Prevalence and penetrance of ZFPM2 mutations and deletions causing congenital diaphragmatic hernia.

Zinc finger protein, FOG2 family member 2 (ZFPM2) (previously named FOG2) gene defects result in the highly morbid congenital diaphragmatic hernia (CDH) in humans and animal models. In a cohort of 275 CDH patient exomes, we estimated the prevalence of damaging ZFPM2 mutations to be almost 5%. Genetic analysis of a multigenerational family identified a heritable intragenic ZFPM2 deletion with an estimated penetrance of 37.5%, which has important implications for genetic counseling. Similarly, a low penetrance ZFPM2 frameshift mutation was observed in a second multiplex family. Isolated CDH was the predominant phenotype observed in our ZFPM2 mutation patients. Findings from the patients described herein indicate that ZFPM2 point mutations or deletions are a recurring cause of CDH.

Training and validation of standardized patients for unannounced assessment of physicians' management of depression.

OBJECTIVE: Standardized patients (SPs) have been developed to measure practitioner performance in actual practice settings, but results have not been fully validated for psychiatric disorders. This study describes the process of creating reliable and valid SPs for unannounced assessment of general-practitioners' management of depression disorders in Iran. METHOD: Ten psychology and nursing students (potential SPs) took part in a five-session course involving training in dialogue and body language. Five scenarios, along with corresponding checklists representing common presentations of mood disorders in primary-care settings, were developed by an expert group. The SPs' role-play performance of their respective scenario was videotaped and scored independently by three psychiatrists according to an observational rating scale to assess validity. The role-play was repeated after 1 week with the same scenario and the same doctor, to assess test-retest reliability. The reliability of each checklist to be used by the SPs was assessed by testing interrater reliability between groups of SPs. RESULTS: The cutoff score for the SPs' portrayal validity was 90% or above for all SPs. Mean interrater reliability for the checklists was acceptable for the SPs watching the same videos and filling in the checklists, while the mean kappa for assessing concurrent validity in filling in the checklists was lower. The test-retest performance for assessing reliability resulted in a mean kappa of 0.72. All SPs except one, who was not recruited, performed acceptably well. CONCLUSION: The authors have demonstrated a thorough validation of the technique of using standardized patients in the portrayal of depressive disorders in primary-care settings in Iran, which creates confidence in employing this technique to evaluate doctors' performance, for example, after an educational intervention. Similar methods of validation can be used for SPs' portrayal of other psychiatric disorders.

Effects on readiness to change of an educational intervention on depressive disorders for general physicians in primary care based on a modified Prochaska model--a randomized controlled study.

BACKGROUND: The Prochaska model of readiness to change has been proposed to be used in educational interventions to improve medical care. OBJECTIVE: To evaluate the impact on readiness to change of an educational intervention on management of depressive disorders based on a modified version of the Prochaska model in comparison with a standard programme of continuing medical education (CME). METHODS: This is a randomized controlled trial within primary care practices in southern Tehran, Iran. The participants included 192 general physicians working in primary care (GPs) were recruited after random selection and randomized to intervention (96) and control (96). Intervention consisted of interactive, learner-centred educational methods in large and small group settings depending on the GPs' stages of readiness to change. Change in stage of readiness to change measured by the modified version of the Prochaska questionnaire was the RESULTS: The final number of participants was 78 (81%) in the intervention arm and 81 (84%) in the control arm. Significantly (P < 0.01), more GPs (57/96 = 59% versus 12/96 = 12%) in the intervention group changed to higher stages of readiness to change. The intervention effect was 46% points (P < 0.001) and 50% points (P < 0.001) in the large and small group setting, respectively. CONCLUSIONS: Educational formats that suit different stages of learning can support primary care doctors to reach higher stages of behavioural change in the topic of depressive disorders. Our findings have practical implications for conducting CME programmes in Iran and are possibly also applicable in other parts of the world.

Fluid retention in cirrhosis: pathophysiology and management.

Accumulation of fluid as ascites is the most common complication of cirrhosis. This is occurring in about 50% of patients within 10 years of the diagnosis of cirrhosis. It is a prognostic sign with 1-year and 5-year survival of 85% and 56%, respectively. The most acceptable theory for ascites formation is peripheral arterial vasodilation leading to underfilling of circulatory volume. This triggers the baroreceptor-mediated activation of renin-angiotensin-aldosterone system, sympathetic nervous system and nonosmotic release of vasopressin to restore circulatory integrity. The result is an avid sodium and water retention, identified as a preascitic state. This condition will evolve in overt fluid retention and ascites, as the liver disease progresses. Once ascites is present, most therapeutic modalities are directed on maintaining negative sodium balance, including salt restriction, bed rest and diuretics. Paracentesis and albumin infusion is applied to tense ascites. Transjugular intrahepatic portosystemic shunt is considered for refractory ascites. With worsening of liver disease, fluid retention is associated with other complications; such as spontaneous bacterial peritonitis. This is a primary infection of ascitic fluid caused by organisms originating from large intestinal normal flora. Diagnostic paracentesis and antibiotic therapy plus prophylactic regimen are mandatory. Hepatorenal syndrome is a state of functional renal failure in the setting of low cardiac output and impaired renal perfusion. Its management is based on drugs that restore normal renal blood flow through peripheral arterial and splanchnic vasoconstriction, renal vasodilation and/or plasma volume expansion. However, the definitive treatment is liver transplantation.

