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Objective Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate whether kidney function modifies the association of subclinical thyroid dysfunction and the risk of cardiovascular outcomes. Methods In total, 5804 patients were included in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). For the current analysis, 426 were excluded because of overt thyroid disease at baseline or 6 months, 266 because of inconsistent thyroid function at baseline and 6 months, 294 because of medication use that could influence thyroid function, and 16 because of missing kidney or thyroid values. Participants with normal fT4 were classified, based on TSH both at inclusion and 6 months, into three groups: subclinical hypothyroidism (TSH >4.5 mIU/L); euthyroidism (TSH = 0.45–4.5 mIU/L); and subclinical hyperthyroidism (TSH 60 mL/min/1.73 m2. The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke. Results Mean age was 75.3 years, and 49.0% patients were male. Mean follow-up was 3.2 years. Of all participants, 109 subjects (2.2%) had subclinical hypothyroidism, 4573 (94.0%) had euthyroidism, and 182 (3.7%) subclinical hyperthyroidism. For patients with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, primary outcome occurred in 9 (8.3%), 712 (15.6%), and 23 (12.6%) patients, respectively. No statistically significant relationship was found between subclinical thyroid dysfunction and primary endpoint with adjusted hazard ratios of 0.51 (0.24–1.07) comparing subclinical hyperthyroidism and 0.90 (0.58–1.39) comparing subclinical hypothyroidism with euthyroidism. Neither was this relationship present in any of the strata of kidney function, nor did kidney function interact with subclinical thyroid dysfunction in the association with primary endpoint (P interaction = 0.602 for subclinical hyperthyroidism and 0.388 for subclinical hypothyroidism). Conclusions In this secondary analysis from PROSPER, we found no evidence that the potential association between thyroid hormones and cardiovascular disease is modified by kidney function in older patients with subclinical thyroid dysfunction.

Rationale & Objective Both hypo- and hyperkalemia can cause fatal cardiac arrhythmias. Although predialysis serum potassium level is a known modifiable risk factor for death in patients receiving hemodialysis, especially for hypokalemia, this risk may be underestimated. Therefore, we investigated the relationship between predialysis serum potassium level and death in incident hemodialysis patients and whether there is an optimum level. Study Design Prospective multicenter cohort study. Setting & Participants 1,117 incident hemodialysis patients (aged >18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 study were included and followed from their first hemodialysis treatment until death, transplantation, switch to peritoneal dialysis, or a maximum of 10 years. Exposure Predialysis serum potassium levels were obtained every 6 months and divided into 6 categories: ≤4.0 mmol/L, >4.0 mmol/L to ≤4.5 mmol/L, >4.5 mmol/L to ≤5.0 mmol/L, >5.0 mmol/L to ≤5.5 mmol/L (reference), >5.5 mmol/L to ≤6.0 mmol/L, and >6.0 mmol/L. Outcomes 6-month all-cause mortality. Analytical Approach Cox proportional hazards and restricted cubic spline analyses with time-dependent predialysis serum potassium levels were used to calculate the adjusted HRs for death. Results At baseline, the mean age of the patients was 63 years (standard deviation, 14 years), 58% were men, 26% smoked, 24% had diabetes, 32% had cardiovascular disease, the mean serum potassium level was 5.0 mmol/L (standard deviation, 0.8 mmol/L), 7% had a low subjective global assessment score, and the median residual kidney function was 3.5 mL/min/1.73 m2 (IQR, 1.4-4.8 mL/min/1.73 m2). During the 10-year follow-up, 555 (50%) deaths were observed. Multivariable adjusted HRs for death according to the 6 potassium categories were as follows: 1.42 (95% CI, 1.01-1.99), 1.09 (95% CI, 0.82-1.45), 1.21 (95% CI, 0.94-1.56), 1 (reference), 0.95 (95% CI, 0.71-1.28), and 1.32 (95% CI, 0.97-1.81). Limitations Shorter intervals between potassium measurements would have allowed for more precise mortality risk estimations. Conclusions We found a U-shaped relationship between serum potassium level and death in incident hemodialysis patients. A low predialysis serum potassium level was associated with a 1.4-fold stronger risk of death than the optimal level of approximately 5.1 mmol/L. These results may imply the cautious use of potassium-lowering therapy and a potassium-restricted diet in patients receiving hemodialysis., Graphical abstract

