Prekallikrein (PK), a zymogen of the contact system, and its activation products, kallikrein (KAL), KAL-inhibitor complexes and fragments containing KAL epitope(s) have been detected in human plasma by immunoblotting with a monoclonal anti-human plasma PK antibody, MAb 13G11. Detection of antigen-MAb 13G11 complexes with peroxidase-conjugated anti-IgG showed that the two variants of PK (85- and 88-kDa) are the only major antigen species in normal, non-activated plasma. Upon plasma activation with kaolin, the intensity of the PK bands decreased with formation of complexes of KAL with C1 inhibitor (C1 INH) and alpha 2-macroglobulin (alpha 2 M) identical to those formed by the purified proteins. Immunoblots of normal plasma showed good correlation between the PK detected and the amount of plasma assayed. Increasing amounts of KAL incubated with a constant volume of PK-deficient plasma showed increasing amounts of KAL and of KAL-C1 INH and KAL-alpha 2 M complexes. Complexes of KAL-antithrombin III (ATIII) and the ratio of KAL-alpha 2 M/KAL-C1 INH were higher in activated C1 INH-deficient plasmas than in activated normal plasmas. Protein resolution by 3-12% gradient SDS-PAGE and epitope detection with [125I]MAb 13G11 showed four KAL-alpha 2 M species and a 45-kDa fragment(s) in both surface-activated normal plasma and complexes formed by purified KAL and alpha 2 M. Immunoblots of activated plasma also showed bands at the position of KAL-C1 INH and KAL-ATIII complexes. When alpha 1-antitrypsin Pittsburgh (alpha 1-AT. Pitts) was added to plasma before activation, KAL-alpha 1-AT. Pitts was the main complex.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

Ovarian inhibins (INH) are hormones participating in the regulation of gametogenesis. We monitored inhibin A and B levels in serum (S) and follicular fluids (FF), depending on the type of fertility failure and treatment outcome.

METHODS

We examined INHA and B levels in S and FF of 72 women undergoing ovarian stimulation for in vitro fertilization, including embryo transfer We took serum samples at the time of egg collection (S1), embryo transfer (S2), and diagnostics of early pregnancy (S3). FF samples were obtained during egg collection. INH A and B levels were measured by ELISA set kit in all media.

RESULTS

Healthy women had median of INHA S1 592.02pg/ml INHA S2 593.58pg/ml, INHA S3 15.17pg/ml and INH B S1 242.46pg/ml, INH B S2 and INH B S3 zero levels. Women with ovarian disorders had significantly lower levels of INH A S1 and INH A S2 (p<0.05). Women with polycystic ovaries had significant higher INH B S2 levels (p<0. 05). No statistically significant differences were found in women with endometriosis. Presence of oocyte in the dominant follicle positively correlated with INH B FF levels (p<0.05).

CONCLUSIONS

WE confirmed differences in the levels of inhibins in sera depending on type of fertility failure. Inhibin B better reflected the presence of an oocyte. The potential paracrine role of inhibins needs to be examined to improve preparation for the in vitro fertilization treatment (IVF).

The carbon-centered isonicotinic acyl radical of isoniazid (INH), a widely-used frontline anti-tuberculosis drug, has been considered to play a critical role in inhibiting Mycobacterium tuberculosis, but not fully identified. Here we show that this radical intermediate can be unequivocally characterized by complementary applications of ESR spin-trapping and HPLC/MS methods by employing N-tert-butyl-α-phenylnitrone (PBN) as the suitable spin-trapping agent, which can form the most stable radical adduct. More importantly, for the first time, analogous carbon-centered acyl radicals and their respective NAD⁺ adducts have also been detected and identified from its two isomers (nicotinic acid hydrazide and 2-pyridinecarbohydrazide) and benzhydrazide which are structurally-related to INH, but not by 2-chloroisonicotinohydrazide. This study represents the first unequivocal identification of the carbon-centered acyl radicals of INH and other hydrazide analogs by both ESR spin-trapping and HPLC/MS methods, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.

