Multiple endocrine neoplasia type two B A case report with light and electron microscopic and immunohistochemical correlation

Purpose: To describe a case of multiple endocrine neoplasia type two B (MEN IIB) where ocular and systemic clinicopathological findings are correlated, in association with light and electron microscopic and immunohistochemical findings.
Methods: A 23-year-old man presented with mucosal neuromas of the lips, tongue and eyelids, a Marfanoid habitus and prominent corneal nerves. These findings led to the diagnosis of multiple endocrine neoplasia type two B. The patient subsequently developed phaeochromocytoma and metastatic medullary thyroid carcinoma (MTC) which led to his demise. Correlation of light and electron microscopic and immunohistochemical findings with the systemic and ocular findings is presented to emphasise the aggressiveness of MTC in MEN IIB. Clinicopathological correlation was obtained by examining the eyes post mortem.
Results and conclusions: Three new findings in MEN IIB have been established by this study. The enlarged corneal nerves can now be regarded as ganglioneuromas. Medullary thyroid carcinoma metastases were found in the choroid. Light and electron microscopic examination of the eye showed ganglioneuromas of the nerves in the limbus, trabecular meshwork, uveal tract and posterior ciliary nerves; this finding may account for the glaucoma occasionally seen in patients with MEN IIB.     

National public health information system

Information production and its communication being a key public health activity, developing modern information systems is a precondition for its fulfilling these assignments. A national public health information system (NPHIS) is a set of human resources combined with computing and communication technologies. It enables data linkage and data coverage as well as undertaking information production and dissemination in an effective, standardized and safe way. The Croatian Institute of Public Health LAN/WAN modules are under development. Health Safety System, Health Workers Registry, and Digital Library are among the Institute's developmental priorities. Communication between NPHIS participants would unfold over the Internet by using every relevant data protection method. Web technology-based applications would be run on special servers. Between individual applications, use would be made of the transaction module of communication through an exchange of the HL7 standard-based xml messages. In the conditions of transition, the health system must make an optimal use of the resources, which is not feasible without applying modern information and communication technologies.     

Plunging ranula

Saliva extravasation from the sublingual gland causes ductal lesion or obstruction and results in the formation of a ranula. It spreads through or behind the mylohyoid muscle situated on the neck. Most frequently it is located in the submandibular or submental region. The diagnosis of plunging ranula is simple if the signs of ranula are present in the intraoral cavity, whereas in case of a ranula localized on the neck definite diagnosis is made by histologic analysis of the pseudocyst that has been surgically excised in toto. Cases are presented of both types of plunging ranula treated by various surgical approaches. Plunging ranula in the submental region was treated by transoral approach, marsupialization and aspiration of the content, whereas the ranula in the submandibular region was treated by exterior cervical approach. In both cases, sublingual gland was removed. During the 3.5-year follow-up, neither recurrence of the disease in the neck area nor the occurrence of simple ranula in the intraoral region was observed.     

Immunomodulatory Effects of Dietary Polyphenols

Functional and nutraceutical foods provide an alternative way to improve immune function to aid in the management of various diseases. Traditionally, many medicinal products have been derived from natural compounds with healing properties. With the development of research into nutraceuticals, it is becoming apparent that many of the beneficial properties of these compounds are at least partly due to the presence of polyphenols. There is evidence that dietary polyphenols can influence dendritic cells, have an immunomodulatory effect on macrophages, increase proliferation of B cells, T cells and suppress Type 1 T helper (Th1), Th2, Th17 and Th9 cells. Polyphenols reduce inflammation by suppressing the pro-inflammatory cytokines in inflammatory bowel disease by inducing Treg cells in the intestine, inhibition of tumor necrosis factor-alpha (TNF-α) and induction of apoptosis, decreasing DNA damage. Polyphenols have a potential role in prevention/treatment of auto-immune diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis by regulating signaling pathways, suppressing inflammation and limiting demyelination. In addition, polyphenols cause immunomodulatory effects against allergic reaction and autoimmune disease by inhibition of autoimmune T cell proliferation and downregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), IL-1, interferon-γ (IFN-γ)). Herein, we summarize the immunomodulatory effects of polyphenols and the underlying mechanisms involved in the stimulation of immune responses.     