Background and Aims Older patients with advanced chronic kidney disease (CKD) are at increased risk for a severe course of the coronavirus disease-2019 (COVID-19) and vulnerable to mental health problems. We aimed to investigate prevalence and associated patient (demographic and clinical) characteristics of mental wellbeing (health-related quality of life [HRQoL] and symptoms of depression and anxiety) before and during the COVID-19 pandemic in older patients with advanced CKD. Method An ongoing Dutch multicentre prospective cohort study enrols patients of ≥70 years with an eGFR Results The 82 included patients had a median age of 77.5 years (inter-quartile range 73.9-82.1), 77% was male and none had tested positive for COVID-19. Cross-sectionally, 67% of the patients reported to be more anxious for COVID-19 because of their kidney disease, and 43% of the patients stated that their quality of life was reduced due to the COVID-19 pandemic (Figure 1). Higher COVID-19-related stress was associated with a lower education level (p=0.036), and patients who reported to feel more down due to COVID-19 were more often female (p=0.020). Anxiety scores were higher among females compared to males (median 4.0 [IQR 3.0-9.0] versus 2.0 [0.0-6.0], p=0.020), and weakly associated to a decline in eGFR (correlation coefficient 0.197, p=0.023). Compared to pre-COVID-19, presence of depressive symptoms had increased (11% to 22%; p=0.022) and physical HRQoL declined (40.4±10.1 to 36.1±10.4, p Conclusion Our findings show that older patients with advanced CKD suffered from disease-related anxiety for COVID-19, increased depressive symptoms, and reduced physical HRQOL during the COVID-19 pandemic. The impact of the pandemic on this vulnerable patient group extends beyond increased mortality risk, and awareness of mental health problems during the pandemic is essential. More in-depth investigation on disease-related COVID-19 concerns and its implications for the CKD population is needed.

Objectives There have been very few longitudinal studies of dental caries in adolescents, and little study of the caries risk factors in this age group. The purpose of this study was to describe different caries trajectories and associated risk factors among members of the Iowa Fluoride Study (IFS) cohort. Methods The IFS recruited a birth cohort from 1992 to 1995, and has gathered dietary, fluoride and behavioural data at least twice yearly since recruitment. Examinations for dental caries were completed when participants were ages 5, 9, 13 and 17 years. For this study, only participants with decayed and filled surface (DFS) caries data at ages 9, 13 and 17 were included (N=396). The individual DFS counts at age 13 and the DFS increment from 13 to 17 were used to identify distinct caries trajectories using Ward's hierarchical clustering algorithm. A number of multinomial logistic regression models were developed to predict trajectory membership, using longitudinal dietary, fluoride and demographic/behavioural data from 9 to 17 years. Model selection was based on the akaike information criterion (AIC). Results Several different trajectory schemes were considered, and a three-trajectory scheme—no DFS at age 17 (n=142), low DFS (n=145) and high DFS (n=109)—was chosen to balance sample sizes and interpretability. The model selection process resulted in use of an arithmetic average for dietary variables across the period from 9 to 17 years. The multinomial logistic regression model with the best fit included the variables maternal education level, 100% juice consumption, brushing frequency and sex. Other favoured models also included water and milk consumption and home water fluoride concentration. The high caries cluster was most consistently associated with lower maternal education level, lower 100% juice consumption, lower brushing frequency and being female. Conclusions The use of a clustering algorithm and use of Akaike's Information Criterion (AIC) to determine the best representation of the data were useful means in presenting longitudinal caries data. Findings suggest that high caries incidence in adolescence is associated with lower maternal educational level, less frequent tooth brushing, lower 100% juice consumption and being female.

