Sudden infant death syndrome: how significant are the cardiac channelopathies?

Having an apparently healthy, thriving infant fail to reach his/her first birthday is profoundly tragic. This tragedy is compounded when the infant's death is unexpected and unexplained, signed out as sudden infant death syndrome (SIDS). Despite impressive success and welcome reductions in these tragic deaths due in large measure to "Back-to-Sleep" campaigns, the fundamental pathogenic mechanisms precipitating such deaths remain dimly exposed. Here, we review the causal link between SIDS and mutations involving the SCN5A-encoded cardiac sodium channel, provide new findings following extensive postmortem genetic testing of long QT syndrome (LQTS)-associated potassium channel genes in a population-based cohort of SIDS, and summarize the current understanding regarding the spectrum and prevalence of cardiac channelopathies in the pathogenesis of SIDS.     

Propofol withdrawal syndrome in an adult patient with thermal injury

A 48-year-old man with a history of ethanol abuse and bipolar disease fell asleep while smoking in an intoxicated state. The patient received a 30% total body surface area burn involving his face and upper torso that resulted in an inhalation injury. Several attempts at weaning from mechanical ventilation failed due to his extreme agitation, which was unresponsive to benzodiazepines, opiates, and antipsychotic agents. Propofol therapy was begun in combination with valproic acid, fluoxetine, and risperidone to assist in the treatment of his severe agitation associated with the bipolar disease, inhibiting ventilatory weaning. Repeated attempts to discontinue propofol were associated with withdrawal symptoms such as severe agitation, tremors, tachycardia, tachypnea, and hyperpyrexia. His symptoms resolved only after each time the propofol infusion was restarted. The patient received propofol for 95 days for management of his agitation before dying from refractory septic shock and multiple organ failure.     

Optimal management for surgically Stage 1 serous cancer of the uterus

OBJECTIVE: To describe the outcomes of patients who have undergone well-conducted surgery and found to have Stage 1 serous uterine cancer. METHODS: This retrospective cohort study includes women who have been treated for Stage 1 serous cancer of the uterus from 1985 to 2001. Cases were included from the regional cancer centers in Hamilton, London, Sunnybrook Toronto and Cancer Care Manitoba. RESULTS: Forty-three women met the inclusion criteria: Complete surgical staging (n = 27), surgery followed by pelvic radiation therapy (n = 4), surgery followed by whole abdominal radiation therapy (n = 6), surgery followed by adjuvant chemotherapy (n = 6). Patient age or depth of invasion did not influence survival. Progression free interval was 22 months (SD = 14.29). Recurrence rate was highest for adjuvant chemotherapy (66%). Survival was assessed by treatment modality and a statistically significant poorer survival was seen in the adjuvant chemotherapy group (OR 17.5; 95% CI 1.3-227.6). No comment can be made on a superior treatment regimen given the small numbers in each treatment strata. CONCLUSION: This study supports the findings of others in the literature. In a group of patients where surgical staging shows limited disease (i.e., surgically Stage 1 disease), then surgery alone appears to be adequate treatment.     

Alopecia mucinosa is mycosis fungoides

Confusion abounds regarding the terms "follicular mucinosis" and "alopecia mucinosa," not only concerning definition and essential character, but of relationships between themselves on one hand and between themselves and mycosis fungoides on the other. We address here those issues in methodical fashion, first in historical perspective by review, scrupulously and critically, of what has been said in the many articles devoted to the subject; we next tell how the terms "alopecia mucinosa" and "follicular mucinosis" came to be and how they are employed currently; we then set forth our own observations pertinent to clinical, histopathologic, and biologic aspects of the condition called, conventionally, "alopecia mucinosa," those observations based on our own findings in sections of tissue cut from 54 biopsy specimens taken from 45 patients, all of them having been signed out previously as "follicular mucinosis;" we proceed to forge clinico-pathologic correlation of lesions in 14 of those 45 patients, utilizing assessments, by examination grossly and microscopically, of attributes in the very same lesion. Last, we propose a concept, and a terminology that derives from it, that synthesizes all that is known now about "alopecia mucinosa" and "follicular mucinosis," in particular the relationship of "alopecia mucinosa" to mycosis fungoides, including "follicular," "syringotropic," and erythrodermic manifestations of it. In short, we affirm that so-called alopecia mucinosa is but one of many morphologic manifestations of mycosis fungoides.     

Intragenic suppression of trafficking-defective KCNH2 channels associated with long QT syndrome

Mutations in the KCNH2 or human ether-a-go-go-related gene-encoded K(+) channel reduce functional KCNH2 current (I(KCNH2)) to cause long QT syndrome (LQT2) by multiple mechanisms, including defects in intracellular transport (trafficking). Trafficking-deficient, or class 2, LQT2 mutations reduce the Golgi processing and surface membrane expression of KCNH2 channel proteins. Drugs that associate with pore-S6 intracellular drug binding domain of KCNH2 channel proteins to cause high-affinity block of I(KCNH2) also can increase the processing of class 2 LQT2 channel proteins through the secretory pathway. We used a strategy of intragenic suppression to test the hypothesis that amino acid substitutions in the putative drug binding domain at residue Y652 could compensate for protein folding abnormalities caused by class 2 LQT2 mutations. We found that the Y652C substitution, and to lesser extent the Y652S substitution, resulted in intragenic suppression of the class 2 LQT2 G601S phenotype; these substitutions increased Golgi processing of G601S channel proteins. The Y652C substitution also caused intragenic suppression of the class 2 LQT2 V612L and F640V phenotypes but not the LQT2 N470D or F805C phenotypes. These are the first findings to demonstrate that a single amino acid substitution in the putative KCNH2 drug binding domain can cause intragenic suppression of several LQT2 mutations.     

Staging of melanoma: a critique in historical perspective: part I

During the last half of the 20th century until the present day, general pathologists have been obsessed by staging melanoma. That the method employed for achieving that desideratum, which had as its animating force a longing to determine prognosis for an individual patient with that malignant neoplasm, failed miserably can be inferred from the fact that successive efforts every few years by teams of supposed authorities, such as those of the American Joint Committee on Cancer (AJCC), resulted in a new system for staging that bore little resemblance to the one immediately before it or the one that was to come after it. In short, the various attempts to stage melanoma were nothing more than witchcraft and sorcery in which pathologists sought to be diviners, seers, and prophets about prognosis, rather than the diagnosticians that they were trained to be and should be. The job of a pathologist is to render an accurate diagnosis (which, in itself, has implications prognostic for a patient, eg, "benign" or "malignant"), not to speculate about prognosis. To guess about how a patient with melanoma will fare, the system for staging being nothing other than pure conjecture, not only is unscientific, it is unethical.