Controlled Trial of Azathioprine and Prednisone in Chronic Renal Disease

Patients with various forms of glomerulonephritis, but excluding those with minimal glomerular changes, were admitted to a controlled trial of a regimen which combined azathioprine in a dosage of 2·5 mg/kg/day with prednisone in a dosage of 20 mg/day (adults) or 0·5 mg/kg/day (children). Of 149 patients included, 32 of them under the age of 15, 72 were randomly allocated to the “treatment” group and 77 to the “control” group. There was no evidence of benefit from the treatment group as a whole; and the mortality was in fact higher in the treated group.     

MANDIBULAR HERPES ZOSTER—With Report on the Use of Cortisone in a Case with Geniculate Ganglion Symptoms

Herpes zoster, an acute specific viral infection, occurs more commonly than is generally supposed. It should be differentiated from other diseases involving the ear and skin; it must be considered as a possible etiologic agent in some palsies of the facial, glossopharyngeal or vagal nerves.The type of cephalic herpes zoster should be carefully differentiated; cases involving the “geniculate zone” may be other than “Ramsay Hunt''s syndrome.” This syndrome is now defined as a herpes zoster eruption of the external ear at the “geniculate zone” with involvement of the seventh or seventh and eighth nerves.The “topognostic” method is the best for determining the level at which the facial nerve has been affected.It is questioned whether there is a single outstanding therapeutic agent for this disease. Cortisone had no apparent therapeutic effect in a case reported herein.     

Modification of Plasma Corticosteroid Concentrations during and after Surgery by Epidural Blockade

The adrenocortical response to major surgery was assessed by the measurement of plasma corticosteroid concentrations in patients receiving either a general anaesthetic alone or in combination with an epidural block. The expected increase in plasma corticosteroid concentration seen in the general anaesthesia group was significantly inhibited by epidural block. The inhibition was related to the duration of the epidural block. The lack of the normal adrenocortical response to surgery was not associated with cardiovascular collapse and indeed did not seem detrimental in any way. These findings question the need for corticosteroid “cover” for the stress of surgery in patients who have been taking corticosteroid drugs.     

Irritable Bowel Syndrome Is Positively Related to Metabolic Syndrome: A Population-Based Cross-Sectional Study

Irritable bowel syndrome is a common gastrointestinal disorder that may affect dietary pattern, food digestion, and nutrient absorption. The nutrition-related factors are closely related to metabolic syndrome, implying that irritable bowel syndrome may be a potential risk factor for metabolic syndrome. However, few epidemiological studies are available which are related to this potential link. The purpose of this study is to determine whether irritable bowel syndrome is related to metabolic syndrome among middle-aged people. We designed a cross-sectional study of 1,096 subjects to evaluate the relationship between irritable bowel syndrome and metabolic syndrome and its components. Diagnosis of irritable bowel syndrome was based on the Japanese version of the Rome III Questionnaire. Metabolic syndrome was defined according to the criteria of the American Heart Association scientific statements of 2009. Dietary consumption was assessed via a validated food frequency questionnaire. Principal-components analysis was used to derive 3 major dietary patterns: “Japanese”, “sweets-fruits”, and “Izakaya (Japanese Pub) “from 39 food groups. The prevalence of irritable bowel syndrome and metabolic syndrome were 19.4% and 14.6%, respectively. No significant relationship was found between the dietary pattern factor score tertiles and irritable bowel syndrome. After adjustment for potential confounders (including dietary pattern), the odds ratio (95% confidence interval) of having metabolic syndrome and elevated triglycerides for subjects with irritable bowel syndrome as compared with non-irritable bowel syndrome are 2.01(1.13–3.55) and 1.50(1.03–2.18), respectively. Irritable bowel syndrome is significantly related to metabolic syndrome and it components. This study is the first to show that irritable bowel syndrome was significantly related to a higher prevalence of metabolic syndrome and elevated triglycerides among an adult population. The findings suggest that the treatment of irritable bowel syndrome may be a potentially beneficial factor for the prevention of metabolic syndrome. Further study is needed to clarify this association.     

A NEW CORTICOID FOR TOPICAL THERAPY—Fluocinolone Acetonide

Sixty-seven patients with chronic and subacute cutaneous lesions of varying long duration that had previously been resistant to topical use of corticosteroid compounds were treated with a cream containing fluocinolone acetonide. To avoid subjective bias, only two classifications were used in appraising results: “complete clearing of treated lesions” and “not effective.”Forty-eight patients had complete clearing of the treated area. Results were best in atopic dermatitis, chronic eczematous dermatitis and nummular dermatitis. Granuloma annulare, dyshidrotic dermatitis of the palms and psoriasis were not affected.In some cases in which there were multiple lesions some of the lesions were treated with fluocinolone acetonide cream and some were treated concurrently with other corticoid ointments or with noncorticoid compounds, either bland or with active ingredients. Fluocinolone was effective in more than twice as many cases as the other agents.In some of the patients with chronic disease it was possible to greatly reduce or discontinue systemic steroid therapy after fluocinolone acetonide became available.No untoward effects were observed.     