Prevalence of coronary artery disease risk factors in Iran: a population based survey.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of mortality, morbidity, and disability with high health care cost in Iran. It accounts for nearly 50 percent of all deaths per year. Yet little is known about CAD and CAD risk factors in the Iranian population. We aimed to assess the prevalence of different CAD risk factors in an Iranian population. METHODS: A descriptive cross sectional survey was conducted involving 3000 healthy adults at 18 years of age or above who were recruited with cluster random sampling. Demographic data and risk factors were determined by taking history, physical examination and laboratory tests. RESULTS: The average age was 36.23 +/- 15.26. There was 1381 female (46%) and 1619 male (54%) out of which 6.3% were diabetic, 21.6% were smoker, and 15% had positive familial heart disease history. 61% had total cholesterol level > 200 mg/dL, 32% triglyceride > 200 mg/dl, 47.5% LDL-c > 130 mg/dl, 5.4% HDL-c < 35 mg/dl, 13.7% systolic blood pressure > 140 mmHg, 9.1% diastolic blood pressure > 90 mmHg and 87% of them were physically inactive. CONCLUSION: Clinical and Para-clinical data indicated that Iranian adult population are of a high level of CAD risk factors, which may require urgent decision making to address national control measures regarding CAD.

Meningeal-cutaneous relationships in anencephaly: evidence for a primary mesenchymal abnormality.

The pathogenesis of cranial and spinal dysraphia has been controversial. Studies of spinal dysraphia have shown that the relationships of the pia and dura to the cutaneous layers were best understood as the result of a primary abnormality of mesenchymal structures, with the nervous system lesions occurring as a result of exposure of the bare spinal cord on the body surface. This study was undertaken to determine if the relationship of the cutaneous layers in anencephaly were similar to those found in spinal dysraphia. We reviewed serial histologic sections of the cranial structures of 10 anencephalic fetuses autopsied at The Johns Hopkins Hospital. We found the dura to be continuous with the deep dermis and the pia continuous with the superficial dermis and epidermis, the same arrangement observed in myelomeningocele. The development of eyes and cranial nerves, the absence of a bony calvarium, and the meningeal-cutaneous relationships found in this study support the idea that anencephaly can originate as an abnormality of mesenchymal structures and that the brain is secondarily lost to injury in utero because of its exposed position.

Plasma cell variant of Castleman's disease occurring concurrently with Hodgkin's disease in the neck.

BACKGROUND: Castleman's disease, a benign lymphoproliferative disorder, may be seen as a self-limited, curable unifocal process, or highly aggressive multicentric disease frequently resulting in death despite aggressive management. Non-Hodgkin's lymphoma has been known to arise within the context of Castleman's disease, usually when multicentric. Hodgkin's lymphoma, however, can also arise within the context of Castleman's disease, but this is a rare process. We report a case of unifocal Castleman's disease (plasma cell variant) occurring concurrently with Hodgkin's disease in the neck of a young woman. METHODS: The presentation, workup, pathologic evaluation, and management of a young woman diagnosed with Castleman's disease occurring concurrently with Hodgkin's disease in the neck is presented and discussed. RESULTS: A 32-year-old woman with a 5-year history of unifocal right cervicoparotid Castleman's disease (plasma cell variant) underwent right functional neck dissection and superficial parotidectomy for cosmetic and functional purposes. Pathologic and immunohistochemical analysis confirmed Hodgkin's lymphoma occurring in a background of the plasma cell variant of Castleman's disease. The patient subsequently underwent external beam radiation therapy as definitive management for her early-stage Hodgkin's lymphoma. CONCLUSIONS: Castleman's disease can occur as an isolated regional process in the head and neck. Furthermore, lymphoma (and specifically Hodgkin's lymphoma) can develop within regionally isolated cervical Castleman's disease. Although complete surgical excision of unifocal Castleman's disease is curative, the management of lymphoma occurring within the context of the Castleman's disease warrants a standard lymphoma workup and management strategy.

Hypertonic enhancement of transmitter release from frog motor nerve terminals: Ca2+ independence and role of integrins.

