Structure-activity relationship of quaternary acetylcholinesterase inhibitors - outlook for early myasthenia gravis treatment.

Myasthenia gravis is a rare autoimmune neuromuscular junction disorder mainly caused by antibodies being targeted against the muscle acetylcholine receptors (AChRs). The loss of AChRs leads to a defect in neuromuscular transmission resulting in muscle weakness and fatigue. Although once an often fatal illness, Myasthenia gravis can now be well managed with relatively safe and effective treatments. However, the severe myasthenic cases associated with thymus tumors remain often fatal exception in the management of the disease. The early treatment includes the use of acetylcholinesterase inhibitors (AChEI) which enhance neuromuscular transmission. To ensure a peripheral effect, charged molecules are used, particularly quaternary ammonium salts. The structure of AChEIs has been continuously modified to obtain the optimal ratio between AChE inhibition and potential side-effects. This review summarizes progress in the use of quaternary compounds as AChE inhibitors in vitro with respect to their structure and inhibitory ability. Namely, carbamic acid esters, piperidinium and pyridinium salts, bisquaternary pyridinium salts and heterogeneous quaternary inhibitors are all discussed. Among data found in the literature, many compounds have shown promising inhibition of AChE when compared to commercial standards (pyridostigmine, neostigmine). Besides a promising inhibitory ability, selectivity for AChE versus butyrylcholinesterase (BChE) for the most potent compounds (sub-nanomolar IC(50)) was also identified.

Synthesis of (2E)-2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl)prop-2-enoic acid (VUFB 20609) and 2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl)propanoic acid (VUFB 20584) as potential antileukotrienic agents.

The syntheses of (2E)-2-methyl-3-(4-([4-(quinolin-2-ylmethoxy)phenyl]sulfanyl)phenyl) prop-2-enoic acid (VUFB 20609) and racemic 2-methyl-3-(4-([4-(quinolin-2-ylmethoxy) phenyl]sulfanyl)phenyl)propanoic acid (VUFB 20584) as new potential antileukotrienic drugs are described. Due to a low reactivity of the 4-substituted aryl bromides (coupling of the 4-substituted aryl bromides do not provide an activating functional group with 4-methoxybenzene-1-thiol), special conditions, in particular specific heterogeneous copper catalysts, were used. Catalytic hydrogenation of the conjugated double bond on Pd/C in the presence of the sulfanyl group is discussed. In-vitro cytotoxicity testing was performed using a microplate colorimetric acid phosphatase assay. Antiplatelet activity was evaluated using an in-vitro test in human platelet-rich plasma. Some substances inhibited arachidonic acid-induced platelet aggregation.

Hormonal profile of men with premature balding.

OBJECTIVE: Premature androgenic alopecia has been suggested as a feature of the male equivalent of the syndrome of polycystic ovary. However, the hormonal pattern of men with premature balding has been investigated in only a few studies with inconsistent results. MATERIAL AND METHODS: We examined 37 men with premature balding (defined as frontoparietal and vertex hair loss before the age of 30 years with alopecia defined as grade 3 vertex or more on the alopecia classification scale of Hamilton with Norwood modification). The plasma concentrations of total testosterone, dihydrotestosterone, epitestosterone, androstenedione, cortisol, 17-OH-progesterone (17OHP), estradiol, LH, FSH, prolactin, SHBG and TSH and free thyroxine were measured. RESULTS: The frequency of subnormal values in SHBG, FSH, testosterone and epitestosterone (but not in free androgen index) was significant in the balding men. A borderline significant trend was recorded with respect to increased levels in 17OH-P and prolactin. CONCLUSIONS: The hormonal pattern of a substantial number of men with premature balding resembles in some respects the hormonal pattern of women with polycystic ovary syndrome.

[Proportion of fungi among isolated microorganisms from blood of patients treated in the teaching departments of The University Hospital in Cracow in 1993-1998]. / Udzial grzybów wsród drobnoustrojów izolowanych ze krwi chorych leczonych w oddzialach klinicznych Szpitala Uniwersyteckiego w Krakowie w latach 1993-1998.