Role of the notochord in the development of cephalic structures in normal and anencephalic human fetuses

Summary Normal and anencephalic human conceptuses were analysed histologically to investigate the role of differentiation of the intracranial notochord and its relation to the formation of the basichondrocranium. We have examined 16 normal embryos and fetuses and 4 anencephalic fetuses. Each developmental stage of formation of the normal basichondrocranium presented specific morphological changes during the course of notochord depletion. In contrast with normal specimens, anencephalic fetuses presented malformations of the basichondrocranium which were always related to an abnormal position of the notochord. Macroscopical differences between craniorachischisis and cranioschisis in fetuses with anencephaly correlated with the existence of two histologically different degrees of malformation. In fetuses with craniorachischisis we found severe disturbances in the shape, position and ossification of the basichondrocranium and in the course of the intracranial notochord. In fetuses with cranioschisis the described disturbances of the basichondrocranium and intracranial notochord were mild. In addition, marked differences in affection of the central nervous system and the hypophysis were observed. These findings suggest different periods of dysmorphogenesis. Our results underline the importance of the chordal mesoderm in the differentiation for the formation of cephalic structures in Man.     

Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress,ethanol, indomethacin,and capsaicin neurotoxicity

Very recently, the integrity of capsaicin somatosensory neurons and their protection were suggested to be related to the activity in nociception of a newly discovered 15-amino acid peptide, BPC 157, shown to have strong beneficial effect on intestinal and liver lesions. Therefore, from this viewpoint, we have studied the gastroprotective effect of the pentadecapeptide BPC 157, on gastric lesions produced in rats by 96% ethanol, restraint stress, and indomethacin. The possible involvement of sensory neurons in the salutary actions of BPC 157 (10µg/kg, 10 ng/kg intraperitoneally) was studied with capsaicin, which has differential effects on sensory neurons: a high dose in adult (125 mg/kg subcutaneously, 3 months old) or administration (50 mg/kg subcutaneously) to neonatal animals (age of the 7 days) destroys sensory fibers, whereas a low dose (500µg/kg intraperitoneally) activates neurotransmitter release and protective effects on the mucosa. In the absence of capsaicin, BPC 157 protected gastric mucosa against ethanol, restraint, and indomethacin application. In the presence of neurotoxic doses of capsaicin, the negative influence of capsaicin on restraint, ethanol, or indomethacin lesions consistently affected salutary activity of BPC 157. However, BPC 157 protection was still evident in the capsaicin-treated rats (either treated as adults or as newborns) in all of these assays. Interestingly, after neonatal capsaicin treatment, a complete abolition of BPC gastroprotection was noted if BPC 157 was applied as a single nanogram-regimen, but the mucosal protection was fully reversed when the same dose was used daily. In line with the excitatory dose of capsaicin the beneficial effectiveness of BPC 157 appears to be increased as well. Taken together, these data provide evidence for complex synergistic interaction between the beneficial effectiveness of BPC 157 and peptidergic sensory afferent neuron activity.     

Measurement of cerebrospinal fluid formation and absorption by ventriculo-cisternal perfusion: what is really measured?

