The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Tolerability and outcome of sunitinib by giving 4/2 schedule versus 2/1 schedule in metastatic renal cell carcinoma patients: a prospective randomized multi-centric Egyptian study.

INTRODUCTION: Sunitinib is a standard of care first line treatment for patients with metastatic renal cell carcinoma (RCC). Sunitinib standard dose is 50 mg once daily for 4 consecutive weeks followed by 2 weeks' off (4/2 schedule). Long-term and high exposure to this medication lead to severe adverse events (AEs); therefore, this trial was done to find the best schedule which gives the best outcome with minimal toxicity. MATERIALS AND METHODS: Seventy patients were randomly assigned into 2 groups, then received 50 mg/day of sunitinib. Group 1 (40 patients) received sunitinib for 4 consecutive weeks followed by 2 weeks off (4/2 schedule) while 30 patients were admitted to group 2 with 2 weeks on and 1 week off (2/1 schedule). RESULTS: All patients (100%) had significantly higher AEs on schedule 4/2 vs. 73.3% on schedule 2/1 (p = 0.001). Furthermore, the grade 3 AEs on schedule 2/1 were significantly lower than those on schedule 4/2 (26.7% vs. 82.5%) respectively (p = 0.001), such as fatigue, diarrhea, hypertension, hand foot syndrome (HFS) and mucositis. Progression-free survival (PFS) rate was significantly higher in 2/1 schedule (60.9% vs. 38.6%) than in 4/2 schedule (p < 0.008). Multivariate analysis suggested that: age > 60 years, poor International Metastatic RCC Database Consortium (IMDC) risk category, tumor size > 10 cm and treatment schedule (group 1) were poor prognostic factors of PFS. CONCLUSIONS: Our study supported the use of 2/1 schedule of sunitinib in patients with metastatic RCC because of lower toxicity profile and better efficacy with improved PFS in comparison to 4/2 schedule.

Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials.

INTRODUCTION: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. METHODS: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. RESULTS: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). DISCUSSION: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect.

Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant.

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

Emergency Physician Interpretation of Point-of-care Ultrasound for Identifying and Grading of Hydronephrosis in Renal Colic Compared With Consensus Interpretation by Emergency Radiologists.

OBJECTIVE: The ability of emergency physicians (EPs) to identify hydronephrosis using point-of-care ultrasound (POCUS) has been assessed in the past using computed tomography (CT) scans as the reference standard. We aimed to determine the ability of EPs to identify and grade hydronephrosis on POCUS using the consensus interpretation of POCUS by emergency radiologists as the reference standard. METHODS: The study was conducted at an urban academic emergency department (ED) as a secondary analysis of previously collected ultrasound data from the EP-performed POCUS databank. Patients were eligible for inclusion if they had both POCUS and CT scanning performed during the index ED visit. Two board-certified emergency radiologists and six EPs interpreted each POCUS study independently. The interpretations were compared with the consensus interpretation by emergency radiologists. Additionally, the POCUS interpretations were also compared with the corresponding CT findings. Institutional approval was obtained for conducting this study. All the analyses were performed using Stata MP 14.0 (StataCorp). RESULTS: A total of 651 patient image-data sets were eligible for inclusion in this study. Hydronephrosis was reported in 69.6% of POCUS examinations by radiologists and 72.7% of CT scans (p = 0.22). Using the consensus radiology interpretation of POCUS as the reference standard, EPs had an overall sensitivity of 85.7% (95% confidence interval [CI] = 84.3%-87.0%), specificity of 65.9% (95% CI = 63.1%-68.7%), positive likelihood ratio of 2.5 (95% CI = 2.3-2.7), and negative likelihood ratio of 0.22 (95% CI = 0.19-0.24) for hydronephrosis. When using CT scan as the reference standard, the EPs had an overall sensitivity of 81.1% (95% CI = 79.6% to 82.5%), specificity of 59.4% (95% CI = 56.4%-62.5%), positive likelihood ratio of 2.0 (95% CI = 1.8-2.2), and negative likelihood ratio of 0.32 (95% CI = 0.29-0.35) for hydronephrosis. The specificity of EPs was improved to 94.6% (95% CI = 93.7%-95.4%) for categorizing the degree of hydronephrosis as "moderate or severe" versus "none or mild," with positive likelihood ratio of 6.33 (95% CI = 5.3-7.5) and negative likelihood ratio of 0.69 (95% CI = 0.66-0.73). CONCLUSIONS: Emergency physicians were found to have moderate to high sensitivity for identifying hydronephrosis on POCUS when compared with the consensus interpretation of the same studies by emergency radiologists. These POCUS findings by EPs produced more definitive results when at least moderate degree of hydronephrosis was present.

Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease.