“Complications” of the Landry-Guillain-Barré-Strohl syndrome

Prognosis for life in the Landry-Guillain-Barré-Strohl syndrome is dependent upon the development of respiratory and non-respiratory “complications” and their successful management. Review of the literature, a case history, and a study of 14 patients with this syndrome at the University Hospital, Edmonton, indicate that “complications” can be anticipated in virtually all areas of acute care management, including respiratory, gastrointestinal, urinary tract, central and autonomic nervous systems, metabolic, cardiovascular, and infectious disease. The proper management of patients with the Landry-Guillain-Barré-Strohl syndrome demands an awareness of the totality of care required and the presence of a hospital system that provides for vital system monitoring and support, and for ready interdisciplinary consultation.     

Psychological Aspects of Headache

Headache is considered as a non-specific syndrome illustrating the concept of pain as an emotion. Viewed in this way, its meaning looms larger than its site.Pain indicates dis-ease of the patient, sometimes with his body, but more often with his life. No pain is “imaginary”, nor can some pain be assigned to physiological and some to psychological pathways. Such a decision is often merely a judgmental one.Just as the “brain” cannot easily be separated from the “mind”, so to believe that some pain is “physical” and some “emotional” is a distortion. All painful syndromes are mixed and the problem is to decipher the meaning of the pain. Only rarely will headache respond to physical measures alone.     

Nephrotic Syndrome in Adult Africans in Nairobi

The adult nephrotic syndrome as met with in Nairobi is predominantly encountered in young sophisticated African women, most of whom began to use skin-lightening creams containing mercury before the symptomatic onset of their illness. The particular form of mercury involved is well known to cause the nephrotic syndrome in other circumstances—for example, when applied to the skin in the treatment of psoriasis. In these circumstances the pathogenetic mechanism is thought to be of an idiosyncratic type. The use of mercury-containing skin-lightening creams in the patients studied seemed to be particularly associated with a “minimal-change” (“light-negative”) renal glomerular lesion, this lesion being present in half of the patients. The prognosis in this group of patients seems remarkably good, with 50% entering remission, 77% of these doing so spontaneously on discontinuing the use of the creams.     

The Antibiotic Dosage of Fastest Resistance Evolution: Gene Amplifications Underpinning the Inverted-U

To determine the dosage at which antibiotic resistance evolution is most rapid, we treated Escherichia coli in vitro, deploying the antibiotic erythromycin at dosages ranging from zero to high. Adaptation was fastest just below erythromycin’s minimal inhibitory concentration (MIC) and genotype-phenotype correlations determined from whole genome sequencing revealed the molecular basis: simultaneous selection for copy number variation in three resistance mechanisms which exhibited an “inverted-U” pattern of dose-dependence, as did several insertion sequences and an integron. Many genes did not conform to this pattern, however, reflecting changes in selection as dose increased: putative media adaptation polymorphisms at zero antibiotic dosage gave way to drug target (ribosomal RNA operon) amplification at mid dosages whereas prophage-mediated drug efflux amplifications dominated at the highest dosages. All treatments exhibited E. coli increases in the copy number of efflux operons acrAB and emrE at rates that correlated with increases in population density. For strains where the inverted-U was no longer observed following the genetic manipulation of acrAB, it could be recovered by prolonging the antibiotic treatment at subMIC dosages.     

Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (“waitlist”), placebo treatment alone (“limited”) and, placebo treatment “augmented” with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.     

Patent and Exclusivity Status of Essential Medicines for Non-Communicable Disease

Objective

The threat of non-communicable diseases (“NCDs”) is increasingly becoming a global health crisis and are pervasive in high, middle, and low-income populations resulting in an estimated 36 million deaths per year. There is a need to assess intellectual property rights (“IPRs”) that may impede generic production and availability and affordability to essential NCD medicines.

Methods

Using the data sources listed below, the study design systematically eliminated NCD drugs that had no patent/exclusivity provisions on API, dosage, or administration route. The first step identified essential medicines that treat certain high disease burden NCDs. A second step examined the patent and exclusivity status of active ingredient, dosage and listed route of administration using exclusion criteria outlined in this study.

Materials

We examined the patent and exclusivity status of medicines listed in the World Health Organization’s (“WHO”) Model List of Essential Drugs (Medicines) (“MLEM”) and other WHO sources for drugs treating certain NCDs. i.e., cardiovascular and respiratory disease, cancers, and diabetes. We utilized the USA Food and Drug Administration Orange Book and the USA Patent and Trademark Office databases as references given the predominant number of medicines registered in the USA.

