Association between EEG metrics and continuous cerebrovascular autoregulation assessment: a scoping review.

OBJECTIVE: Cerebrovascular autoregulation is defined as the capacity of cerebral blood vessels to maintain stable cerebral blood flow despite changing blood pressure. It is assessed using the pressure reactivity index (the correlation coefficient between mean arterial blood pressure and intracranial pressure). The objective of this scoping review is to describe the existing evidence concerning the association of EEG and cerebrovascular autoregulation in order to identify key concepts and detect gaps in the current knowledge. METHODS: Embase, MEDLINE, SCOPUS, and Web of Science were searched considering articles between their inception up to September 2023. Inclusion criteria were human (paediatric and adult) and animal studies describing correlations between continuous EEG and cerebrovascular autoregulation assessments. RESULTS: Ten studies describing 481 human subjects (67% adult, 59% critically ill) were identified. Seven studies assessed qualitative (e.g. seizures, epileptiform potentials) and five evaluated quantitative (e.g. bispectral index, alpha-delta ratio) EEG metrics. Cerebrovascular autoregulation was evaluated based on intracranial pressure, transcranial Doppler, or near infrared spectroscopy. Specific combinations of cerebrovascular autoregulation and EEG metrics were evaluated by a maximum of two studies. Seizures, highly malignant patterns or burst suppression, alpha peak frequency, and bispectral index were associated with cerebrovascular autoregulation. The other metrics showed either no or inconsistent associations. CONCLUSION: There is a paucity of studies evaluating the link between EEG and cerebrovascular autoregulation. The studies identified included a variety of EEG and cerebrovascular autoregulation acquisition methods, age groups, and diseases allowing for few overarching conclusions. However, the preliminary evidence for the presence of an association between EEG metrics and cerebrovascular autoregulation prompts further in-depth investigations.

Intraparenchymal near-infrared spectroscopy for detection of delayed cerebral ischemia in poor-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Detection of delayed cerebral ischemia (DCI) is challenging in comatose patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH). Brain tissue oxygen pressure (PbtO2) monitoring may allow early detection of its occurrence. Recently, a probe for combined measurement of intracranial pressure (ICP) and intraparenchymal near-infrared spectroscopy (NIRS) has become available. In this pilot study, the parameters PbtO2, Hboxy, Hbdeoxy, Hbtotal and rSO2 were measured in parallel and evaluated for their potential to detect perfusion deficits or cerebral infarction. METHODS: In patients undergoing multimodal neuromonitoring due to poor neurological condition after aSAH, Clark oxygen probes, microdialysis and NIRS-ICP probes were applied. DCI was suspected when the measured parameters in neuromonitoring deteriorated. Thus, perfusion CT scan was performed as follow up, and DCI was confirmed as perfusion deficit. Median values for PbtO2, Hboxy, Hbdeoxy, Hbtotal and rSO2 in patients with perfusion deficit (Tmax > 6 s in at least 1 vascular territory) and/or already demarked infarcts were compared in 24- and 48-hour time frames before imaging. RESULTS: Data from 19 patients (14 University Hospital Zurich, 5 Charité Universitätsmedizin Berlin) were prospectively collected and analyzed. In patients with perfusion deficits, the median values for Hbtotal and Hboxy in both time frames were significantly lower. With perfusion deficits, the median values for Hboxy and Hbtotal in the 24 h time frame were 46,3 [39.6, 51.8] µmol/l (no perfusion deficits 53 [45.9, 55.4] µmol/l, p = 0.019) and 69,3 [61.9, 73.6] µmol/l (no perfusion deficits 74,6 [70.1, 79.6] µmol/l, p = 0.010), in the 48 h time frame 45,9 [39.4, 51.5] µmol/l (no perfusion deficits 52,9 [48.1, 55.1] µmol/l, p = 0.011) and 69,5 [62.4, 74.3] µmol/l (no perfusion deficits 75 [70,80] µmol/l, p = 0.008), respectively. In patients with perfusion deficits, PbtO2 showed no differences in both time frames. PbtO2 was significantly lower in patients with infarctions in both time frames. The median PbtO2 was 17,3 [8,25] mmHg (with no infarctions 29 [22.5, 36] mmHg, p = 0.006) in the 24 h time frame and 21,6 [11.1, 26.4] mmHg (with no infarctions 31 [22,35] mmHg, p = 0.042) in the 48 h time frame. In patients with infarctions, the median values of parameters measured by NIRS showed no significant differences. CONCLUSIONS: The combined NIRS-ICP probe may be useful for early detection of cerebral perfusion deficits and impending DCI. Validation in larger patient collectives is needed.