At present, isoniazid (INH) is being used prophylactically to reduce the side effects of intravesical BCG therapy for superficial bladder cancer, although it is not clear whether or not this reduces the antitumor efficacy of BCG. In this study the impact of INH treatment on the immune response after repeated intravesical BCG administration was investigated in guinea pigs. INH was given during 3 days starting on the day prior to the BCG administration. It was found that the administration of INH severely impaired the immunological effects of BCG. The induction of mononuclear cell infiltration in the bladder wall was reduced. Enlargement of the regional lymph nodes (weight and number of cells), and increase of Major Histocompatibility Complex (MHC) class II expression on the lymph node cells, normally observed after intravesical BCG administration, were inhibited by INH. Systemic immunity, measured by the DTH reaction in the skin to PPD, was also diminished due to the combined treatment of BCG with INH. A five-fold increase of the dose of BCG did not overcome the effect of INH. INH probably did not exert a direct suppression of the immune system of the guinea pig as the DNCB skin reactivity was not influenced. Although INH concentrations in the urine were high at the onset of the instillation, in vitro experiments indicated that the effect of INH was probably not caused by killing of the BCG organisms shortly after application in the bladder. In conclusion, our data in guinea pigs suggest that the use of INH may impair the immune response to intravesical BCG. As this response may be important for the antitumor effect of BCG, urologists should be cautious with the prophylactic use of INH. The influence on the antitumor efficacy is now investigated in man.

BACKGROUND

Tuberculosis occurrence was evaluated in patients that applied tuberculosis chemoprophylaxis and currently receiving tumor necrosis factor-alpha (TNF-α) blocker.

METHODS

Incidence of tuberculosis were retrospectively evaluated in patients that currently receiving TNF-α-blocking therapy and received tuberculosis chemoprophylaxis at Ankara Numune Education and Research Hospital, Lung Disease Department, between 2006-2013 years. 134 patients that were diagnosed with rheumatologic and dermatologic diseases, were evaluated. Patients were in the age range 18-80 years. Age, gender, smoking status, BCG vaccination, chest radiography, diagnose of disease, presence of concomitant disease, tuberculosis story, PPD value, chemoprophylaxis acquisition, which anti-tuberculosis agents received, duration of chemoprophylaxis, duration of TNF-α blocker, other immunosuppressive using were measured.

RESULTS

Rheumatologic diseases were often. Prophylaxis has given at 73.9% of patients. Patients with received anti-TNF-α therapy (n= 134) have not developed pulmonary or extra-pulmonary tuberculosis disease.

CONCLUSIONS

Patients with received anti-TNF-α therapy, are scanned with TST or Quantiferon. If latent tuberculosis infection are diagnosed, tuberculosis prophylaxis should be started pre-anti-TNF-α therapy at least one month and INH chemoprophylaxis should be completed on 9 months or RIF should be completed on 4 months. Serum liver enzymes and bilirubin measurements monthly; follow-up physical examination and chest radiography should be performed for 3 months.

BACKGROUND

The use of anti-TNF drugs for rheumatic diseases has increased in recent years. Several studies have reported an increased risk of reactivation of tuberculosis (TB) with anti-TNF agents.

OBJECTIVE

The aim of this study was to present the follow-up results of a single center from Turkey, a country with a high rate of active and latent tuberculosis infection (LTBI), for INH chemoprophylaxis in patients receiving anti-TNF-α therapy for rheumatic diseases infection.

METHODS

In this prospective observational study, consenting patients who were to be administered an anti-TNF agent for a rheumatic disease were evaluated for the presence of active infection or LTBI by a chest X-ray and a tuberculin skin test. Patients with LTBI were given chemoprophylaxis 1 month prior to commencement of anti-TNF treatment. All patients were followed-up bimonthly for any signs of pulmonary or extrapulmonary TB.

RESULTS

A total of 73 patients, 23 female (31.5 %) and 50 male (68.5 %), with a mean age of 41.0 ± 13.1 years (18-78) were enrolled in the study. Overall, 44 patients (60.3 %) had ankylosing spondylitis, 18 (24.7 %) had rheumatoid arthritis, 7 (9.6 %) had juvenile rheumatoid arthritis, and 3 (4.1 %) had psoriatic arthritis. LTBI was identified in 58 patients all of whom received chemoprophylaxis for 9 months. None of the patients in the study developed any signs of tuberculosis reactivation during follow-up.

CONCLUSIONS

TST is a reliable and cost-effective method for the diagnosis of LTBI in patients prior to anti-TNF therapy. Moreover, chemoprophylaxis with INH seems to be effective for the prevention of TB reactivation in individuals with LTBI.