Results

Of the 359 MLEM medicines identified, 22% (79/359) address targeted NCDs. Of these 79, only eight required in-depth patent or exclusivity assessment. Upon further review, no NCD MLEM medicines had study patent or exclusivity protection for reviewed criteria.

Conclusions

We find that ensuring availability and affordability of potential generic formulations of NCD MLEM medicines appears to be more complex than the presence of IPRs with API, dosage, or administration patent or exclusivity protection. Hence, more sophisticated analysis of NCD barriers to generic availability and affordability should be conducted in order to ensure equitable access to global populations for these essential medicines.     

The Desmethyl Metabolite of Imipramine (G-35020) in the Treatment of Depression: Further Clinical Experience

The desmethyl metabolite of imipramine (DMI) was used to treat 103 depressed patients, standard dosage being 50 mg. thrice daily orally. Seventy patients recovered or were much improved. The indication for DMI and its activity spectrum were of the same order as imipramine. Side effects were less frequent and less severe. Average onset of definitive improvement was three days; earliest changes noted were in facies, motility, and relief of guilt feelings. Besides the classical straightforward response, seven patients improved early but relapsed, and 12 showed a “plateau effect”. Absence of favourable response after seven days necessitated reevaluation and/or substitution of other approaches. DMI may be the drug of choice in initiating treatment of depression, but seemed insufficient alone to deal with agitated, acutely suicidal patients. Although DMI appeared an effective, fast-acting antidepressant, there is still no panacea for this ubiquitous syndrome, whose proper management calls for flexibility and awareness of its multifactorial etiology.     

Recovery of Adrenocortical Function during Long-term Treatment with Corticosteroids

The recovery of adrenocortical function during very slow withdrawal of corticosteroids was studied in a homogeneous group of patients suffering from sarcoidosis. All patients had been treated with gradually decreasing doses of prednisone for at least two years. The initial dose had been 40 mg. daily in all cases. Determination of the cortisol production rate and of plasma fluorogenic corticosteroids was done under basal conditions and after tetracosactrin stimulation. There was good correlation between cortisol production rate and plasma fluorogenic corticosteroids throughout all the tests. Cortisol production rate and plasma fluorogenic corticosteroids started to rise when the dosage of prednisone was lowered to 7·5 mg. daily and reached normal values when the dosage was reduced to 2·5 mg. The response to tetracosactrin began to increase at the same dosage level, but was not normal at 2·5 mg., or when prednisone treatment was stopped. At a dosage level of 7·5 mg. of prednisone plasma fluorogenic corticosteroids already showed a nyctohemeral rhythm.It may be calculated that even very low dosages of prednisone given during the last stage of a treatment schedule enhance total corticosteroid activity beyond the normal level, which would account for their therapeutic value.     

Identification of Two Missense Mutations of ERCC6 in Three Chinese Sisters with Cockayne Syndrome by Whole Exome Sequencing

Cockayne syndrome (CS) is a rare autosomal recessive disorder, the primary manifestations of which are poor growth and neurologic abnormality. Mutations of the ERCC6 and ERCC8 genes are the predominant cause of Cockayne syndrome, and the ERCC6 gene mutation is present in approximately 65% of cases. The present report describes a case of Cockayne syndrome in a Chinese family, with the patients carrying two missense mutations (c.1595A>G, p.Asp532Gly and c.1607T>G, p.Leu536Trp) in the ERCC6 gene in an apparently compound heterozygote status, especially, p.Asp532Gly has never been reported. The compound heterozygote mutation was found in three patients in the family using whole exome sequencing. The patients’ father and mother carried a heterozygous allele at different locations of the ERCC6 gene, which was confirmed by Sanger DNA sequencing. The two mutations are both located in the highly conserved motif I of ATP-binding helicase and are considered “Damaging,” “Probably Damaging,” “Disease Causing,” and “Conserved”, indicating the role of DNA damage in the pathogenetic process of the disease. The results not only enrich the ERCC6 mutations database, but also indicate that whole exome sequencing will be a powerful tool for discovering the disease causing mutations in clinical diagnosis.     