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.

Background: Peritoneal dialysis (PD) solutions with reduced sodium content may have advantages for hypertensive patients; however, they have lower osmolarity and solvent drag, so the achieved Kt/V-urea may be lower. Furthermore, the increased transperitoneal membrane sodium gradient can influence sodium balance with consequences for blood pressure (BP) control.Study Design: Prospective, randomized, double-blind clinical trial to prove the noninferiority of total weekly Kt/V-urea with low-sodium versus standard-sodium PD solution, with the lower confidence limit above the clinically accepted difference of 0.5. Setting & Participants: Hypertensive patients (1 antihypertensive drug, including diuretics, or office systolic BP 130 mm Hg) on continuous ambulatory PD therapy from 17 sites.Intervention: 108 patients were randomly assigned (1:1) to 6-month treatments with either low-sodium (125 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 338-491 mOsm/L) or standard-sodium (134 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 356-509 mOsm/L) PD solution.Outcomes: Primary end point: weekly total KtNurea; secondary outcomes: BP control, safety, and tolerability. Measurements: Total KtNurea was determined from 24-hour dialysate and urine collection; BP, by office measurement.Results: Total Kt/Vurea after 12 weeks was 2.53 +/- 0.89 in the low -sodium group (n = 40) and 2.97 +/- 1.58 in the control group (n = 42). The noninferiority of total KtNurea could not be confirmed. There was no difference for peritoneal KtNurea (1.70 +/- 0.38 with low sodium, 1.77 +/- 0.44 with standard sodium), but there was a difference in renal KtNurea (0.83 +/- 0.80 with low sodium, 1.20 +/- 1.54 with standard sodium). Mean daily sodium removal with dialysate at week 12 was 1.188 g higher in the low-sodium group (P Limitations: Broader variability of study population than anticipated, particularly regarding residual kidney function.Conclusions: The noninferiority of the low -sodium PD solution for total Kt/Vurea could not be proved; however, it showed beneficial clinical effects on sodium removal and BP. Am J Kidney Dis. 67(5):753-761. 2016 Fresenius Medical Care. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.orgIlicenses/by-nc-nd14.01).

Background Sugar-sweetened beverages (SSBs) have been associated with obesity in children and adults; however, associations between beverage patterns and obesity are not understood. Objective Our aim was to describe beverage patterns during adolescence and associations between adolescent beverage patterns and anthropometric measures at age 17 years. Design We conducted a cross-sectional analyses of longitudinally collected data. Participants/setting Data from participants in the longitudinal Iowa Fluoride Study having at least one beverage questionnaire completed between ages 13.0 and 14.0 years, having a second questionnaire completed between 16.0 and 17.0 years, and attending clinic examination for weight and height measurements at age 17 years (n=369) were included. Exposure Beverages were collapsed into four categories (ie, 100% juice, milk, water and other sugar-free beverages, and SSBs) for the purpose of clustering. Five beverage clusters were identified from standardized age 13 to 17 years mean daily beverage intakes and named by the authors for the dominant beverage: juice, milk, water/sugar-free beverages, neutral, and SSB. Outcomes Weight, height, and body mass index (BMI; calculated as kg/m 2 ) at age 17 years were analyzed. Statistical analyses We used Ward's method for clustering of beverage variables, one-way analysis of variance and χ 2 tests for bivariable associations, and γ-regression for associations of weight or BMI (outcomes) with beverage clusters and demographic variables. Linear regression was used for associations of height (outcome) with beverage clusters and demographic variables. Results Participants with family incomes P =0.070) and were heavier (2.0±0.7 BMI units; P =0.002) than participants with family incomes ≥$60,000/year. Adjusted mean weight, height, and BMI estimates differed by beverage cluster membership. For example, on average, male and female members of the neutral cluster were 4.5 cm ( P =0.010) and 4.2 cm ( P =0.034) shorter, respectively, than members of the milk cluster. For members of the juice cluster, mean BMI was lower than for members of the milk cluster (by 2.4 units), water/sugar-free beverage cluster (3.5 units), neutral cluster (2.2 units), and SSB cluster (3.2 units) (all P Conclusions Beverage patterns at ages 13 to 17 years were associated with anthropometric measures and BMI at age 17 years in this sample. Beverage patterns might be characteristic of overall food choices and dietary behaviors that influence growth.