BACKGROUND: Dry eye disease is a common debilitating ocular disease. Current diagnostic tests used in dry eye disease are often neither sensitive nor reproducible, making it difficult to accurately diagnose and determine end points for clinical trials, or evaluate the usefulness of different medications in the treatment of dry eye disease. The recently developed fluorophotometer can objectively detect changes in the corneal epithelium by quantitatively measuring its barrier function or permeability. The purpose of the study is to investigate the use of corneal fluorescein penetration measured by the fluorophotometer as a diagnostic tool in the evaluation of dry eye patients. METHODS: Dry eye patients (16 eyes), who presented with a chief complaint of ocular irritation corresponding with dry eye, low Schirmer's one test (<10 mm after 5 minutes) and corneal fluorescein staining score of more than two, were included in the study. Normal subjects (16 eyes), who came for refraction error evaluation, served as controls. Institutional Review Board (IRB) approved consent was obtained before enrolling the subjects in the study and all questions were answered while explaining the risks, benefits and alternatives. All Fluorophotometry of the central corneal epithelium was done utilizing the Fluorotron Master. Each eye had a baseline fluorescein scan performed, after which 50 l of 1% sodium fluorescein dye was instilled. Three minutes later, the fluorescein was washed with 50 ml of normal saline. Fluorescein scans were then started immediately after washing and were recorded at 10, 20, 40, and 60 minutes thereafter. The corneal peak values of fluorescein concentration were recorded within the central cornea in both dry eyes and in controls. RESULTS: Ten minutes after fluorescein installation, patients with dry eye disease averaged a five-fold increase in corneal tissue fluorescein concentration (mean = 375.26 +/- 202.67 ng/ml) compared with that of normal subjects (mean = 128.19 +/- 85.84 ng/ml). Sixty minutes after dye installation, patients with dry eye disease still revealed higher corneal tissue fluorescein concentration (mean = 112.87 +/- 52.83 ng/ml) compared with that of controls (mean = 40.64 +/- 7.96 ng/ml), averaging a three-fold increase. CONCLUSION: Patients with dry eye disease demonstrated an increased corneal permeability and a slower rate of elimination to topically administered fluorescein when measured by the fluorophotometer. This suggests that fluorophotometry may serve as a valuable quantitative and objective tool for the diagnosis of dry eye disease, and in following patients' response to new treatment modalities. Fluorophotometry may serve as an objective non-invasive tool for end-point analysis in clinical trials of new treatments for dry eye disease.

Additivity of pilocarpine to bimatoprost in ocular hypertension and early glaucoma.

PURPOSE: To determine if the intraocular pressure (IOP) effect of pilocarpine at various concentrations is additive to that of bimatoprost and to assess the tolerability of this combination. METHODS: This was a randomized, prospective trial of patients with IOP > 21 mm Hg following appropriate medication washout. For all visits IOP was measured at 9:00 AM and 11:00 AM. Following baseline visit (#1), bimatoprost 0.03% was instilled qhs OU through visit 6. Following visits 2, 3, and 4 pilocarpine (2%, 4%, 6%) was instilled qid in one randomly selected eye. Pilocarpine was discontinued after visit 5 and bimatoprost after visit 6. Two-tailed, paired t test was used to compare treated and contralateral eyes for their IOP, IOP change, percentage IOP change from baseline, and to compare IOP in the same eye at 9:00 AM and 11:00 AM (before and after pilocarpine administration). IOPs using bimatoprost alone or in combination with various pilocarpine concentrations were compared using single variant Analysis of Variance (ANOVA). RESULTS: Seventeen patients were enrolled and 13 patients completed the study. Bimatoprost reduced IOP 28.7% to 30.5% (P < 0.0001) from baseline to visit 2. IOPs in eyes treated with bimatoprost alone or with bimatoprost and various pilocarpine concentrations were similar (P > 0.81, ANOVA). The IOP (P > 0.17) and percentage IOP change from baseline (P > 0.10) was similar in treated and contralateral eyes with all three strengths of pilocarpine. IOP values at 9:00 AM and 11:00 AM, before and after pilocarpine administration, were similar (P > 0.22). CONCLUSION: Bimatoprost alone reduces IOP substantially. Pilocarpine added to bimatoprost at concentrations of 2%, 4%, or 6% was neither additive nor antagonistic to the ocular hypotensive efficacy of bimatoprost.

The effect of laser iridotomy on the anterior segment anatomy of patients with plateau iris configuration.