A Novel,Single Algorithm Approach to Predict Acenocoumarol Dose Based on CYP2C9 and VKORC1 Allele Variants

The identification of CYP2C9 and VKORC1 genes has strongly stimulated the research on pharmacogenetics of coumarins in the last decade. We assessed the combined influence of CYP2C9 *2 and *3, and VKORC1 c.-1639G>A, 497C>G, and 1173C>T variants, on acenocoumarol dosage using a novel algorithm approach, in 193 outpatients who had achieved stable anticoagulation. We constructed an “acenocoumarol-dose genotype score” (AGS, maximum score = 100) based on the number of alleles associated with higher acenocoumarol dosage carried by each subject for each polymorphism. The mean AGS was higher in the high-dose (>28mg/week) compared with the low-dose (<7mg/week) group (mean(SEM) of 84.1±3.4 vs. 62.2±4.8, P = 0.008). An AGS>70 was associated with an increased odds ratio (OR) of requiring high acenocoumarol dosage (OR: 3.347; 95%CI: 1.112–10.075; P = 0.032). In summary, although more research is necessary in other patient cohorts, and this algorithm should be replicated in an independent sample, our data suggest that the AGS algorithm could be used to help discriminating patients requiring high acenocoumarol doses to achieve stable anti-coagulation.     

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the “first hit” and an unknown “second hit.” We hypothesized that “a binge” could be a “second hit” to develop NASH from obesity-induced simple steatosis. Thirty-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were administered 10 mL of 10% ethanol orally for 5, 3, 2, and 1 d/wk for 3 consecutive weeks. As control, male Otsuka Long-Evans Tokushima (OLET) rats were administered the same amount of alcohol. Various biochemical parameters of obesity, steatosis and NASH were monitored in serum and liver specimens in untreated and ethanol-treated rats. The liver sections were evaluated for histopathological alterations of NASH and stained for cytochrome P-4502E1 (CYP2E1) and 4-hydroxy-nonenal (4-HNE). Simple steatosis, hyperinsulinemia, hyperglycemia, insulin resistance, hypertriglycemia and marked increases in hepatic CYP2E1 and 4-HNE were present in 30-wk-old untreated OLETF rats. Massive steatohepatitis with hepatocyte ballooning was observed in the livers of all OLETF rats treated with ethanol. Serum and hepatic triglyceride levels as well as tumor necrosis factor (TNF)-α mRNA were markedly increased in all ethanol-treated OLETF rats. Staining for CYP2E1 and 4-NHE demonstrated marked increases in the hepatic tissue of all the groups of OLETF rats treated with ethanol compared with OLET rats. Our data demonstrated that “a binge” serves as a “second hit” for development of NASH from obesity-induced simple steatosis through aggravation of oxidative stress. The enhanced levels of CYP2E1 and increased oxidative stress in obesity play a significant role in this process.     

Chloe’s Law: A Powerful Legislative Movement Challenging a Core Ethical Norm of Genetic Testing

Since the early 1970s, the ethical norm governing counselors involved in testing and screening for genetic conditions related to reproduction has been strict neutrality. Counseling about reproductive genetics was to be patient centered but nondirective. Many advocates for people with Down syndrome believe that high abortion rates following a diagnosis of this condition show an unfounded bias against those with Down syndrome. These advocates have succeeded in enacting federal and state legislation that requires women who receive a prenatal diagnosis of Down syndrome to receive positive information about the condition, thereby ending the nominal goal of value-neutral counseling and setting the stage for further normative shifts in clinical reproductive genetics as counseling expands because of cell-free testing.

This Perspective is part of the “Where Next?” Series.

     

Pseudohypertension secondary to a noncompressible brachial artery

The interesting problem is considered of a comatose alcoholic diabetic with an extremely high systolic blood pressure, as determined by the usual means, who was subsequently found to have severe medial calcinosis and normal intraarterial blood pressure. The syndrome of the noncompressible brachial artery surely accounts for this patient''s falsely elevated blood pressure reading. Though infrequently reported, this condition can be one cause of “difficult to control” hypertension in the elderly and in the diabetic patient.     

Meralgia paresthetica as a cause of leg discomfort

A series of 74 cases of meralgia paresthetica is presented. All patients were satisfactorily treated with nonsurgical modalities. A brief review of the etiological factors involved supports the impression that it is an entrapment syndrome related primarily to external pressure against the lateral femoral cutaneous nerve in the region of the anterior superior iliac spine. Though its peripheral symptomatology is relatively straightforward, often associated pain referred to the gluteal area results in an incorrect diagnosis of sciatic radiculopathy due to “disc disease”. The correct diagnosis can be easily made from the relief obtained by injecting the lateral femoral cutaneous nerve with an anesthetic agent.     

The Dynamic Treatment of the Low Back Strain Syndrome

The modalities at present in use for the treatment of soft-tissue injuries responsible for the low back strain syndrome are predominantly passive, yet similar soft-tissue injuries elsewhere in the body receive and respond to an early program of active movement. To assess the feasibility of such an approach to the low back strain syndrome, a program of therapeutic exercises with and without the addition of heat and massage was employed for the treatment of this condition. Exercises alone were found to be as effective as a program of “heat, massage and exercises” in resolving the presenting complaints. At the same time this dynamic approach served to reduce the undesirable effects, both local and general, of the enforced inactivity of the patient.