Nonconvulsive status epilepticus in neurocritical care: A critical reappraisal of outcome prediction scores.

OBJECTIVE: Nonconvulsive status epilepticus (NCSE) is a frequent condition in the neurocritical care unit (NCCU) patient population, with high morbidity and mortality. We aimed to assess the validity of available outcome prediction scores for prognostication in an NCCU patient population in relation to their admission reason (NCSE vs. non-NCSE related). METHODS: All 196 consecutive patients diagnosed with NCSE during the NCCU stay between January 2010 and December 2020 were included. Demographics, Simplified Acute Physiology Score II (SAPS II), NCSE characteristics, and in-hospital and 3-month outcome were extracted from the electronic charts. Status Epilepticus Severity Score (STESS), Epidemiology-Based Mortality Score in Status Epilepticus (EMSE), and encephalitis, NCSE, diazepam resistance, imaging features, and tracheal intubation score (END-IT) were evaluated as previously described. Univariable and multivariable analysis and comparison of sensitivity/specificity/positive and negative predictive values/accuracy were performed. RESULTS: A total of 30.1% died during the hospital stay, and 63.5% of survivors did not achieve favorable outcome at 3 months after onset of NCSE. Patients admitted primarily due to NCSE had longer NCSE duration and were more likely to be intubated at diagnosis. The receiver operating characteristic (ROC) for SAPS II, EMSE, and STESS when predicting mortality was between .683 and .762. The ROC for SAPS II, EMSE, STESS, and END-IT when predicting 3-month outcome was between .649 and .710. The accuracy in predicting mortality/outcome was low, when considering both proposed cutoffs and optimized cutoffs (estimated using the Youden Index) as well as when adjusting for admission reason. SIGNIFICANCE: The scores EMSE, STESS, and END-IT perform poorly when predicting outcome of patients with NCSE in an NCCU environment. They should be interpreted cautiously and only in conjunction with other clinical data in this particular patient group.

Sex-specific extracerebral complications in patients with aneurysmal subarachnoid hemorrhage.

Background: Extracerebral complications in patients with aneurysmal subarachnoid hemorrhage (aSAH) often occur during their stay at the neurocritical care unit (NCCU). Their influence on outcomes is poorly studied. The identification of sex-specific extracerebral complications in patients with aSAH and their impact on outcomes might aid more personalized monitoring and therapy strategies, aiming to improve outcomes. Methods: Consecutive patients with aSAH admitted to the NCCU over a 6-year period were evaluated for the occurrence of extracerebral complications (according to prespecified criteria). Outcomes were assessed with the Glasgow Outcome Scale Extended (GOSE) at 3 months and dichotomized as favorable (GOSE 5-8) and unfavorable (GOSE 1-4). Sex-specific extracerebral complications and their impact on outcomes were investigated. Based on the results of the univariate analysis, a multivariate analysis with unfavorable outcomes or the occurrence of certain complications as dependent variables was performed. Results: Overall, 343 patients were included. Most of them were women (63.6%), and they were older than men. Demographics, presence of comorbidities, radiological findings, severity of bleeding, and aneurysm-securing strategies were compared among the sexes. More women than men suffered from cardiac complications (p = 0.013) and infection (p = 0.048). Patients with unfavorable outcomes were more likely to suffer from cardiac (p < 0.001), respiratory (p < 0.001), hepatic/gastrointestinal (p = 0.023), and hematological (p = 0.021) complications. In the multivariable analysis, known factors including age, female sex, increasing number of comorbidities, increasing World Federation of Neurosurgical Societies (WFNS), and Fisher grading were expectedly associated with unfavorable outcomes. When adding complications to these models, these factors remained significant. However, when considering the complications, only pulmonary and cardiac complications remained independently associated with unfavorable outcomes. Conclusion: Extracerebral complications after aSAH are frequent. Cardiac and pulmonary complications are independent predictors of unfavorable outcomes. Sex-specific extracerebral complications in patients with aSAH exist. Women suffered more frequently from cardiac and infectious complications potentially explaining the worse outcomes.