One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal alpha-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure-activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR. Here, we present the effect of GPact-11a on CFTR activity using in vitro (iodide efflux, fluorescence imaging and patch-clamp recordings), ex vivo (short-circuit current measurements) and in vivo (salivary secretion) experiments. We report that GPact-11a: 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulates ex vivo the colonic chloride secretion and increases in vivo the salivary secretion in cftr(+/+) but not cftr(-/-) mice; and 4) is selective for CFTR because its effect is inhibited by CFTR(inh)-172, GlyH-101, glibenclamide and GPinh-5a. To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis.

<Abstr<em>a</em>ctText>Perin<em>a</em>t<em>a</em>l diethylstilbestrol (DES) tre<em>a</em>tment induces the polyovul<em>a</em>r follicle cont<em>a</em>ining two or more oocytes in <em>a</em> follicle of mouse ov<em>a</em>ry through estrogen receptor (ER) β. The <em>a</em>im of the study w<em>a</em>s to investig<em>a</em>te the direct effects of DES on the neon<em>a</em>t<em>a</em>l mouse ov<em>a</em>ry <em>a</em>nd the gene expression of <em>a</em>ctivins.</Abstr<em>a</em>ctText><Abstr<em>a</em>ctText>Ov<em>a</em>ries from neon<em>a</em>t<em>a</em>l wild-type (WT) or ERβ- knockout (ERβKO) mice were org<em>a</em>n-cultured in <em>a</em> serum-free medium with or without DES, <em>a</em>nd polyovul<em>a</em>r follicle induction <em>a</em>nd expression of <em>a</em>ctivin sign<em>a</em>ling rel<em>a</em>ted genes were ex<em>a</em>mined.</Abstr<em>a</em>ctText><Abstr<em>a</em>ctText>The polyovul<em>a</em>r follicle <em>a</em>nd cyst incidence in DES-tre<em>a</em>ted org<em>a</em>n-cultured ov<em>a</em>ries from WT mice, but not from ERβKO mice, w<em>a</em>s signific<em>a</em>ntly higher th<em>a</em>n th<em>a</em>t of control non-tre<em>a</em>ted cultures. DES <em>a</em>ltered inhibin (<em>Inh</em>) <em>a</em>, <em>Inh</em>b<em>a</em> <em>a</em>nd <em>Inh</em>bb expression in org<em>a</em>n-cultured ov<em>a</em>ries from C57BL/6J mice, while no ch<em>a</em>nge in <em>Inh</em><em>a</em> <em>a</em>nd <em>a</em>n incre<em>a</em>se of <em>Inh</em>bb were observed by DES, in both WT <em>a</em>nd ERβKO mice.</Abstr<em>a</em>ctText><Abstr<em>a</em>ctText>Alter<em>a</em>tions in <em>a</em>ctivin sign<em>a</em>ling <em>a</em>re involved in the polyovul<em>a</em>r follicle induction by DES.</Abstr<em>a</em>ctText>

We report the case of a pituitary stalk germinoma initially misdiagnosed and treated as infundibuloneurohypophysitis (INH). A 27-year-old man presented with a 1-year history of polydipsia, polyuria, nycturia consistent with central diabetes insipidus and a hyperintense pituitary stalk lesion on MRI. A possible INH diagnosis was considered, after excluding other pathologies. Lesion biopsy was discarded at that time on the ground of a small target and the high risk of added morbidity. Oral desmopressin led to initial symptoms resolution but, in the following months, an anterior panhypopituitarism developed, in spite of appropriate treatment and, by that time, the brain MRI also revealed lesion growth, which prompted a biopsy recommendation. The pathology analysis revealed a germinoma. After chemotherapy and radiotherapy, there was complete disappearance of the pituitary lesion, but the panhypopituitarism persisted. In conclusion, this case highlights the importance and difficulty of precise diagnosis in the initial assessment of pituitary stalk lesions and the need for close monitoring of treatment response. Diagnostic reassessment and biopsy in atypical cases is the only path to achieve the correct diagnosis and treatment.

Keywords: CNS cancer; pituitary disorders.

