Profile of in Vitro Binding Affinities of Neuroleptics at Different Rat Brain Receptors: Cluster Analysis Comparison with Pharmacological and Clinical Profiles

A series of 21 neuroleptics with different chemical structures (phenothiazines, thioxanthenes, dibenzodiazepines, butyrophenones, benzamides, etc.) was examined for their in vitro interactions with 12 neurotransmitter binding sites in the rat brain (alpha- and beta-noradrenergic, dopaminergic, muscarinic, serotoninergic, histaminic, and opioid receptors, calcium channels, and serotonin uptake binding sites). The biochemical profile obtained from the binding data was compared with reported pharmacological and clinical profiles for this class of compounds by cluster analysis. Cluster analysis on binding data classified the compounds in three main subgroups: benzamides, compounds with an affinity mainly for DA2 and 5-HT2 receptors and inactive at muscarinic receptors, and compounds with a high affinity for alpha 1-adrenergic receptors and muscarinic receptors. The main subgroups resulting from cluster analysis of previously published pharmacological and clinical data for neuroleptics contain compounds common to the present study, with some correlations. The results extend previous observations that a complete binding profile corresponds to the pharmacological and clinical profile of this class of compounds.     

The potential role of lonidamine (LND) in the treatment of malignant glioma

Summary Up-to-date unsatisfactory results obtained in multimodality treatments of malignant glioma have prompted the research of new therapeutic modalities with unconventional modes of action. Lonidamine (LND) is a drug which reduces aerobic glycolytic activity in both human and experimental tumors. This effect mainly depends on the inhibition of mitochondrially-bound hexokinase (HK) which is present in large amounts in malignant cells. A Phase II study was conducted on patients with recurrent glioma; 12 patients were admitted to the study. Clinical side effects were moderate, necessitating a reduction of the dosage in only 1 case. The objective results were evaluated according to the indications of Levin. 2 responders and 3 cases of stable disease were observed out of 10 evaluable patients. The potential value of this new drug is discussed.     

Recombination does not generate pinworm susceptibility during experimental crosses between two mouse subspecies

The susceptibility to Aspiculuris tetraptera of European Mus musculus hybrids is thought to reflect the disruption of genomic co-adaptation through recombination of the parental genomes. Here, we compared the susceptibility to this parasite between parents and experimental hybrids (intersubspecific until F4, intrasubspecific F1, F2) to clarify the contributions of heterosis and subspecies incompatibility. F1 showed hybrid vigor. Unlike intrasubspecific F2, intersubspecific F2 were less resistant than F1, but revealed no increased susceptibility relative to the parents. Intersubspecific F3 and F4 showed the same hybrid vigor as F1. Heterosis contributed most to the resistance, but the differences between intra- and intersubspecific F2 suggested genomic incompatibilities between subspecies. However, the susceptibility did not increase through the recombination process, showing that disruption of co-adaptation does not directly affect resistance. Even if previous studies still support the selective role of parasites in the current hybrid zone, an alternative hypothesis on the origin of hybrid susceptibility is warranted.     

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients

Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio‐facio‐cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r‐FLACC, Wang‐Baker scale, NPSI, BPI, NCCPC‐R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs‐QL, SF‐36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscle‐skeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level.     

A severe form of amyloidotic polyneuropathy in a Costa Rican family with a rare transthyretin mutation (Glu54Lys)

Four affected siblings in a Costa Rican family presented an aggressive polyneuropathy with widespread involvement of many visceral organs and onset during the third decade of life with rapid loss of muscle mass in the lower limbs and severe dysautonomy. The medical histories include vitreous opacity, cardiac enlargement, dermal and gastrointestinal infiltration, and autonomic dysfunction including circulatory compromise and gastrointestinal disturbances. Histological studies using Congo red stain and immunohistochemical assays with antibodies against the transthyretin (TTR) protein showed widespread deposition of amyloid in extracellular areas, including dermis and gastrointestinal lamina propia, endo- and perineural spaces, and vascular walls. A mutation search in the transthyretin (ttr) gene was performed seeking the cause of this severe form of familial amyloidotic polyneuropathy (FAP). We applied single-stranded conformational polymorphism (SSCP)-analyses followed by sequencing of the four exons of the ttr gene, revealing a point mutation in exon 3, a G to A transition that causes a Glu54Lys codon change. Western blots of plasma proteins incubated with anti-transthyretin antibodies after gel electrophoresis provided separation of wild-type and mutant TTR protein in affected family members.     