The study was carried out of 9742 blood cultures obtained in 1993-1998 from patients of selected departments of the University Hospital. The received samples were assessed from the standpoint of the participation of fungi strains of clinical importance as aetiological factors in systemic infections and the resistance status of a selected group of pathogens. Microbiological blood studies were conducted in the system of continuous monitoring of the obtained cultures by means of the automatic ATB system using a commercially available ID 32C set. ATB Fungus tests were used for drug resistance assessment. In all, 95 strains of yeasts (5.1%) were obtained in cultures, and an increasing variety of these pathogenic species was noted in sepsis. A systematic reduction was noted in the proportion of C. albicans and a steep rise of C. parapsilosis were observed among the aetiological factors of generalized nosocomial fungal infections. A tendency was noted for a continuous rise in the frequency of invasive candidemias with a most significant rise in their proportion in patients in general surgery and haematology departments. Among the fungi isolated from septic complications the proportion of strains resistant to antifungal drugs has been rising.

Neurocysticercosis and oncogenesis.

Recent studies suggest that neurocysticercosis may be a risk factor for human cancer. Pathogenetic mechanisms explaining possible oncogenic effects of cysticerci include the following: (a) parasite-induced modulation of the host immune response that may be associated with loss of regulatory mechanisms implicated in the immunological surveillance against cancer; (b) transfer of genetic material from the parasite to the host, causing DNA damage and malignant transformation of host cells, and (c) chronic inflammation with liberation of nitric oxide and inhibition of tumor suppressor genes. Further research is needed to confirm the potential role of cysticercosis in the development of cancer. These studies should determine the presence of cysticercotic factors responsible for the transfer of genetic material and potential mutations in the tumor suppressor genes in proliferating astrocytes surrounding cysticercotic lesions. Additionally, the complex interaction between the immune state of the host with variable cytokine release and the presence of inflammatory cells releasing nitric oxide that cause DNA damage and impair tumor suppressive mechanisms needs to be investigated.

Clonal VDJ recombination of the immunoglobulin heavy chain gene by PCR in classical Hodgkin's disease.

Although Hodgkin's disease (HD) has been a subject of much investigation, fundamental questions remain unanswered regarding its lineage and clonality. The authors used a polymerase chain reaction (PCR) technique to investigate whether clonal Variable-Diversity-Joining recombination of the immunoglobulin heavy (IgH) chain gene, a phenomenon that characterizes clonal B-cell proliferations, exists in nodular sclerosing (NSHD) and mixed cellularity (MCHD) Hodgkin's disease (so-called "classical" Hodgkin's disease). The isolation of DNA from paraffin-embedded tissue sections allowed for direct correlation of PCR results with the cell populations that were analyzed. Thirty-two cases were studied. These included 12 cases in which the Reed-Sternberg (RS) cells expressed the B-cell antigen, CD20, and 10 cases that were classified as syncytial variant of NSHD (3 CD20+, 7 B-cell antigen negative). Overall, clonal patterns of VDJ PCR products were found in 14 of 32 (44%) cases. These clonal patterns were identified in 7 of 12 (58%) cases of CD20+ classical HD and in 7 of 20 (35%) cases of B-antigen-negative classical HD. Clonal patterns were found in 3 of 10 cases of syncytial variant of NSHD, including 2 of 3 (67%) CD20+ cases and 1 of 7 (14%) B-cell antigen-negative cases. The results of this study provide support that a subset of HD represents a clonal B-cell neoplasm, and indicate that clonal IgH VDJ sequences are more frequently found in CD20+ HD.

Virus-associated hemophagocytic syndrome characterized by clonal Epstein-Barr virus genome.