We wanted to investigate whether Isoniazid (INH) can directly stimulate activation of hepatic stellate cells (HSCs) and enhance production of collagen. Treatment of human hepatic stellate cell line LX2 with or without 5μM INH for 24 to 72 hours was performed to look into content of cytochrome P450 2E1 (CYP2E1), activity of NADPH oxidase (NOX) and intracellular oxidative stress. Protein level as well as mRNA expression of alpha smooth muscle actin (α-SMA) and collagen1A1 (COL1A1) were assessed by western blot and real time PCR. In some experiments pyrazole (PY) was pre-treated to LX2 cells to induce CYP2E1 prior to INH treatment. CYP2E1 level as well as NOX activity was gradually increased with INH treatment in LX2 cells till 72 hours. Following 72 hours of INH exposure, intracellular glutathione (GSH) level was found to be reduced compared to control (p<0.01) and showed expression of α-SMA, indicating activation of HSC. We could not found any change in collagen expression in this experimental study. Pyrazole (PY) pre-treatment to LX2 cells caused significant increase in cellular CYP2E1 content associated with increase of NOX, intracellular reactive oxygen species (ROS), and expression of α-SMA and collagen1 after INH exposure. CYP2E1 is present in insignificant amount in HSCs and INH treatment could not induce collagen expression, although altered cellular oxidant levels was observed. But in LX2 cells when CYP2E1 was over-expressed by PY, INH administration provokes oxidative stress mediated stellate cells activation along with collagen type I expression.

The emergence of drug-resistant tuberculosis (DR-TB) as well as the requirement for long, expensive and toxic drug regimens impede efforts to control and eliminate TB. Therefore, there's a need for effective and affordable anti-mycobacterial agents which can shorten the duration of therapy and are active against Mycobacterium tuberculosis (Mtb) in both active and latent phases. Nitrofurantoin (NFT) is a hypoxic agent with activity against a myriad of anaerobic pathogens and, like the first-line TB drug, rifampicin (RIF), kills non-replicating bacilli. However, the poor ability of NFT to cross host cell membranes and penetrate tissue means that it does not reach therapeutic concentrations. To improve TB efficacy of NFT, a series of NFT analogues was synthesized and evaluated in vitro for anti-mycobacterial activity against the laboratory strain, Mtb H37Rv, and for potential cytotoxicity using human embryonic kidney (HEK-293) and Chinese hamster ovarian (CHO) cells. The NFT analogues showed good safety profiles, enhanced anti-mycobacterial potency, improved lipophilicity, as well as reduced protein binding affinity. Analogue 9 which contains an eight carbon aliphatic chain was the most active, equipotent to isoniazid (INH), a major front-line agent, with MIC₉₀ = 0.5 μM, 30-fold more potency than the parent drug, nitrofurantoin (MIC₉₀ = 15 μM), and 100-fold more selective towards mycobacteria. Therefore, 9 was identified as a validated hit for further investigation in the urgent search for new, safe and affordable TB drugs.

The in vivo release segregation of rifampicin (RIF) and isoniazid (INH) has been proposed as a strategy to avoid RIF acid degradation, which is known as one of the main factors for reduced RIF bioavailability and can result in drug-resistant tuberculosis. So far, this strategy has been scarcely explored. The aims of this study were to investigate the stability and bioavailability of RIF after combination of a very fast release matrix of RIF with a sustained delivery system of INH. A series of INH-alginic acid complexes (AA-INH) was obtained and characterized. Independent and sequential release profile of AA-INH at biorrelevant media of pH 1.20 and 6.80 was explored. In addition, AA-INH was combined with a RIF-carboxymethylcellulose very fast release complex (CMC-RIF) obtained previously and subjected to acid dissolution assays to evaluate RIF acid stability and determine RIF and INH dissolution efficiencies. Finally, a pharmacokinetic study in dogs was carried out. The AA-INH was easily obtained in solid-state. Their characterization revealed its ionic nature, with a loading capacity of around 30%. The dissolution efficiencies (15 min) confirmed release segregation in acid media with 7.8 and 65.6% for AA-INH and CMC-RIF, respectively. INH release rate from the AA-INH system was slow in acid media and increased in simulated intestinal media. The complete release of INH was achieved after 2 h in simulated intestinal media in the sequential release experiments. The acid degradation of RIF was significantly reduced (36.7%) when both systems were combined and oral administration to dogs revealed a 42% increase in RIF bioavailability. In conclusion, CMC-RIF and AA-INH may be useful for the formulation of a site-specific solid dosage form to overcome some of the main obstacles in tuberculosis treatment. Graphical abstract.