Hyperosmotic solutions cause markedly enhanced spontaneous quantal release of neurotransmitter from many nerve terminals. The mechanism of this enhancement is unknown. We have investigated this phenomenon at the frog neuromuscular junction with the aim of determining the degree to which it resembles the modulation of release by stretch, which has been shown to be mediated by mechanical tension on integrins. The hypertonicity enhancement, like the stretch effect, does not require Ca2+ influx or release from internal stores, although internal release may contribute to the effect. The hypertonicity effect is sharply reduced (but not eliminated) by peptides containing the RGD sequence, which compete with native ligands for integrin bonds. There is co-variance in the magnitude of the stretch and osmotic effects; that is, individual terminals exhibiting a large stretch effect also show strong enhancement by hypertonicity, and vice versa. The stretch and osmotic enhancements also can partially occlude each other. There remain some clear-cut differences between osmotic and stretch forms of modulation: the larger range of enhancement by hypertonic solutions, the relative lack of effect of osmolarity on evoked release, and the reported higher temperature sensitivity of osmotic enhancement. Nevertheless, our data strongly implicate integrins in a significant fraction of the osmotic enhancement, possibly acting via the same mechanism as stretch modulation.

Double-blind randomized controlled trial of baclofen vs. clonidine in the treatment of opiates withdrawal.

BACKGROUND: A variety of detoxification methods have been utilized for the treatment of opiate withdrawal syndrome, of which alpha-adrenergic agonists have attracted considerable attention over the last two decades. However, accumulating evidence in rats shows the efficacy of the GABAB receptor agonist, baclofen, in reducing alcohol intake and self-administration of cocaine. OBJECTIVE: To examine the ability of baclofen, in the management of opiate withdrawal. METHOD: A total of 62 opiate addicts randomly assigned to treatment with baclofen or clonidine during a 14-day, double-blind clinical trial. All patients met the DSM IV criteria for opioid dependence. Maximum daily doses were 40 mg for baclofen and 0.8 mg for clonidine given three times a day in divided doses. The severity of the opiate withdrawal syndrome was measured on days 0, 1, 2, 3, 4, 7 and 14 using the Short Opiate Withdrawal Scale (SOWS). RESULTS: Baclofen and clonidine were equally effective in treating the physical symptoms of withdrawal syndromes. However, baclofen showed a significant superiority over clonidine in the management of mental symptoms. CONCLUSION: These results suggest that baclofen might be a novel therapeutic agent for opiate withdrawal syndrome. However, a larger study to confirm our results is warranted.

Safety of repeated intravitreous injections of antibiotics and dexamethasone.

PURPOSE: To determine the retinotoxicity of repeated intravitreous injections of vancomycin, ceftazidime, and dexamethasone in rabbit eyes. METHODS: Twenty pigmented New Zealand rabbits were divided into two groups. In Group 1, the right eyes received repeated intravitreous injections with vancomycin 0.3 mg, ceftazidime 0.7 mg, and dexamethasone sodium phosphate 0.13 mg at three consecutive 48-hour intervals. Group 2 right eyes received three times higher dose of the same intravitreous drugs as used in Group 1, repeated at the same frequency. All left eyes served as control eyes. Retinotoxicity was monitored by slit-lamp biomicroscopy, indirect ophthalmoscopy, electroretinography, and light and electron microscopy. RESULTS: No evidence of retinotoxicity was found in Group 1 eyes. Photopic A-waves were significantly elevated, and 30- and 50-Hz flicker fusion amplitudes were significantly depressed in Group 2 eyes. No changes were found by clinical or histopathologic examination in the retinas of either group. CONCLUSIONS: Three repeated intravitreous injections at 48-hour intervals of a combination of vancomycin, ceftazidime, and dexamethasone in rabbit eyes at dosages that approximate drug concentrations recommended for human endophthalmitis were nontoxic. Similar injections at three times higher doses resulted in mild electroretinogram changes.

High dose intramuscular methylprednisolone in experimental Staphylococcus aureus endophthalmitis.

We attempted to determine whether treatment using intramuscular methylprednisolone plus intravitreal vancomycin decreased ocular inflammation and preserved retinal function better in experimental Staphylococcus aureus (S. aureus) endophthalmitis than treatment with intravitreal vancomycin alone. Sixteen rabbits received intravitreal inoculations in both eyes with S. aureus and the rabbits were divided into two groups (group I and group II) of eight rabbits each. Group I rabbits were treated with one injection of intravitreal vancomycin in each eye at either 24, 36, 48 or 72 hours after bacterial inoculation followed by seven consecutive days of high dose intramuscular methylprednisolone (30 mg/kg per day). Group II rabbits were treated with only one intravitreal injection of vancomycin in each eye at equivalent time intervals as in Group I. Clinical evaluations of ocular inflammation were performed by slit-lamp biomicroscopy and indirect ophthalmoscopy. Electroretinography (ERG) was performed eight days after bacterial inoculation to assess retinal function in all eyes. The combination of intramuscular methylprednisolone and intravitreal vancomycin resulted in a degree of ocular inflammation equal to eyes treated with intravitreal vancomycin alone at all treatment intervals. ERG responses were not significantly different in either group. A single intravitreal injection of vancomycin plus daily intramuscular methylprednisolone for seven days were found neither to decrease ocular inflammation nor preserve retinal function better than a single intravitreal injection of vancomycin in our experimental model of S. aureus endophthalmitis.