OBJECTIVES Amplification is a core component of early intervention for children who are hard of hearing, but hearing aids (HAs) have unique effects that may be independent from other components of the early intervention process, such as caregiver training or speech and language intervention. The specific effects of amplification are rarely described in studies of developmental outcomes. The primary purpose of this article is to quantify aided speech audibility during the early childhood years and examine the factors that influence audibility with amplification for children in the Outcomes of Children with Hearing Loss study. DESIGN Participants were 288 children with permanent hearing loss who were followed as part of the Outcomes of Children with Hearing Loss study. All of the children in this analysis had bilateral hearing loss and wore air-conduction behind-the-ear HAs. At every study visit, hearing thresholds were measured using developmentally appropriate behavioral methods. Data were obtained for a total of 1043 audiometric evaluations across all subjects for the first four study visits. In addition, the aided audibility of speech through the HA was assessed using probe microphone measures. Hearing thresholds and aided audibility were analyzed. Repeated-measures analyses of variance were conducted to determine whether patterns of thresholds and aided audibility were significantly different between ears (left versus right) or across the first four study visits. Furthermore, a cluster analysis was performed based on the aided audibility at entry into the study, aided audibility at the child's final visit, and change in aided audibility between these two intervals to determine whether there were different patterns of longitudinal aided audibility within the sample. RESULTS Eighty-four percent of children in the study had stable audiometric thresholds during the study, defined as threshold changes

Objectives: Children who are hard of hearing (CHH) have restricted access to acoustic and linguistic information. Increased audibility provided by hearing aids (HAs) influences language outcomes, but the advantages of appropriately fit HAs can only be realized if children wear their devices on a consistent basis. The purpose of this article was to characterize long-term HA use in CHH, based on parent-report measures, and identify factors that influence longitudinal trends in HA use. Design: Participants were parents of 290 children with mild to severe hearing loss. At every visit, parents estimated the average amount of time the child used HAs per day during the week and on the weekends. Parent reports of daily HA use were analyzed to determine if different patterns of HA use were observed longitudinally during the study. Independent predictor variables were then related to longitudinal trends in HA use within three age groups (infant, preschool, school age). Results: On average across multiple visits, parents reported that their children wore their HAs for 10.63 hr per day (SD = 3.29). Data logging values were lower than parent-report measures (M = 8.44, SD = 4.06), suggesting that parents overestimated daily HA use. The majority of children in each age group wore HAs at least 8 hr per day from their first research testing interval to their last, based on parent-report measures. Maternal education level predicted longitudinal trends in HA use for infants and school-age CHH. Degree of hearing loss was related to trends in school-age children only. Conclusions: These results indicated that the majority of CHH increased HA use over time, but a sizable minority demonstrated a low level of use or decreased use in the time period studied. Maternal education level influenced longitudinal trends in daily HA use. Degree of hearing loss influenced trends in school-age children only. Audiologists and early intervention service providers might aid in improving HA use by providing regular hands-on training with the HAs and individualized problem-based strategies to address the challenges families experience with attaining a high level of use. Families may also benefit from practical demonstrations of the benefits of consistent HA use, such as hearing loss simulations, examples of listening in noise with and without HAs, or listening to malfunctioning HAs.