The generally accepted hypothesis on cerebrospinal fluid (CSF) hydrodynamics suggests that CSF is actively formed mainly by choroid plexuses, circulates unidirectionally along the brain ventricles and subarachnoid space, and is passively absorbed mainly into the dural venous sinuses. CSF formation rate (V_f) has been extensively studied using the ventriculo-cisternal perfusion technique and the results have been used as the key evidence confirming the mentioned hypothesis. This method and the equation for V_f calculation are based on the assumption that the dilution of the indicator substance is a consequence of the newly formed CSF, ie, that a higher CSF formation rate will result in a higher degree of dilution. However, it has been experimentally shown that the indicator substance dilution inside the CSF system does not occur because of a “newly formed” CSF, but as consequence of a number of other factors (departure of substances into the surrounding tissue, flowing around the collecting cannula into the cortical and spinal subarachnoid space, departure into the contralateral ventricle, etc). This technique allows “calculation” of the CSF formation even in dead animals, in an in vitro model, and in any other part of the CSF system outside the ventricles that is being perfused. Therefore, this method is indirect and any dilution of the indicator substance in the perfusate caused by other reasons would result in questionable and often contradictory conclusions regarding CSF formation rates.According to the classic hypothesis of cerebrospinal fluid (CSF) physiology, CSF is actively formed inside the brain ventricles, after which it flows unidirectionally along the subarachnoid spaces (SAS) to be absorbed into the venous sinuses across the arachnoid villi and/or via the paraneural sheaths into the lymphatics (1-8). Thus, CSF physiology is based on three key premises: 1) active CSF formation (secretion; V_f) inside the brain ventricles mainly by choroid plexuses; 2) passive CSF absorption (V_a) mostly into the venous sinuses on the brain surface via the villi arachnoidales; and 3) unidirectional CSF flow from the site of formation to the site of absorption. This hypothesis has so far been presented as a proven fact in all textbooks and review articles.According to the classic hypothesis, it is unquestionable that in physiological conditions CSF secretion and absorption inside the CSF space are balanced:V_f = V_a [1]In other words, the secreted CSF volume (inside brain ventricles) has to be the same as the passively absorbed CSF volume (into the venous sinuses and/or lymphatics). If this is not so, a pathological state may occur (eg, hydrocephalus). The same is true for the CSF flow (circulation; Q_CSF). Namely, CSF secretion and absorption take place at different CSF system sites, and therefore, the flow rate (Q_CSF) between these two sites has to be of the same magnitude to keep V_f equal to V_a.V_f = Q_CSF = V_a [2]Thus, CSF secretion changes should be passively followed by CSF flow and absorption changes, in order to maintain the physiological state inside the CSF system. We can conclude from this that active CSF secretion is the main generator of the CSF circulation, to maintain the physiological CSF volume (9). Therefore, it is extremely important to use a precise and reliable method for CSF formation measurement.However, based on our experimental results, we have recently seriously brought into question the plausibility of this, a nearly hundred-year-old, classic CSF physiology hypothesis, and have suggested a new one (9-16). According to this new hypothesis, interstitial fluid (ISF) and CSF are created by water filtration through the arterial capillary walls across the entire central nervous system (CNS). At the same time, plasma osmolytes are being accumulated inside the capillaries, which generates osmotic counterpressure crucial for the process of ISF/CSF water absorption into the venous capillaries and postcapillary venules. Thus, we can conclude that osmotic and hydrostatic forces are the main factors in the regulation of ISF-CSF volume. If we have in mind the fluid exchange capacity, it is reasonable to say that the choroid plexuses are less likely to be a relevant site for this process, and that this is probably the role of cerebral and spinal capillaries. A constant substances exchange takes place between the CSF system and the adjacent tissue. This process is under influence of pathophysiological conditions inside the CSF compartments. Therefore, CSF secretion cannot take place in only one of these compartments (brain ventricles), and this is also unlikely to be the case with absorption (predominantly inside the cortical subarachnoidal space). This hypothesis (9-11) has recently been tested by water influx into the CSF in aquaporin-1, aquaporin-4 knockout, and wild-type mice using a newly developed water molecular MRI technique based on JJ vicinal coupling between ¹⁷O and adjacent protons, and water molecules proton exchange (17). The findings have strongly supported the new hypothesis that water movement within the pericapillary spaces, rather than within choroid plexuses and arachnoid villi, is essential for CSF homeostasis.The recent understanding of CSF physiology has been developed from the quantitative utilization of the ventriculo-cisternal perfusion method. Since other methods have mainly been abandoned, or are used very rarely (9), the aim of this article is primarily to reevaluate the ventriculo-cisternal perfusion method, which is today the only generally accepted method used for determination of the CSF formation rate (18,19). This method produced experimental results that were used to confirm the classic CSF physiology hypothesis and therefore represent its foundation. The method has been considered to be a precise physiological approach for studying cerebrospinal fluid secretion (18), and Cutler et al (19) have concluded that: “Important advances in understanding of cerebrospinal fluid physiology have been made since the introduction of a method for perfusion of the Pappenheimer et al (20). This technique has permitted accurate measurement of both the rate of formation and rate of absorption….” Although the method itself still represents the headstone of the classic CSF physiology hypothesis, the question is whether the situation is the same after fifty years, and whether the method can withstand criticism of new scientific results. This question will be thoroughly analyzed further in the article.