Keywords: Dissolution; Pharmacokinetics; Solid state characterization; Stability; Swellable drug-polyelectrolyte matrices.

(<em>A</em>bstractText>This study aims to investigate the association between polycystic ovary syndrome (PCOS) and obesity and insulin resistance (IR) with respect to anti-Müllerian hormone (<em>A</em>MH), inhibin <em>A</em> (<em>INH</em>-<em>A</em>), inhibin B (<em>INH</em>-B), and insulin-like peptide 3 (INSL3) levels, all factors which may have an impact on IR.</<em>A</em>bstractText>(<em>A</em>bstractText>In this cross sectional study, 52 adolescent girls diagnosed with PCOS[groups:nonobese (NO), n = 23; overweight/obese (OW/O), n = 29] were included. Blood samples were obtained to measure <em>A</em>MH, <em>INH</em>-B, <em>INH</em>-<em>A</em>, and INSL3 levels, together with hormonal and biochemical assessments. Oral glucose tolerance test (OGTT) was performed and the indexes of IR [homeostasis model assessment: insulin resistance (HOM<em>A</em>-IR) and Matsuda index] were calculated.</<em>A</em>bstractText>(<em>A</em>bstractText>Insulin resistance was 56.5% with OGTT and 30.4% with HOM<em>A</em>-IR in nonobese-PCOS girls. There was a correlation between <em>INH</em>-<em>A</em> and HOM<em>A</em>-IR even when controlled for body mass index (BMI). <em>INH</em>-B and F<em>A</em>I also had correlations with HOM<em>A</em>-IR which disappeared when controlled for BMI. In regression analyses, <em>A</em>MH (odds ratio = [0.903, P = 0.015) and F<em>A</em>I (odds ratio = 1.353, P = 0.023) are found to be contributors to IR. Their effect was BMI-independent. In ROC analysis, the cutoff value for F<em>A</em>I was 5.93 (sensitivity 71%) to define IR in PCOS girls.</<em>A</em>bstractText>(<em>A</em>bstractText><em>A</em>MH and F<em>A</em>I may contribute to IR (defined by OGTT) in PCOS. F<em>A</em>I might be used as a supporting IR marker (defined by OGTT) in adolescent girls with PCOS.</<em>A</em>bstractText>

To further improve fertility of animals, a novel gene RFRP-3 (RF-amide related peptide-3, RFRP-3) was used to construct DNA vaccines with INH α (1-32) (inhibin, INH) fragment for the first time. The aim of this study was to evaluate the effects of novel DNA vaccines on fertility in mice. Synthesized SINH and SRFRP (INH and RFRP genes were separately ligated to the C-terminus of the small envelope protein of the hepatitis B virus (HBV-S) gene) fragments were inserted into multiple cloning site of pIRES vector to develop p-SINH/SRFRP. The synthesized tissue plasminogen activator (TPA) signal sequence was then inserted into the p-SINH/SRFRP to construct p-TPA-SINH/TPA-SFRFP. Meanwhile, p-SINH was prepared and considered as positive control. Forty Kunming mice were equally divided into four groups and respectively immunized by electroporation with p-SINH, p-SINH/SRFRP and p-TPA-SINH/TPA-SRFRP vaccine (three times at 2 weeks interval) and saline as control. Results showed that the average antibodies (P/N value) of anti-INH and anti-RFRP in mice inoculated with p-TPA-SINH/TPA-SFRFP were significantly higher (P<0.05) than those inoculated with p-SINH/SRFRP and the positive rates were 100% (anti-INH) and 90% (anti-RFRP) respectively, at 2 weeks after the third immunization. Litter size of mice immunized with the three recombinant plasmids was higher (P<0.05) than that of the control, and litter size of mice immunized with p-TPA-SINH/TPA-SRFRP significantly increased (P<0.05) compared with p-SINH. These results suggested that the p-TPA-SINH/TPA-SRFRP harboring INH and RFRP genes was successfully constructed and had good immunogenicity, and might effectively increase litter size.