Summary Background Hydration to prevent contrast-induced acute kidney injury (CI-AKI) induces a diagnostic delay when performing computed tomography–pulmonary angiography (CTPA) in patients suspected of having acute pulmonary embolism. Aim To analyze whether withholding hydration is non-inferior to sodium bicarbonate hydration before CTPA in patients with chronic kidney disease (CKD). Methods We performed an open-label multicenter randomized trial between 2009 and 2013. One hundred thirty-nine CKD patients were randomized, of whom 138 were included in the intention-to-treat population: 67 were randomized to withholding hydration and 71 were randomized to 1-h 250 mL 1.4% sodium bicarbonate hydration before CTPA. Primary outcome was the increase in serum creatinine 48–96 h after CTPA. Secondary outcomes were the incidence of CI-AKI (creatinine increase > 25%/> 0.5 mg dL−1), recovery of renal function, and the need for dialysis within 2 months after CTPA. Withholding hydration was considered non-inferior if the mean relative creatinine increase was ≤ 15% compared with sodium bicarbonate. Results Mean relative creatinine increase was −0.14% (interquartile range −15.1% to 12.0%) for withholding hydration and −0.32% (interquartile range −9.7% to 10.1%) for sodium bicarbonate (mean difference 0.19%, 95% confidence interval −5.88% to 6.25%, P-value non-inferiority

Background. Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e. g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates.Methods. Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions.Results. One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015).Conclusions. If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

We studied the effects of a single dose (100 mg orally) and repeated administration (100 mg o.d. for 7 days) of FK453, a novel adenosine-1 receptor antagonist, on renal sodium handling and blood pressure in eight patients with essential hypertension. Within 60 minutes after administration of FK453, sodium excretion increased threefold. This occurred in the absence of a change in renal hemodynamics, assessed from inulin and para-aminohippurate clearance, and was accompanied by increased fractional excretion of lithium, phosphate, and uric acid and by increased excretion of calcium and magnesium. Maximal free water clearance data showed an increase in maximal urine flow and distal delivery term and a decrease in the diluting segment reabsorption term. FK453 also decreased blood pressure and increased heart rate, but this did not occur until about 3 hours after ingestion, that is, when the natriuresis was already over. The natriuretic effect of FK453 was short-lasting, and continued use of FK453 was in fact accompanied by some net sodium retention. Blood pressure on the seventh day before FK453 treatment was not different from blood pressure before administration of the first dose of FK453. Again an acute natriuretic response followed, although less than after the first dose. Changes in intrarenal sodium handling parameters, blood pressure, and heart rate were similar to those seen after the first dose. The natriuretic and hypotensive effects of FK453 indicate that adenosine-1 receptor activity plays a role in the regulation of blood pressure and renal sodium handling in patients with essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Contains fulltext : 69499.pdf (Publisher’s version ) (Open Access) PURPOSE: To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas. EXPERIMENTAL DESIGN: Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10). RESULTS: Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with < or =50% of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no effect on cancer-specific survival or recurrence-free survival. CONCLUSIONS: Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient's prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed.

Plasmodium falciparum infection causes serious symptoms in the acute phase of the illness. Long-term sequelae are less common. In the following case report we describe a patient who developed hypopituitarism after a severe cerebral malaria infection, which was only recognized 17 years thereafter.

Lumbar cerebrospinal fluid (CSF) norepinephrine concentrations determined by radioenzymatic assay in 9 patients with caudate atrophy associated with Huntington's disease were lower (p < 0.02) than those in 9 age- and sex-matched control patients. Preoperative lumbar CSF norepinephrine concentrations were determined in 5 patients undergoing stereotaxic thalamotomy. No significant alterations in prestimulation lumbar CSF norepinephrine levels were recorded 12 days after electrode installation and thalamic coagulation. Lumbar CSF norepinephrine concentrations were reduced (p < 0.03), however, 12 hours following intermittent selective electrical stimulation of the caudate nucleus. These data suggest that noradrenergic pathways in man are (1) impaired in Huntington's disease and (2) inhibited by direct caudate stimulation.