Blood Pressure Variability Indices for Outcome Prediction After Thrombectomy in Stroke by Using High-Resolution Data.

BACKGROUND: Blood pressure variability (BPV) is associated with outcome after endovascular thrombectomy in acute large vessel occlusion stroke. We aimed to provide the optimal sampling frequency and BPV index for outcome prediction by using high-resolution blood pressure (BP) data. METHODS: Patient characteristics, 3-month outcome, and BP values measured intraarterially at 1 Hz for up to 24 h were extracted from 34 patients treated at a tertiary care center neurocritical care unit. Outcome was dichotomized (modified Rankin Scale 0-2, favorable, and 3-6, unfavorable) and associated with systolic BPV (as calculated by using standard deviation, coefficient of variation, averaged real variability, successive variation, number of trend changes, and a spectral approach using the power of specific BP frequencies). BP values were downsampled by either averaging or omitting all BP values within each prespecified time bin to compare the different sampling rates. RESULTS: Out of 34 patients (age 72 ± 12.7 years, 67.6% men), 10 (29.4%) achieved a favorable functional outcome and 24 (70.6%) had an unfavorable functional outcome at 3 months. No group differences were found in mean absolute systolic BP (SBP) (130 ± 18 mm Hg, p = 0.82) and diastolic BP (DBP) (59 ± 10 mm Hg, p = 1.00) during the monitoring time. BPV only reached predictive significance when using successive variation extracted from downsampled (averaged over 5 min) SBP data (median 4.8 mm Hg [range 3.8-7.1]) in patients with favorable versus 7.1 mmHg [range 5.5-9.7] in those with unfavorable outcome, area under the curve = 0.74 [confidence interval (CI) 0.57-0.85; p = 0.031], or the power of midrange frequencies between 1/20 and 1/5 min [area under the curve = 0.75 (CI 0.59-0.86), p = 0.020]. CONCLUSIONS: Using high-resolution BP data of 1 Hz, downsampling by averaging all BP values within 5-min intervals is essential to find relevant differences in systolic BPV, as noise can be avoided (confirmed by the significance of the power of midrange frequencies). These results demonstrate how high-resolution BP data can be processed for effective outcome prediction.

Dizziness and benign paroxysmal positional vertigo among retirement home residents: a cross-sectional descriptive and interventional study.

