flow into the venous (arachnoid villi and nerve roots) and lymphatic (nasal) systems, and by carrier-mediated reabsorptive transport systems in CP. The CSF also presents many exogenous compounds to CP for metabolism or removal, indirectly cleansing the extracellular space of brain (e.g., of xenobiotics like penicillin). The CSF also carries hormones (e.g., leptin) from blood via CP or synthesized in CP (e.g., IGF-2) to the brain. In summary the CP/CSF, the third circulation, performs many functions comparable to the kidney including nourishing the brain and contributing to a stable internal milieu for the brain. These tasks are essential to normal adult brain functioning.

The Signature Program: Bringing the Protocol to the Patient.

Early-phase clinical development in oncology has evolved dramatically with the deciphering of the human genome in 2004. Genomic analysis and the tools identifying genetically disrupted pathways within a patient's tumor have been a driving force for personalized medicine and for the development of highly targeted novel therapies. Tumors are often genetically heterogeneous, with multiple concurrent genetic abnormalities. On the other hand, tumors arising from different tissues may share identical molecular drivers.

A balanced view of choroid plexus structure and function: Focus on adult humans.

Recently tremendous progress has been made in studying choroid plexus (CP) physiology and pathophysiology; and correcting several misconceptions about the CP. Specifically, the details of how CP, a locus of the blood-CSF barrier (BCSFB), secretes and purifies CSF, generates intracranial pressure (ICP), maintains CSF ion homeostasis, and provides micronutrients, proteins and hormones for neuronal and glial development, maintenance and function, are being understood on a molecular level. Unequivocal evidence that the CP secretory epithelium is the predominant supplier of CSF for the ventricles comes from multiple lines: uptake kinetics of tracer (22)Na and (36)Cl penetration from blood to CSF, autoradiographic mapping of rapid (22)Na and (36)Cl permeation (high permeability coefficients) into the cerebroventricles, CSF sampling from several different in vivo and in vitro CP preparations, CP hyperplasia that increases CSF formation and ICP; and in vitro analysis of CP ability to transport molecules (with expected directionality) and actively secrete fluid against an hydrostatic fluid column. Furthermore, clinical support for this CP-CSF model comes from neurosurgical procedures to remove lateral ventricle CPs in hydrocephalic children to reduce CSF formation, thereby relieving elevated ICP. In terms of micronutrient transport, ascorbic acid, folate and other essential factors are transported by specific (cloned) carriers across CP into ventricular CSF, from which they penetrate across the ependyma and pia mater deeply into the brain to support its viability and function. Without these choroidal functions, severe neurological disease and even death can occur. In terms of efflux or clearance transport, the active carriers (many of which have been cloned and expressed) in the CP basolateral and apical membranes perform regulatory removal of some metabolites (e.g. choline) and certain drugs (e.g. antibiotics like penicillin) from CSF, thus reducing agents such as penicillin to sub-therapeutic levels. Altogether, these multiple transport and secretory functions in CP support CSF homeostasis and fluid dynamics essential for brain function.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Repeat instability in the 27-39 CAG range of the HD gene in the Venezuelan kindreds: Counseling implications.

The instability of the CAG repeat size of the HD gene when transmitted intergenerationally has critical implications for genetic counseling practices. In particular, CAG repeats between 27 and 35 have been the subject of debate based on small samples. To address this issue, we analyzed allelic instability in the Venezuelan HD kindreds, the largest and most informative families ascertained for HD. We identified 647 transmissions. Our results indicate that repeats in the 27-35 CAG range are highly stable. Out of 69 transmitted alleles in this range, none expand into any penetrant ranges. Contrastingly, 14% of alleles transmitted from the incompletely penetrant range (36-39 CAGs) expand into the completely penetrant range, characterized by alleles with 40 or more CAG repeats. At least 12 of the 534 transmissions from the completely penetrant range contract into the incompletely penetrant range of 36-39 CAG repeats. In these kindreds, none of the individuals with 27-39 CAGs were symptomatic, even though they ranged in age from 11 to 82 years. We expect these findings to be helpful in updating genetic counseling practices.

Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.

Calculating pass-through and outlier payments under APCs.

Medicare's outpatient prospective payment system is based on ambulatory payment classifications (APCs) that group services into categories for payment. The relative weight of each APC is based on the median operating and capital cost of the services within the group based on hospital outpatient claims data for 1996. These data, however, do not accurately reflect the cost of innovative medical devices, drugs, and biologicals currently in use. To account for these developments, the Balanced Budget Refinement Act of 1999 (BBRA) established the transitional pass-through payment system to provide additional amounts above the applicable APC rate for innovative medical devices, drugs, and biologicals. The BBRA also established a cost-outlier adjustment. Successfully calculating payments for pass-through and outlier devices requires that financial managers have a thorough knowledge of the medical devices, drugs, and biologicals being used in their outpatient surgery departments.