Acquired angioedema due to C1-INH deficiency (C1-INH-AAE) can occur when there are acquired (not inherited) deficiencies of C1-INH. A quantitative or functional C1-INH deficiency with negative family history and low C1q is diagnostic of C1-INH-AAE. The most common conditions associated with C1-INH-AAE are autoimmunity and B-cell lymphoproliferative disorders. A diagnosis of C1-INH-AAE can precede a diagnosis of lymphoproliferative disease and confers an increased risk for developing non-Hodgkin lymphoma. Treatment focuses on symptom control with therapies that regulate bradykinin activity (C1-INH concentrate, icatibant, ecallantide, tranexamic acid, androgens) and treatment of any underlying conditions.

Tumor necrosis factor-alpha inhibitors (TNFIs) increase the risk of tuberculosis (TB). The aim of this study was to evaluate pediatric patients who are under TNFIs regarding the emergence of TB, and to determine the effectiveness of screening methods. This was a retrospective observational study of 73 patients receiving TNFIs therapy for at least 6 months duration between January 2011 and January 2016. Detailed demographic and clinical data were gathered from patients` files. Seventy-three patients (female n=41, 56.2%) with a median age of 129 (38-215) months were enrolled. Median follow-up period was 18 (6-60) months. Median duration of primary illness prior to TNFI therapy was 24 (2-184) months. Sixteen patients (21.9%) with latent tuberculosis infection (LTBI) were given isoniazid (INH) prior to TNFI therapy. TNFIs were adalimumab (n=39, 53.5%), infliximab (n=22, 30.1%) and etanercept (n=12, 16.4%). During follow-up, 16 patients (21.9%) were started on INH treatment. Median time of starting INH was 20 (4-42) months. One patient (3.1%) who received INH had elevated liver transaminases. One patient (1.3%) developed active TB during follow-up. In conclusion, patients who are candidates for TNFI treatment should be screened for TB before and during therapy.

Background and aims: Differentiating biliary atresia (BA) from idiopathic neonatal hepatitis (INH) is vital in routine pediatric practice. However, on liver biopsy, few cases offer a diagnostic challenge to discriminate these entities with certainty. Bile ductular reaction (DR), intermediate hepatobiliary cells (IHBC) and extra-portal ductules (EPD) indicate progenitor cell activation, as a response to various hepatic insults. The present study aims to quantify DR, IHBC and EPD by Keratin 7 (CK7) immunohistochemistry (IHC) in BA and INH and to devise a mathematical approach to better differentiate the two, especially in histologically equivocal cases.

Methods: A total of 98 cases were categorized on biopsy as BA, INH or equivocal histology, favoring BA or INH. CK7 DR mean, IHBC mean and EPD mean values were compared between BA and INH. A formula was derived to help distinguish these two entities, the cut-off value, sensitivity and specificity of which were determined by receiver operating characteristic (ROC) curve. This formula was applied and validated on histologically equivocal cases.

Results: Univariate logistic regression revealed significant difference between BA and INH with respect to CK7 DR and CK7 EPD mean (p < 0.001 in both); however, CK7 IHBC mean was not significant (p = 0.08). On multivariate logistic regression, only CK7 DR had significant impact on diagnosis (p < 0.001). A formula: (CK7 DR)² + (CK7 EPD)/(CK7 IHBC) was derived to help distinguish BA from INH. Cut off value of 10.5 and above, determined by ROC curve, favored a diagnosis of BA (sensitivity= 93.4%, specificity= 94.6%). Histologically equivocal and discrepant cases could be correctly categorized using this formula.

Conclusions: Formula using CK7 IHC parameters may aid pathologists better distinguish BA from INH, especially in histologically equivocal cases.

Keywords: biliary atresia; idiopathic neonatal hepatitis; immunohistochemistry; keratin 7; liver biopsy; neonatal cholestasis.

Hereditary Angio-Edema (HAE) is manifested by recurrent attacks of acute circumscribed edema of the extremities, face, trunk, and respiratory or abdominal tract, occurring after minor physical or emotional trauma, or spontaneously. The clinical diagnosis can be confirmed by low serum-levels of the inhibitor of the activated first component of complement (C1-INH). A family of 35 members over six generations was investigated. About 40 per cent of the members were HAE-patients. An autosomal dominant inheritance with high penetrance was present. Four patients died by suffocation from laryngeal edema. In all HAE-patients the C1-INH serum-level was diminished, and also in two children who have yet had no complaints. Adequate medical advice, including the provision of a medical alert card and the prescription of C1-INH concentrate (for short-term prophylaxis and the treatment of attacks of laryngeal edema), is necessary. In patients with frequent serious attacks, long-term prophylaxis with Danazol is indicated.