BACKGROUND: The prevalence of dizziness increases with age. We aimed to determine the point prevalence of dizziness and, in particular, of benign paroxysmal positional vertigo (BPPV) among retirement home residents. Furthermore, we aimed to evaluate the efficacy of a 2-axis turntable based BPPV treatment. METHODS: We contacted all large retirement homes in or around the city of Zurich (Switzerland). 10 retirement homes (with a total of 536 residents) agreed to participate in this study. 83 rejected inquiries by residents led to a potential study population of 453 residents. After a structured interview evaluating the presence and characteristics of dizziness, all willing patients were tested for positional vertigo and nystagmus on a portable and manually operated 2-axis turntable that was transported to the retirement home. Testing consisted of the Dix-Hallpike and supine roll maneuvers to both sides. Participants were immediately treated with the appropriate liberation maneuver whenever BPPV was diagnosed. Otherwise, taking the resident's medical history, a neuro-otological bedside examination, and a review of the available medical documentation was used to identify other causes of dizziness. RESULTS: Out of the 453 residents, 75 (16.6%; average age: 87.0 years; 68% female) were suffering from dizziness presently or in the recent past and gave their consent to participate in this study. Among the participants tested on the turntable (n = 71), BPPV was present in 11.3% (point prevalence). Time-related properties, triggering factors and qualitative attributes of vertigo or dizziness were not significantly different between the dizzy participants with and those without BPPV. In all BPPV patients, appropriate liberation maneuvers were successful. CONCLUSIONS: BPPV could be demonstrated in about one tenth of retirement home residents with dizziness or recent dizziness. Such point prevalence of BPPV translates to a much higher yearly prevalence if one assumes that BPPV is not present on every day. Our finding suggests that retirement home residents suffering from dizziness should be regularly tested for BPPV and treated with appropriate liberation maneuvers, ideally on turntable to reduce strain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03643354 .

Open Quantum Systems' Decay across Time.

The description of an open quantum system's decay almost always requires several approximations so as to remain tractable. In this Letter, we first revisit the meaning, domain, and seeming contradictions of a few of the most widely used of such approximations: (semigroup) Markovianity, linear response theory, Wigner-Weisskopf approximation, and rotating-wave approximation. Second, we derive an effective time-dependent decay theory and corresponding generalized quantum regression relations for an open quantum system linearly coupled to an environment. This theory covers all timescales and subsumes the Markovian and linear-response results as limiting cases. Finally, we apply our theory to the phenomenon of quantum friction.

Orientational Dependence of the van der Waals Interactions for Finite-Sized Particles.

Dispersion forces, especially van der Waals forces as interactions between neutral and polarizable particles act at small distances between two objects. Their theoretical origin lies in the electromagnetic interaction between induced dipole moments caused by the vacuum fluctuations of the ground-state electromagnetic field. The resulting theory well describes the experimental situation in the limit of the point dipole assumption. At smaller distances, where the finite size of the particles has to be taken into account, this description fails and has to be corrected by higher orders of the multipole expansion, such as quadrupole moments and so on. With respect to the complexity of the spatial properties of the particles this task requires a considerable effort. In order to describe the van der Waals interaction between such particles, we apply the established method of a spatially spread out polarizability distribution to approximate the higher orders of the multipole expansion. We thereby construct an effective theory for effects from anisotropy and finite size on the van der Waals potential.

Effective Polarizability Models.

Theories for the effective polarizability of a small particle in a medium are presented using different levels of approximation: we consider the virtual cavity, real cavity, and the hard-sphere models as well as a continuous interpolation of the latter two. We present the respective hard-sphere and cavity radii as obtained from density-functional simulations as well as the resulting effective polarizabilities at discrete Matsubara frequencies. This enables us to account for macroscopic media in van der Waals interactions between molecules in water and their Casimir-Polder interaction with an interface.

The role of transforming growth factor beta isoforms in tendon-to-bone healing.