PURPOSE: To determine if laser iridotomy altered the anterior segment anatomy of patients with plateau iris configuration. METHODS: Twenty eyes of 9 female and 1 male patients were imaged using an ultrasound biomicroscope within 19 weeks before and 52 weeks after laser iridotomy. Measurements obtained included the anterior chamber depth (ACD), trabecular-ciliary process distance (TCPD), iris thickness (IT), angle opening distance at 500 micrometers (AOD), iridozonular distance (IZD), and trabecular-iris angle (TIA). Comparisons of the pre- and post- iridotomy measurements were made using a two-tailed paired t test. RESULTS: Laser iridotomy elicited no statistically significant change in ACD, TCPD, IT, AOD, or TIA. However, IZD was decreased (P < 0.05) in both eyes after laser iridotomy. Configuration of the irides was flat before and after laser iridotomies. CONCLUSION: This study suggests that laser iridotomy did not alter anterior segment anatomy, probably because of the fixed anterior insertion of the iris and ciliary body in plateau iris configuration. The decrease in IZD distance may be the result of a small posterior movement of the iris due to a reduction in relative pupillary block, secondary to laser iridotomy. The small reduction in relative papillary block in plateau iris configuration does not alter the width of the anterior chamber angle as measured by AOD and TIA.

Altered [125I]epidermal growth factor binding and receptor distribution in psoriasis.

Stimulation of growth and differentiation of human epidermis by epidermal growth factor (EGF) is mediated by its binding to specific receptors. Whether EGF receptors primarily mediate cell division or differentiation in hyperproliferative disease such as psoriasis vulgaris is unclear. To study the pathogenesis of psoriasis, 4-mm2 punch biopsy specimens of normal, uninvolved, and involved psoriatic skin were assayed for EGF receptors by autoradiographic, immunohistochemical, and biochemical methods. Using autoradiographic and immunohistochemical methods, basal keratinocytes were found to contain the greatest number of EGF binding sites and immunoreactive receptors as compared to the upper layers of the epidermis in both normal epidermis and psoriatic skin. No EGF receptor differences between normal and psoriatic epidermis were observed in this layer. In the upper layers of the epidermis, a 2-fold increase in EGF binding capacity was observed in psoriatic skin as compared with normal thin or thick skin. Biochemical methods indicated that [125I]EGF binding was increased in psoriatic epidermis as compared with similar thickness normal epidermis when measured on a protein basis. Epidermal growth factor was shown to increase phosphorylation of the EGF receptor in skin. EGF receptors retained in the nonmitotic stratum spinosum and parakeratotic stratum corneum may reflect the incomplete, abnormal differentiation that occurs in active psoriatic lesions. Alternatively, retained EGF receptors may play a direct role in inhibiting cellular differentiation in the suprabasal layers.

Comparison of epidermal growth factor binding and receptor distribution in normal human epidermis and epidermal appendages.

To localize epidermal growth factor (EGF) receptors in normal human epidermis and other skin structures, two different light microscopic methods were used. EGF binding [( 125I]EGF/R) to the extracellular portion of the EGF receptor was studied by incubating intact skin samples with [125I]EGF, sectioning the tissues, and performing autoradiography. Immunoreactive EGF receptor molecules (IR-EGF/R) were localized with a mono-specific anti-EGF receptor antibody using a 2-step indirect immunocytochemical method (horseradish peroxidase) and detergent permeabilized tissues. This latter method measured the total pool of EGF receptors: occupied and/or internalized forms, precursor forms, and partially degraded forms of the EGF receptor that retain immunoreactivity. Both the [125I]EGF/R and IR-EGF/R localization studies indicated that EGF receptors were present in basal epidermal keratinocytes, sebocytes, outer root sheath cells in hair follicles, smooth muscle cells of arrector pili muscles, and dermal arteries. The highest levels of [125I]EGF/R and IR-EGF/R were found in the dermal ducts of eccrine sweat glands. The distribution of both [125I]EGF/R and IR-EGF/R was not consistent with the concept that EGF exclusively is involved in cellular division and proliferation in normal human epidermis and its appendages, i.e., EGF receptors were also found in tissues that do not undergo rapid proliferation. The present study indicates that EGF may have a more complex regulatory role in the skin than was previously thought.

Epidermal growth factor binding and receptor distribution in term human placenta.

Human placenta has a large number of epidermal growth factor (EGF) receptors when measured either by [125I]iodoEGF binding or by protein yield after purification. To localize EGF receptors in situ in normal human term placenta, two different light microscopic methods were used. To detect unoccupied, accessible EGF binding sites on the extracellular surface of placental cells in intact blocks of tissue, samples were incubated with [125I]iodoEGF, sectioned and autoradiography performed. To detect the total pool of intracellular and extracellular EGF receptors, placental tissue was sectioned, treated with detergent, and then anti-EGF receptor antibody was localized by immunohistoperoxidase techniques. Both [125I]iodoEGF and anti-EGF receptor antibody methods showed that EGF receptors were primarily present on syncytiotrophoblast cells of placental villi. Smooth muscle cells of placental blood vessels also contained EGF receptors. Neither connective tissue cells within the core of terminal chorionic villi nor endothelium of fetal blood vessels had detectable [125I]iodoEGF binding or immunoreactive EGF receptors. Since the quantity of placental smooth muscle cells is only a small fraction compared to trophoblast cells, we conclude that syncytiotrophoblast cells are primarily responsible for the high levels of EGF receptors found in extracts prepared from human term placenta.