Virus-associated hemophagocytic syndromes are a heterogeneous group of disorders in which viral infection is associated with a proliferation of hemophagocytic histiocytes throughout the reticuloendothelial system. The authors report the case of a 24-year-old Vietnamese male who developed a hemophagocytic syndrome associated with Epstein-Barr virus (EBV) and who died following a rapidly progressive course. A proliferation of reactive-appearing lymphoid cells was associated with an extensive proliferation of erythrophagocytic histiocytes. Immunophenotypically, the lymphoid infiltrate consisted of CD56+ natural killer cells, predominantly CD8+ T-cells and rare B-cells (CD20+). Double-label immunohistochemical studies showed CD3+ T-cells and CD56+ natural killer cells to be distinct cell populations. Combined immunohistochemical-in situ hybridization studies localized EBV to CD43+, CD3-, CD68-, lymphoid-appearing cells, indicating the presence of EBV within natural killer cells. Southern hybridization analysis of EBV genomic termini revealed clonal EBV genome. However, there was no detectable immunoglobulin or T-cell receptor gene rearrangements. The findings indicate that this case of hemophagocytic syndrome represents a clonal proliferation of natural killer cells containing EBV and highlights the importance of the analysis of EBV genomic termini for determination of clonality in EBV-associated proliferations. It is possible that other cases of fulminant EBV-associated hemophagocytic syndromes represent clonal natural killer cell proliferations.

Prognostic value of beta human chorionic gonadotrophin in blood serum of patients with urinary bladder tumours.

Beta human chorionic gonadotrophin levels have been assessed in blood serum of 79 patients with bladder tumours before and seven days after transurethral electroresection (TUR). With the growth grade of anaplasia and staging the mean serum beta HCG level increased. Beta HCG was a good biological marker to differentiate between superficial and deep tumours.

Clustered mutations in the second exon of the MYC gene in sporadic Burkitt's lymphoma.

The primary tumors from 15 untreated patients with Burkitt's lymphoma were analysed for abnormalities in the coding region of the MYC gene by single stranded conformational polymorphism (SSCP) analysis followed by DNA sequencing. Fourteen of the 15 tumors had one or more clonal mutations. Forty one mutations were found in the second exon; only one occurred in the third exon. Seven tumors had mutations that clustered in a region spanning amino acids 38-63. Four of these possessed mutations that altered prolines at positions 57 (3), 60 (1), and 63 (1). Seven tumors were mutated in the central portions of the second exon. These occurred at position 95 (2), position 115 (2), position 137 (1), and position 138 (3). Analysis of the published sequences from five lymphoma cell lines and one primary tumor showed a similar clustering of mutations, with all six having mutations in codons between positions 38-63. The regions where mutations occurred have been associated with a variety of properties, including transcriptional activation and cellular transformation. The number and location of mutations showed no correlation with either chromosome 8 or chromosome 14 breakpoints or with the Epstein-Barr virus positivity of the tumors. This unexpected, frequent occurrence of clustered mutations in the second exon of the MYC gene suggests a role for the mutated MYC proteins in the pathogenesis of Burkitt's lymphoma, possibly through altered interactions of this domain with other cellular factors.

A trial of isolating a tumor-like form of pulmonary cavities infected with aspergilli. II. Intra- and postoperative, morphologic and serologic data.

In ten specimens of resected pulmonary tissue, a little known and underscribed form of aspergillosis called tumor-like blocked pulmonary cavity with liquid content infected with aspergilli was observed. This designation was based on the finding in the specimens of tumor-like cavitary structures with blocked bronchus and contents from which abundant growth of aspergillus fumigatus was invariably obtained in cultures. Nine of the ten specimens were bronchiectasis, and one was a bronchogenic cyst. The scant literature was review, emphasizing features characteristic of this form of mycetoma and differences from the typical and frequently encountered form of ordinary pulmonary aspergilloma. The serologic response and its long duration were attributed to biological properties of aspergilli in this form caused by inaccessibility of oxygen and by occlusion of the bronchial lumen.