The purpose of this study was to examine the role of two of the three transforming growth factor beta (TGF-ß) isoforms at the healing tendon-to-bone insertion. The supraspinatus tendons of 64 rats were transected at their bony insertions and repaired to the humeral head. One shoulder of each rat received an osmotic pump for sustained delivery of the following factors at the repair site: (1) TGF-ß1 and neutralizing antibodies to TGF-ß2 and 3 (TGF-ß1 group), (2) TGF-ß3 and neutralizing antibodies to TGF-ß1 and 2 (TGF-ß3 group), (3) neutralizing antibodies to TGF-ß1, 2, and 3 (anti-TGF-ß group), and (4) saline (saline group). The contralateral shoulders received saline to serve as paired controls. The repairs were evaluated at multiple time points postmortem using histology-based assays and biomechanical testing. Treated shoulders in the TGF-ß1 group showed increased type III collagen production compared to the paired control shoulders, indicative of a scar-mediated response. There was a trend toward reduced mechanical properties in the TGF-ß1 group, but these changes did not reach statistical significance. The anti-TGF-ß group showed no difference in tissue volume, but significantly inferior mechanical properties, compared to the paired control shoulders. The TGF-ß3 group did not show any differences compared to the paired control shoulders. Although TGF-ß isoforms play important roles in tendon-to-bone development and healing, application of exogenous TGF-ß isoforms and neutralizing antibodies to the subacromial space using osmotic pumps did not improve supraspinatus tendon-to-bone healing.

Decreased muscle loading delays maturation of the tendon enthesis during postnatal development.

Physical environment influences the development and maintenance of musculoskeletal tissues. The current study uses an animal model to explore the role of the physical environment on the postnatal development of the supraspinatus tendon enthesis. A supraspinatus intramuscular injection of botulinum toxin A was used to paralyze the left shoulders of mice at birth. The supraspinatus muscles of right shoulders were injected with saline to serve as contralateral controls. The supraspinatus enthesis was examined after 14, 21, 28, and 56 days of postnatal development. Histologic assays were used to examine fibrocartilage morphology and percentage osteoclast surface. Micro-computed tomography was used to examine muscle geometry and bone architecture. At 14 days there were no differences between groups in fibrocartilage formation, muscle geometry, bone architecture, or osteoclast surface. When comparing groups at 21, 28, and 56 days, muscle volume was decreased, fibrocartilage development was delayed, mineralized bone was decreased, and osteoclast surface was higher at each timepoint in the botulinum group compared to the contralateral saline control group. Our results indicate that the development of the tendon enthesis is sensitive to its mechanical environment. A reduction in muscle loading delayed the development of the tendon-to-bone insertion site by impeding the accumulation of mineralized bone. Physical factors did not play a significant role in enthesis maturation in the first 14 days postnatally, implying that biologic factors may drive early postnatal development.

Characteristics of the rat supraspinatus tendon during tendon-to-bone healing after acute injury.

Rotator cuff repair is known to have a high failure rate. Little is known about the natural healing process of the rotator cuff repair site, hence little can be done to improve the tendon's ability to heal. The purpose of this study was to investigate the collagen formation at the early repair site and to localize TGFbeta-1 and 3 during early healing and compare their levels to cell proliferation and histological changes. Bilateral supraspinatus tendons were transected and repaired in 60 rats. Specimens were harvested and evaluated at 0, 1, 3, 7, 10, 28, and 56 days. Histological sections were evaluated for cell morphology. Immunohistochemistry and in situ hybridization was performed to localize protein and mRNA for collagen types I and III and TGFbeta-1 and 3. Proliferating cell nuclear antigen (PCNA) assay was performed to measure cell proliferation, and cells were counted to determine cell density. Biomechanical properties were evaluated. Repair tissue demonstrated an initial inflammatory response with multinucleated cells present at 1 and 3 days, and lymphocytes and plasma cells presents at 7 and 10 days. Capillary proliferation began at 3 days and peaked at 10 days. Ultimate force increased significantly over the time period studied. Collagen I protein and mRNA significantly increased at 10 days, and reached a plateau by 28 and 56 days. Collagen III showed a similar trend, with an early increase, and remained high until 56 days. TGFbeta-1 was localized to the forming scar tissue and showed a distinct peak at 10 days. TGFbeta-3 was not seen at the healing insertion site. Cell proliferation and density followed the same trend as TGFbeta-1. A wound healing response does occur at the healing rotator cuff insertion site, however, the characteristics of the tendon after healing differ significantly from the uninjured tendon insertion site at the longest time-point studied. A distinctive collagen remodeling process occurred with an initial increase in the formation of collagen types I and III followed by a decrease toward baseline levels seen at time 0. Growth factor TGFbeta-1 was localized to repair tissue and coincided with a peak in cell proliferation and cellularity. Repair sites remained unorganized histologically and biomechanically inferior in comparison to previously described uninjured insertion sites.