Pancreatic disorders in pediatric acquired immune deficiency syndrome.

Acute pancreatitis, reported in 17% of pediatric patients with acquired immune deficiency syndrome (AIDS), is said to have a poor prognosis. We describe the pancreatic changes observed at autopsy from 71 children with human immunodeficiency virus (HIV) infection and document their nature, extent, and clinical relevance. The median age at autopsy of the children was 17 months (range, 2 months to 19 years); 38 were boys and 33 were girls. Parental intravenous drug use was the most frequent risk factor for AIDS, followed by blood transfusions. Respiratory failure and sepsis constituted the predominant causes of death. Nonspecific changes, such as edema, inflammation, fibrosis, inspissated material in acini and ducts, and enlarged Langerhans' islet predominated. Acute and chronic pancreatitis were mild except in one instance of a fatal acute probably dideoxyinosine-associated pancreatitis. Pancreatic involvement by opportunistic infections, such as cytomegalovirus (CMV), Mycobacterium avium intracellulare (MAI), and Candida, was focal and rare despite the high prevalence of these infections at autopsy. Focal lymphoplasmacytic infiltration and vascular calcifications were also observed. We conclude that pancreatic changes were frequently noted at autopsy in children with AIDS. They were usually mild, reflected systemic disease states, and were usually not life threatening. The incidence of opportunistic infections of the pancreas was low.

Hepatic pathology in pediatric acquired immunodeficiency syndrome.

In a retrospective study we assessed the hepatic changes in children with the acquired immunodeficiency syndrome by reviewing 12 biopsy specimens and 48 autopsy specimens from 54 children. Hepatopathology differed in biopsy and autopsy material. In biopsy specimens, chronic active hepatitis with predominantly T8 lymphocytes by tissue immunochemistry was common (five of 12 specimens). Fatty degeneration and hepatocellular necrosis were either absent, mild, or patchy. On the other hand, at autopsy, chronic active hepatitis was not observed. The most prominent changes were extensive fatty degeneration, nonspecific portal mononuclear infiltration, portal fibrosis, and confluent (ischemic) necrosis. Opportunistic infections such as Mycobacterium avium-intracellulare (MAI) were noted only at autopsy. In addition, three unusual morphologic characteristics were noted: nodular lymphoplasmacytic portal infiltrate, a pseudosarcomatous variant of Mycobacterium avium-intracellulare infection, and multinucleated giant cells (foreign both type and giant cell transformation of hepatocytes).

Treatment of presumed arrhythmogenic right ventricular dysplasia in an adolescent.

Familial arrhythmogenic right ventricular dysplasia is a rare cardiomyopathy that is usually diagnosed on postmortem examination or on presentation with progressive congestive heart failure. We present a patient in whom an automatic implantable cardioverter-defibrillator was inserted prophylactically. A review of the condition and possible therapies is included.

Molecular variants of the EWS-WT1 gene fusion in desmoplastic small round cell tumor.

We report two cases of desmoplastic small round cell tumor (DSRCT) with novel molecular variants of the specific EWS-WT1 gene fusion. This fusion usually encodes a chimeric RNA with an in-frame junction of exon 7 of EWS to exon 8 of WT1. In one variant patient, the EWS-WT1 fusion transcript contained an in-frame junction of exon 9 of EWS to exon 8 of WT1. Moreover, in this patient the tumor arose in the hand, an extremely unusual site for DSRCT. In the second patient, an in-frame junction of exon 10 of EWS to exon 8 of WT1 was present. These two cases of DSRCT show that the molecular variability in the EWS breakpoint observed in the EWS-FLI1 fusion of Ewing's sarcoma can occur in DSRCT as well. This type of heterogeneity is relevant to the interpretation of molecular diagnostic assays and could also affect the functional properties of the encoded chimeric transcription factors.

Thoracolumbar accessory penis: etiology, diagnosis, and management.

Human sacral appendages have rarely been reported. We present a neonate with a thoracolumbar appendage resembling a penis, and discuss the nature of the anomaly and its diagnosis and management.

Disseminated candidiasis. Newer approaches to early recognition and treatment.

The clinical triad of fever, erythematous papular rash, and diffuse muscle tenderness has recently been reported to be presumptive evidence for disseminated candidiasis in the immunocompromised host who is receiving broad-spectrum antibiotics. This case report further explores this clinical association and demonstrates that the immediate institution of antifungal therapy before laboratory test results are known may favorably alter the outcome of this frequently fatal condition. In view of the low positive yield of blood cultures, skin biopsy may represent an effective method for achieving rapid laboratory confirmation of the diagnosis.