The Hageman factor dependent pathways are influenced by several control proteins which modulate the extent of activation and biologic activity of these enzyme substrates (Fig. 1). C1 INH plays a prominent role by acting at the common initiating step for all three Hageman factor dependent systems and its deficiency produces disease in man. Alpha-2 macroglobulin appears to play an important role in the fibrinolytic sequence, having potent activity towards both plasminogen activator and plasmin. Antithrombin most prominently influences the state of activation of the coagulation sequence by regulating the enzymatic activities of activated Factors XI, IX and X and, most importantly, that of thrombin. Significantly, deficiency of antithrombin results in increased thrombosis in man.

The aim of this study was to determine the bidirectional release of immunoreactive inhibin-alpha (irINH-alpha) by different testicular compartments in the adult ram and to assess the effects of FSH on the distribution of inhibin in the testis. Immunoreactive INH-alpha was measured by RIA in fluid samples collected concurrently from the three testicular compartments--the seminiferous tubules, the interstitium, and the vascular system--through catheters inserted surgically into the rete testis, testicular lymphatic duct system, and spermatic veins, respectively. Overall, the concentration of irINH-alpha in rete testis fluid was 25 times the level in testicular lymph and over 500 times the concentration in peripheral blood. The pattern of irINH-alpha concentration in rete testis fluid was inversely related to that in testicular lymph, but i.v. administration of FSH had a decoupling effect on this relationship by depressing inhibin concentration in testicular lymph without affecting inhibin levels in rete testis fluid. Nevertheless, increased flow of testicular lymph more than compensated for the transient fall in irINH-alpha concentration so that, overall, the total output of inhibin via the testicular lymphatic duct system (and the vascular system) increased significantly. No persistent or significant changes were observed in the flow rate of rete testis fluid or concentration of irINH-alpha in the fluid after administration of FSH. The time frame for the response of the testis to FSH is indicative of the involvement of a mediator. Electrophoretic analysis of serially collected testicular lymph samples consistently revealed an FSH-induced release of a series of proteins in the M(r) range of 30,000-32,000.(ABSTRACT TRUNCATED AT 250 WORDS)

(<em>A</em>bstractText>Red blood cell (RBC) transfusions result in the sequestration and metabolism of storage-damaged RBCs within the spleen and liver. These events are followed by increased plasma iron concentrations that can contribute to oxidant stress and cellular injury. We hypothesized that administration of a ferroportin inhibitor (FPN-<em>INH</em>) immediately after acute RBC exchange transfusion could attenuate posttransfusion circulatory compartment iron exposure, by retaining iron in spleen and hepatic macrophages.</<em>A</em>bstractText>(<em>A</em>bstractText>Donor guinea pig blood was leukoreduced, and RBCs were preserved at 4°C. Recipient guinea pigs (n = 5/group) were exchange transfused with donor RBCs after refrigerator preservation and dosed intravenously with a small-molecule FPN-<em>INH</em>. Groups included transfusion with vehicle (saline), 5 mg/kg or 25 mg/kg FPN-<em>INH</em>. <em>A</em> time course of RBC morphology, plasma non-transferrin-bound iron (NTBI) and plasma hemoglobin (Hb) were evaluated. End-study spleen, liver, and kidney organ iron levels, as well as renal tissue oxidation and injury, were measured acutely (24-hr after transfusion).</<em>A</em>bstractText>(<em>A</em>bstractText>RBC transfusion increased plasma NTBI, with maximal concentrations occurring 8 hours after transfusion. Posttransfusion iron accumulation resulted in tubule oxidation and acute kidney injury. FPN inhibition increased spleen and liver parenchymal/macrophage iron accumulation, but attenuated plasma NTBI, and subsequent renal tissue oxidation/injury.</<em>A</em>bstractText>(<em>A</em>bstractText>In situations of acute RBC transfusion, minimizing circulatory NTBI exposure by FPN inhibition may attenuate organ-specific adverse consequences of iron exposure.</<em>A</em>bstractText>