Pediatric patients with undetectable anticonvulsant blood levels: comparison with compliant patients.

Undetectable anticonvulsant blood levels indicate sustained noncompliance (several consecutive doses missed). We compared 91 consecutive outpatients with epilepsy and undetectable anticonvulsant blood levels to 100 patients seen during the same time period, verified as compliant by acceptable serum levels. We hypothesized that pay status, application for Supplemental Security Income, patient age, history of missed appointments, and functional status would differ between compliant and noncompliant patients. We were surprised to find large differences between clinic and insurance patients and between Caucasian and non-Caucasian patients. The 100 compliant patients included 44 Caucasian and 56 non-Caucasian patients, whereas only 9 of 91 noncompliant patients were Caucasian, and only 9 had insurance, compared to 32 compliant patients. Applications for Supplemental Security Income and history of missed appointments were significantly associated with noncompliance, but patient age, seizure type, and seizure control were not. Uninsured Caucasians were more often compliant than non-Caucasians were. Many noncompliant patients had mild epilepsy, which was reportedly doing well. Race and pay status were closely correlated. Several noncompliant females became pregnant, whereas no compliant patients did. Compliant patients were much more likely to be accompanied by a parent or caretaker on clinic visits than noncompliant patients. Noncompliant patients had at least one acceptable subsequent serum level, although 2 patients with intractable epilepsy had undetectable serum levels on three or more occasions. Noncompliance may respond to discussion and advice. We reviewed 124 episodes of undetectable drug levels in the 91 noncompliant patients. Eighteen of these resulted in hospitalization, but in 25 cases, we were told that there had been no seizures since the preceding visit. Many noncompliant patients have infrequent seizures, even if they take little or no medication. Socioeconomic status influences health, life expectancy, and educational success, but it has been claimed to be irrelevant to compliance and adherence issues in epilepsy. Our data and the experience of other centers with childhood diabetes suggest that socioeconomic, racial, and family factors influence compliance or adherence to treatment for many chronic conditions. Educational efforts and support for parents at the start of anticonvulsant treatment may improve compliance. Uninsured patients missed more appointments and were much more likely to be noncompliant than insured patients. Attention to the special problems of Medicaid and minority children is needed.

Anticonvulsant blood levels: historical review with a pediatric focus.

Epilepsy is heterogeneous and its treatment is often complicated by variable drug responses. Buchtal et al reported a close correlation between serum phenytoin levels, electroencephalographic findings, and clinical status in 1960. They suggested that physicians adjust dosage to attain a "therapeutic level." The concept was enthusiastically received. "Therapeutic serum levels" were proposed for most anticonvulsant drugs, and by 1975, most authorities believed that pharmacokinetic factors explained individual differences in drug response. However, Froscher found that measuring levels did not improve patient outcome. More recently, Schumacher's double-blind study found no correlation between phenytoin levels and seizure control or adverse effects. Pharmacodynamic variables (differences in drug responsiveness) are more important than pharmacokinetic factors for many drugs, especially receptor-active drugs. Pharmacokinetic variables were studied first, and led to a simplistic model. They are less significant than pharmacodynamic factors in the case of warfarin anticoagulation. Anticonvulsant levels can reveal noncompliance and pharmacokinetic differences. They say nothing about pharmacodynamics. Reports of "subtherapeutic levels" imply a need to increase dosage, but this is not supported by outcome data. We still lack evidence that specific drug levels are a valid intermediate target 40 years after Buchtal's paper. Responses to some anticonvulsants could depend primarily on pharmacokinetic factors, while pharmacodynamic factors could be supreme for others.

Ambulatory management of children with epilepsy.

Pediatricians can satisfactorily manage epilepsy in children if the diagnosis is confident and if continuity of care and compliance are obtained. The health hazards of epilepsy are overstated, and good outcomes can be expected for most children. If the child has definite motor seizures with an obvious neurologic handicap, parents should be given the option of AED treatment. This type of patient is more likely to develop chronic, refractory epilepsy. If the child is neurologically normal or the diagnosis is uncertain, it is better not to begin therapy after the initial seizure. Simple precautions can reduce the likelihood of injury from seizures, regardless of whether an AED is prescribed. The child and the family are the focus of treatment, not the seizures. There is much more to treating diabetes than prescribing insulin, and much more to the management of epilepsy than prescribing AEDs.