✓ The authors describe the use of temporal lobectomy following careful and repeated electroencephalogram (EEG) evaluation (with implanted electrodes in otherwise unresolvable cases) in the epileptic group characterized by automatisms (psychomotor seizures) with temporal epileptiform activity complicated by EEG foci in the opposite temporal lobe or by extratemporal activity. They found that this can render a significant number of patients (between 25% and 50%) either seizure-free or with significant and useful reduction in their seizure frequency. The cure and improvement rates of cases followed up after temporal resection with or without prior study with implanted electrodes were approximately equal. However, the implanted electrodes permitted surgical treatment of certain cases which would have been rejected on the basis of evidence derived from the scalp recordings alone. Of 28 of these 34 patients with persisting EEG epileptiform activity in the postoperative period, only one had such activity in a different location in a follow-up period of 6 years. No evidence of spreading epileptic activity or appearance of “mirror foci” was seen during a follow-up period averaging 8.2 years. Seizure remission up to 15 years with eventual recurrence of the original seizure type may occur following surgical therapy. Follow-up studies of surgical epileptic treatment of less than 3 to 5 years are of doubtful value.

After an “occipital lobectomy” that resulted in a severe dyslexia and a moderate dysgraphia-dyscalculia, anatomical study showed damage to the posterior extremity of the angular gyrus and degeneration in the posteroinferior pulvinar. This is in contrast to an earlier case that had degeneration in the anterosuperior pulvinar associated with a small anterior temporoparietal infarct and a well-documented receptive-expressive aphasia. However, the role of the pulvinar in speech function remains uncertain. The surgeon should be aware of the short distance between the angular gyrus and both the midline and the occipital pole because a lesion here during an “occipital lobectomy” produces a distressing and durable speech impairment.

A stereotaxic radiotherapy technique that permits accurate delivery of highly localized dose to a small intracranial target has been developed. The technique facilitates precise integration of the diagnostic and therapeutic procedures including target localization, treatment planning, simulation, repetitive patient irradiation, and daily treatment verification. A conventional linear accelerator and computed tomography scanner as well as special diagnostic and therapeutic guides are used. A suitable dosimetric distribution is achieved using arc therapy with small radiation fields and 10-MV x rays.

Cancer involving the ethmoid and sphenoid frontal sinus complex can be successfully eradicated by a combined transcranial and transfacial surgical dissection. Survival rates of 44 to 58 percent with a 3 percent hospital mortality rate in patients whose previous surgery or radiotherapy was largely unsuccessful suggest that this cosmetically acceptable surgical endeavor should be used more often by the head and neck surgeon in treating paranasal sinus cancer. Utilizing the principles of antibiotic prophylaxis, strict attention to principles of tumor removal and surgical technique, and the talents of the combined surgical and neurosurgical team, this aggressive surgical approach to the paranasal sinuses can be safely and successfully carried out. The approach described herein has the following advantages: it allows accurate evaluation of intracranial tumor extension while protecting the intracranial contents, it essentially avoids cerebrospinal fistulization, it provides adequate exposure for hemostasis, facilitates en bloc tumor resection, selectively conserves the orbital contents, and provides patient survival rates up to 58 percent for paranasal cancer that involves the ethmoid and sphenoid frontal sinus complex.