Metastatic Psammomatous Somatostatinoma of the Pancreas Causing Severe Ketoacidotic Diabetes Cured by Surgery

A case of somatostatin-producing pancreatic tumor associated with severe insulindependent diabetes mellitus and ketoacidotic coma is reported. The tumor, a 10-cm expansile mass arising from the pancreatic tail of a 70-yr-old woman, was first detected by ultrasonography, performed because of abdominal pain, and subsequently confirmed by computed tomography and fine-needle tumor aspiration. Pathologic investigation showed a predominatly solid-trabecular structure with scattered microacini and psammomatous bodies. A large proportion of tumor cells expressed somatostatin and/or calcitonin. Following resection of the primary tumor and three peripancreatic lymph nodes with metastases, the patient recovered rapidly from her diabetic syndrome and remained in substantially good health during a subsequent 8-yr follow-up period, without evidence of tumor recurrence.     

Hepatic Function and Fibrinolysis in Patients with Hereditary Angioedema Undergoing Long-Term Treatment with Tranexamic Acid

Prophylactic treatment with antifibrinolytic agents, epsilon-aminocapriod and tranexamic acid, reduces the incidence and severits of attacks in patients with hereditary angioedema. Long-term ellectivenessor risk of antifibrinolytic agents has not been established. Sixteen patients needing continuous prophylaxis because of frequency and severity of attacks were treated with tranexamic acid. In four patients this treatment was ineffective and the drug was withdrawn after 2 months. A remission or reduction in the frequency or serverity of attacks was observed in 12 patients treated for a period ranging from 8 to 34 months. Hepatic tests and blood fibrinolytic activity were not influenced by long term oral treatment with tranexamic acid.     

Effect of sulglycotide treatment on cell kinetics alterations induced by aspirin in humans

The effect on gastric epithelial cell proliferation of small doses of aspirin was evaluated in 9 healthy volunteers, with or without administration of sulglycotide, a sulfated glycopeptide with cytoprotective properties. Cell kinetics study was performed by incubation of gastric biopsies with bromodeoxyuridine (BrdU) and immunohistochemistry. A decrease of BrdU-labeling index and a shortening of the height of gastric columns were observed after treatment with aspirin and placebo. No variations were observed after treatment with aspirin and sulglycotide. A decrease of the epithelial cell renewal could be one of the damaging effects of aspirin on the gastric mucosa. The treatment with sulglycotide seems to be effective to prevent this alteration.     

Administration of ciprofibrate to lactating mothers induces PPARα-signaling pathway in the liver and kidney of suckling rats

It is well known that the hypolipidemic drug ciprofibrate induces peroxisome proliferation in rodent liver, which in turn leads to the oxidative stress, and modifies some parameters related to cell proliferation and apoptosis. The administration of ciprofibrate to rats during the lactating period determined in their pups significant modifications in hepatic peroxisome enzyme activities, induction of the PPARalpha-target gene, Cyp4a10, and perturbation in cell proliferation and apoptosis, which affected the size of the liver. Moreover, this modification was associated to about two-fold induction of mRNA-PPARalpha. On the contrary, in the kidney, although a similar two-fold up-regulation of PPARalpha was detected, the induction of both peroxisomal enzyme activities and Cyp4a10 were weak, and no alterations were detected, neither in cell cycle nor in the size of the tissue. Our results indicate that the response to ciprofibrate is stronger in the liver than in the kidney of newborn rats.