Stimulation of insulin secretion reveals heterogeneity of pancreatic B cells in vivo.

We examined the immunofluorescence and ultrastructural changes of insulin-producing B cells in the center and at the periphery of islets of Langerhans during in vivo stimulation by glucose and glibenclamide. A decreased insulin immunostaining was detected in islets from the splenic rat pancreas after 1.5 h of glucose stimulation. By contrast, immunofluorescence changes became apparent in islets from the duodenal pancreas only after greater than 3 h of hyperglycemia. In both cases, the immunolabeling of central B cells decreased before that of peripheral B cells. Similar changes were seen following in vivo stimulation of insulin secretion by glibenclamide. At the ultrastructural level, hyperglycemia decreased the volume density of B cell secretory granules and increased that of rough endoplasmic reticulum and Golgi apparatus. These changes were also detected earlier in central than in peripheral B cells and earlier in splenic than in duodenal islets. The data show that B cells form a heterogeneous population in vivo.

Loss of insulin response to glucose but not arginine during the development of autoimmune diabetes in BB/W rats: relationships to islet volume and glucose transport rate.

The insulin and glucagon responses to 10 mM glucose and 10 mM arginine were studied in pancreata isolated from nondiabetic diabetes-prone and diabetes-resistant BB/W rats at 60, 80, and 140 days of age and in diabetic BB/W rats on the 1st and 14th days of their diabetes. In the former group the insulin response to glucose declined progressively with age (r = -0.575; P less than 0.01) and at 140 days was significantly below age-matched diabetes-resistant controls (P less than 0.05). The insulin response to arginine did not decline with age in either group. For diabetic rats, on the first day of the diabetes, the insulin response to glucose was absent but the response to arginine did not differ from nondiabetic controls. On day 14 responses to glucose and arginine were both absent. The glucagon response to arginine showed no trend despite a decline in baseline glucagon secretion. Endocrine tissue in nondiabetic diabetes-prone rats made up 0.8 +/- 0.2% of the pancreas at 60 days of age and 0.52 +/- 0.22% at 140 days of age; the latter was significantly less than in 140-day-old diabetes-resistant controls (P less than 0.05). In diabetic rats on the 1st and 14th days of diabetes endocrine tissue was 0.2 +/- 0.1% and 0.07 +/- 0.02%, respectively. The glucose transport rate in islets isolated on the first day of diabetes was profoundly reduced compared to age-matched nondiabetic diabetes-prone controls. Thus, a population of arginine-responsive, glucose-unresponsive islets with low glucose transport rates is present at the onset of overt diabetes in BB/W rats.

Beckwith-Wiedemann syndrome: a quantitative, immunohistochemical study of pancreatic islet cell populations.

The endocrine cell content of the pancreas of two cases of Beckwith-Wiedemann syndrome with islet cell adenomatosis were studied. Insulin, glucagon, somatostatin and pancreatic polypeptide cells were evaluated qualitatively and quantitatively with the indirect immunofluorescence method and morphometry was used to establish the volume density of the four endocrine cell populations. This evaluation showed a marked increase of insulin and glucagon cells and a lesser augmentation of pancreatic polypeptide cells and somatostatin cells. However, the percent of somatostatin cells was decreased in comparison with controls. Qualitatively, the two pancreas were characterized by the lack of segregation of glucagon and pancreatic polypeptide cells to distinct parts of the gland, with each cell type being abundant in the pancreatic region in which they are normally very sparse. The marked increase of endocrine cells often took the form of giant islet-like structures formed by smaller subunits; however, despite this increase, the distribution of insulin cells respected the normal pattern, i.e. clusters of B cells surrounded by non-B cells. These findings indicate that besides the proliferation of pancreatic endocrine cells maintaining a normal topographical distribution of B versus non-B cells, the pancreas of patients with the Beckwith-Wiedemann syndrome may have undergone abnormal development with a consequent lack of segregation of glucagon and pancreatic polypeptide cells to different parts of the gland.