ALIGNANT tumors of the paranasal sinuses account for but a small percentage of human neoplastic disease. This amounts to about 3 % of all cancer of the upper respiratory and alimentary tracts or approximately 0.2 % of all human cancers. TM Watson TM found an incidence of 0.44 % of cancer of the paranasal sinuses in a total of 26,062 patients admitted for malignant disease at Memorial Hospital. Nevertheless, serious study of these patients is merited not only because of the peculiarly unpleasant suffering these patients undergo in the terminal period but because it has been found practical to eradicate the disease in a relatively high proportion of patients. It should be re-emphasized that only histologically malignant tumors are under present consideration. From a statistical point of view, several features suggest that radical therapy should provide a high cure rate. Some 80 % of tumors of the paranasal sinuses are estimated to arise in the maxillary sinus which has long been considered a surgically accessible site. 1 The tumors, appearing as they most commonly do in the fifth to seventh decade, are predominantly carcinomas or adenocarcinomas and frequently of slow-growing type. 8 Certainly one of the greatest difficulties in treatment is diagnosis of the tumor in an early stage. Often, many months of symptomatic treatment is prescribed for the protean symptoms of nasal obstruction, local pain, and epistaxis before a definitive diagnosis of malignancy is made. Despite the late diagnosis, metastases are relatively uncommon. Of 68 patients with cancer of the nasal cavity, MacComb and Martin ~x found that 12 % had metastases on admission and only 17% had metastases later in their course. This incidence is approximately the same as that of Ashley Received for publication July 13, 1967. and Schwartz I who noted at autopsy that only 25 % of maxillary carcinomas spread beyond the local area. Metastases usually appeared in the retropharyngeal and superior cervical lymph nodes if the primary tumor was in the superior and medial portion of the antrum. Tumors involving the floor and lateral wall were more prone to show metastases in the submandibular lymph nodes. Taken together, these features encourage surgical attack upon the local lesion. Unfortunately, hopes of an en bloc resection through a facial approach can only be realized in the cases with very small lesions, since tumors, even if primary in the antrum, seldom remain there. The common extension of tumor into the ethmoidal sinus and the impossibility of removing this sinus en bloc through a facial approach is a particular deterrent to resection, since even as late as 1963, FrazeU and Lewis 6 warned that "the entire cribriform plate can rarely be resected without creating cerebral complications .... "

Summary The combined intracranial transfacial approach to the ethmoid, sphenoid, and frontal sinuses has been satisfactory in performing en bloc resection of cancer arising in or involving these anatomic areas. Fifty-four patients have been treated with this procedure, using the combined expertise of the neurosurgeon and the surgeon interested in the head and neck area. Two postoperative deaths have occurred, both attributed to meningitis. The long range postoperative morbidity is negligible, except as it relates to loss of the palate in all but eight patients and the orbital contents in thirty patients. The cumulative five year survival in this series of patients, forty-two of whom had failure of previous treatment, is 56 per cent. If the procedure is carried out with rigid attention to good surgical technic and the principles of en bloc tumor removal, this combined procedure has the following advantages: (1) allows accurate evaluation of the intracranial tumor extension, (2) protects the brain, (3) avoids cerebrospinal fistulization, (4) provides adequate hemostasis, (5) facilitates en bloc tumor resection, and (6) selectively conserves the orbital contents.

✓ This series included five patients who had suffered 8 to 23 years of severe, medically intractable seizures without remission, severe socioeconomic handicaps, and an average of over one seizure a day on hospital observation and by history. All had combinations of partial and general seizures with focal and/or bilaterally synchronous epileptiform activity consistently on multiple electroencephalograms (EEG's). One patient had nearly continuous myoclonic activity. Serum levels of phenytoin, primidone, and phenobarbital were adjusted to therapeutic ranges. Three patients had additional medication (diazepam, ethosuximide). Cerebellar biopsy in three patients showed reduction in Purkinje cells. After implantation of cerebellar stimulators, seizure frequency was evaluated in hospital during three or four admissions for 4- to 6-week periods over the ensuing 15 to 21 months. No slow trends toward improvement or deterioration were noted. No significant differences in seizure frequency were found when comparing intervals of about 7 days of on-and-off stimulation both in the double-blind and unblinded conditions. No changes in EEG or Intelligence or Memory Quotients occurred unaccounted for by variations in serum levels of antiepileptic drugs. Despite the lack of objective improvement, patient and family acceptance of cerebellar stimulation was positive to enthusiastic. A rise in CSF norepinephrine and a fall in gamma aminobutyric acid (GABA) accompanied cerebellar stimulation and may be related to the results.