Interpersonal sensitivity: expressivity or perceptivity?

S. E. Snodgrass (1985, 1992) examined interpersonal sensitivity within status-discrepant interactions. Using the correlation between how a participant thought another felt with how that person reported actually feeling, S. E. Snodgrass's measure of interpersonal sensitivity included both the expressivity of one person and the perceptivity of another person. The studies reported here were conducted to clarify the relative contributions of expressivity and perceptivity to this measure. Results indicated that interpersonal sensitivity was associated more with high expressivity on behalf of the sender than with the perceiver's perceptivity. Implications are discussed for research and theory on interpersonal sensitivity, and gender and leadership roles.

Effects of drugs on concurrent variable-interval variable-interval schedule performance.

According to the generalized matching law the ratio of responses between two alternatives matches the ratio of reinforcers produced by these responses. In these experiments using concurrent variable-interval variable-interval schedules in pigeons, responding occurred more frequently on the key associated with the lower reinforcement density (undermatching) than would be predicted by perfect matching. Under control conditions, there was no bias toward responding on either key. Pentobarbital, methamphetamine, morphine and phencylidine all increased bias toward responding on the left key with the exception of one 10 mg/kg dose of pentobarbital that increased bias toward responding on the right key. Higher doses of methamphetamine and morphine, and most doses of phencyclidine increased matching, but high doses of pentobarbital further decreased matching. Morphine increased bias toward responding on the left key at much lower doses than those that affected matching, while phencyclidine increased matching at lower doses than those that increased bias. Pentobarbital produced small increases in response rates that were sometimes accompanied by small increases in key switching. All other drugs only decreased response rate and decreased the number of key switches. These data suggest that drugs disrupt responding under concurrent schedules both by increasing bias and by changing baseline matching functions.

Behavior of rats under fixed consecutive number schedules: effects of drugs of abuse.

Four rats responded under a simple fixed consecutive number schedule in which eight or more consecutive responses on the run lever, followed by a single response on the reinforcement lever, produced the food reinforcer. Under this simple schedule, dose-response curves were determined for diazepam, morphine, pentobarbital, and phencyclidine. The rats were then trained to respond under a multiple fixed consecutive number schedule in which a discriminative stimulus signaled when the response requirement on the run lever had been completed in one of the two fixed consecutive number component schedules. Under control conditions, the percentage of reinforced runs under the multiple-schedule component with the discriminative stimulus added was much higher than the percentage of reinforced runs under the multiple-schedule component without the discriminative stimulus. All of the drugs decreased the percentage of reinforced runs under each of the fixed consecutive number schedules by increasing the conditional probability of short run lengths. This effect was most consistently produced by morphine. The drugs produced few differences in responding between the multiple fixed consecutive number components. Responding under the simple fixed consecutive number schedule, however, was affected at lower doses of the drugs than was responding under the same fixed consecutive number schedule when it was a component of the multiple schedule. This result may be due to the difference in schedule context or, perhaps, to the order of the experiments.

Recurrent gallbladder carcinoma at laparoscopy port sites diagnosed by positron emission tomography: implications for primary and radical second operations.

Inapparent gallbladder carcinoma discovered by histologic examination following 1 per cent of cholecystectomies generates a difficult clinical problem. There is evidence that radical resection can prolong survival, especially for locally advanced (> or = PT2, according to the Union International Centre Cancer pathologic T classification) lesions. Case reports of recurrence at port sites after laparoscopic cholecystectomy add another aspect to the management difficulty. A 64-year-old woman underwent laparoscopic cholecystectomy for biliary colic. Histologic evaluation revealed an incidental adenocarcinoma, stage pT3. Radical resection with curative intent occurred 11 days later, including mesohepatectomy, skeletonization resection of the common bile duct with en bloc lymph node dissection, and bilateral Roux-en-Y hepaticojejunostomies. There was no tumor identified in the re-excision specimen (T3N0M0). At 7-month follow-up, the patient presented with nodules in the right subcostal area and in the periumbilical incision. Positron emission tomography demonstrated carcinoma at both sites. Biopsy confirmed metastatic gallbladder carcinoma. This case emphasizes the significance of tumor seeding at port sites during laparoscopy. An open technique is indicated if carcinoma is suspected. To avoid dissemination of unsuspected carcinoma during routine laparoscopic procedures, isolation techniques must be applied. The benefit of radical resection was clearly thwarted in this case, and resection of port sites at the time of reoperation is warranted. Finally, positron emission tomography scan is useful in delineating the recurrence of gallbladder carcinoma and its extent.