A quantitative immunofluorescent study of the endocrine cell populations in the developing human pancreas.

The immunofluorescent cell content of the pancreas of 8--40-wk fetuses and of 1.5--5-mo Caucasian infants was quantitatively evaluated using anti-insulin, anti-glicentin, anti-glucagon, anti-somatostatin, and anti-pancreatic polypeptide antisera. The most significant findings are: (1) the pancreas of 8--10 wk fetuses contains a sizable population of endocrine cells reacting exclusively to anti-glicentin antiserum. This cell population decreases and disappears in later stages and is replaced by the adult type glucagon/glicentin immunoreactive cell; (2) the pancreatic polypeptide-rich region shows a lower relative endocrine cell content as compared with the glucagon-rich region and its islets appear smaller; (3) in the total pancreas, the relative (volume density) and absolute (microliter) insulin cell content increases regularly with age, while the relative volume of glucagon cells peaks in fetal life (wk 17--20) to decrease in infants, although remaining at higher levels than in adults; the relative and absolute volumes of somatostatin cells are elevated in fetal and infant stages studied where they represent the second most abundant cell type, while pancreatic polypeptide cells appear to least abundant cells during prenatal and infant life. These data show several differences with the pattern of the respective endocrine cell populations in the adult pancreas.

Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans.

The application of immunofluorescence technique with anti-insulin, anti-glucagon, anti-somatostatin, and anti-pancreatic polypeptide (PP) antisera to sections of precisely sampled regions of the human pancreas allowed the quantitative evaluation of the total content of these four endocrine cell populations in 13 nondiabetics, in 2 insulin-dependent diabetics (IDDM), and in 2 non-insulin-dependent diabetic subjects (NIDDM) of various age and sex. In nondiabetic subjects, PP-cells appear sex-related. Male individuals have a significantly greater volume of PP-cells than female. In diabetic subjects, the only marked difference as compared with nondiabetics is the reduction of insulin cell volume in IDDM. Other small differences between individual endocrine cell volumes are detectable in both IDDM and NIDDM as compared with nondiabetics, but their significance is at present unclear. The qualitative changes of islet structure accompanying insulin cell reduction in IDDM were not considered in the present study.

Glicentin precedes glucagon in the developing human pancreas.

A quantitative evaluation of immunofluorescence elicited by anti-insulin, anti-glucagon, anti-glicentin, anti-somatostatin and anti-pancreatic polypeptide antisera has been carried out in the pancreas of 5 human fetuses from 3.0 to 9.6 cm C.R. The data obtained indicate that while insulin and somatostatin-containing cells are approximately in similar proportions with respect to the other endocrine cell types in the five fetuses studied, the glucagon and glicentin immunoreactive cells and the pancreatic polypeptide cells are not : a) pancreatic polypeptide-containing cells increase in proportion as fetuses grow older; b) the youngest fetuses (3.0 to 4.3 cm C.R.) contain a high proportion of cells reacting to anti-glicentin antiserum only (GLI-cells) and a small proportion of cells stained both with the anti-glicentin and anti-glucagon antisera (GLI/GLU-cells). However, the latter cell type which stains similarly as the postnatal and adult pancreatic A-cell (GLI-cells are not detectable in the postnatal and adult pancreas) increases iin proportion in older fetuses, while the proportion of GLI-cells decrease. The data suggest that the definitive adult-type A-cell matures from a GLI-cell type which is not able to convert glucagon precursors GLI(s) into glucagon.