This study is based on 28 patients with intractable seizures in whom exclusively extratemporal or a combination of temporal and extratemporal electrodes were chronically implanted for the localization of the epileptogenic process and possible surgical treatment. Clinical and electrographic data are briefly summarized, the indications for the use of implanted electrodes are outlined, and the number and position of the electrodes and the findings in each individual case are given. Four illustrative examples are described in greater detail. Mainly on the basis of data derived from this particular technique of investigation, surgical treatment was eventually carried out in 14 patients. It is concluded that the use of implanted electrodes in seizure disorders of probable extratemporal origin can be of real diagnostic benefit in certain specific situations. In most instances, however, this technique simply serves to demonstrate the complexity of an apparently simple case or, of greater clinical consequence, might tend to oversimplify cases that are actually very complex. Indeed, many data in this study raise some doubts about the validity of the classic concepts of “focal” epilepsy.

Lumbar cerebrospinal fluid norepinephrine concentrations were determined by radioenzymatic assay in five epileptic patients receiving double-blind cerebellar stimulation and in three epileptic patients with subdural cerebral surface electrodes. Mean CSF norepinephrine levels were significantly elevated by chronic cerebellar stimulation and significantly depressed after intermittent cerebral cortical stimulation. Lumbar CSF cyclic adenosine monophosphate levels determined by radioimmunoassay were not significantly altered by either cerebellar or cerebral surface stimulation. Our study suggests that (1) electrical stimulation of the anterodorsal cerebellum in man evokes alterations in noradrenergic metabolism. Cerebellar stimulation-induced elevations in norepinephrine may inhibit cerebellar, cerebral, and spinal neuronal activity. In addition, (2) noradrenergic responses to brain surface stimulation may exhibit regional specificity, and (3) noradrenergic alterations evoked by cerebral surface stimulation may not mimic those induced in isolated brain preparations.

Cerebellar biopsy specimens were obtained at the time of cerebellar electrode installation in three epileptic patients. Cerebellar autopsy specimens also were examined from four epileptic patients and from five patients without epilepsy or neurologic disease. All specimens from seizure patients showed isomorphic gliosis of the cerebellar cortices. Significantly lower Purkinje cell densities were found in epileptic patients as compared with nonepileptic control patients. Our two epileptic patients showing marked Purkinje cell loss before cerebellar stimualtaion appeared to have better seizure control during stimulation than the patient who had only mild reduction in Purkinje cell density. These data suggest that augmentation of Purkinje cell inhibitory discharges in not the dominant mechanism for seizure suppression during cerebellar stimulation. Comparison of cerebellar specimens obtained during electrode installation with those obtained later during electrode revisions may have been prognostic significance.

A patient, suffering from syringomyelia for 34 years and syringobulbia for 27 years, has been under our care for the past 10 years. The symptoms and neurological signs were typical, both developed or rapidly became worse after a minor injury. On three occasions the patient was almost completely disable because of sensory and motor dysfunctions; and, without exceptions, his misery was relieved by surgical drainage of the syrinx.

The following 54 cases are presented as montages of drawings including every 100th section through the hemisphere and every 40th section through the thalamus. The nomenclature and methods have been presented and discussed in Chapters 1 and 2. Using the abbreviations of this nomenclature, a summary of the areas of destruction and degeneration is presented at the start of each anatomical description. The conventions used on the drawings to indicate gliosis, neuron change, and demyelination are shown in Fig. 98. Black indicates total destruction of tissue.

THE PRESENT studies were made on a group of 50 patients studied in collaboration with the Branch of Endocrinology of the National Cancer Institute over a period of approximately two years. Nearly all of the patients were undertaken for the palliation of metastatic breast carcinoma. They were accepted only after oophorectomy in the premenopausal women who had reached their maximum benefit from palliative x-rays and endocrine therapy. In addition, a number of patients had had chemotherapy for their metastatic disease. It became evident rather early in the series that a beneficial response from oophorectomy or endocrine therapy was a rather uncertain indicator of the outcome of the pituitary ablation. Although many patients who had previously responded favorably to the treatment also responded favorably to pituitary ablation, others did not; and, it was soon found that certain patients who had not responded favorably before would respond with remission to pituitary ablation.