Xeroderma Pigmentosum C: A Valuable Tool to Decipher the Signaling Pathways in Skin Cancers.

Xeroderma pigmentosum (XP) is a rare autosomal genodermatosis that manifests clinically with pronounced sensitivity to ultraviolet (UV) radiation and the high probability of the occurrence of different skin cancer types in XP patients. XP is mainly caused by mutations in XP-genes that are involved in the nucleotide excision repair (NER) pathway that functions in the removal of bulky DNA adducts. Besides, the aggregation of DNA lesions is a life-threatening event that might be a key for developing various mutations facilitating cancer appearance. One of the key players of NER is XPC that senses helical distortions found in damaged DNA. The majority of XPC gene mutations are nonsense, and some are missense leading either to the loss of XPC protein or to the expression of a truncated nonfunctional version. Given that no cure is yet available, XPC patients should be completely protected and isolated from all types of UV radiations (UVR). Although it is still poorly understood, the characterization of the proteomic signature of an XPC mutant is essential to identify mediators that could be targeted to prevent cancer development in XPC patients. Unraveling this proteomic signature is fundamental to decipher the signaling pathways affected by the loss of XPC expression following exposure to UVB radiation. In this review, we will focus on the signaling pathways disrupted in skin cancer, pathways modulating NER's function, including XPC, to disclose signaling pathways associated with XPC loss and skin cancer occurrence.

Diabetes supersedes dobutamine stress echocardiography in predicting cardiac events in female patients.

BACKGROUND: The many available choices for testing for coronary artery disease (CAD) brought about several questions regarding suitability of certain tests for different groups of patients and the prognostic value of obtained results in predicting events and mortality. The aim of this study is to describe the prognostic value of dobutamine stress echocardiography (DSE) results in predicting cardiac events and mortality in > or = 60-year-old females. METHODS: 49 women (> or = 60 years old) who were referred for DSE were included in the study. Data including CAD risk factors, and results of tests and a follow-up of events (MI, unstable angina, progression of CHF) and death. RESULTS: Eleven patients were considered to have a positive DSE result. There was no difference between DSE (+) and DSE (-) patients in cardiac events and cardiac death. However when interventions were included to events, analysis showed DSE (+) to have more overall events. Non-cardiac deaths and "all deaths" were 11 and 8 times more common among DSE (+) patients compared with DSE (-) patients p < 0.01. Multivariable logistic regression showed that diabetics and DSE (+) patients were 32 (p = 0.01) and 23 (p = 0.02) times more likely to have an event compared with non-diabetics and DSE (-) patients, respectively. CONCLUSION: DSE is a safe procedure to be used in > or = 60-year-old female patients and can provide informative prognostic information regarding all-cause deaths and cardiac events (including interventions) over a 4-year period. In addition we find that diabetes is a strong predictor of events regardless of DSE result.

In vivo distinction between a target cell for Friend virus (FVP) and murine hematopoietic stem cells.

Busulphan (BU) treatment of DBA/2 mice with hypertransfusion (HT)-induced polycythemia resulted in an ablation of detectable hematopoietic stem cells (CFUS) in pooled marrow from the long bones. Daily injections of erythropoietin (EP) stimulated an EP-responsive population of cells in the absence of detectable CFUS. Mice treated with BU and EP and having HT-induced polycythemia were inoculated with the polycythemia-inducing strain of Friend virus (FVP) and determinations were made for the presence of tumor colony-forming units (tCFU). No change in CFUS/10(6) bone marrow cells was detected as a result of EP treatment. However, tCFU were increased more than 100-fold in HT-BU-EP-treated mice compared with saline-treated controls. The demonstration of tCFU in mice in which CFUS were not detectable indicated that this leukemogenic effect of FVP could occur in the absence of the pluripotent stem cell. Furthermore, the increased numbers of this FVP target cell in the EP-stimulated, BU-treated mice with HT-induced polycythemia supported the model licating the target for this effect in the EP-responsive cell population.

Erythropoietin responsiveness in vivo of Friend virus target cells for transformation and virus replication.

Techniques that allow the selective stimulation of the erythropoietin-responsive cell population in mice with suppressed multipotential hemopoietic stem cells were used to identify (1) the in vivo target cell transformed by Friend virus (FV) into a tumor colony-forming unit and (2) a target cell for FV replication in vivo. Plethoric mice with busulphan-induced reductions in stem cell populations (characterized as colony-forming units) and stimulated erythropoietin-responsive cell compartments were given FV; control groups, not receiving erythropoietin, also received FV. A comparison of the number of target cells transformed in each group provided evidence identifying the ERC as the in vivo compartment in which the target cell detected by tumor colony formation resides. Differences in plasma virus titers revealed that the erythropoietin-responsive cell is also predominantly responsible for the production of FV as measured by focus-forming activity.

Decreased natural killer cell activity in children with untreated acute leukemia.

Natural killer cell activity was evaluated in children with acute lymphocytic and acute myelogenous leukemia. Peripheral blood mononuclear cells isolated at the time of diagnosis and before initiation of therapy were mixed with 51Cr-labeled K562 or MOLT-4 target cells at a ratio of 100:1. In 13 consecutive cases of acute lymphocytic leukemia, the mean percentage of lysis of K562 cells (15.0%) was significantly below that of adult (49.8%) and age-related controls (35.9%). A similar pattern was observed against MOLT-4 targets (acute lymphocytic leukemia, 11.3%; adults, 39.8%; and pediatric controls, 28.4%). The mean activity in 8 cases of acute myelogenous leukemia was also markedly reduced (6.8% versus K562 and 6.0% versus MOLT-4). Linear regression analyses of white blood cell, lymphocyte, and leukemia blast counts failed to demonstrate any correlation between peripheral cell counts and natural killer cell activity. Thus, it would not appear that the observed decrease in lysis was due merely to dilution of effectors with blasts. The lytic activity of cells isolated from patient blood was significantly lower than that from cells isolated from an equal volume of blood from a normal adult. These results suggest that the decreased natural killer cell activity is not explained by simple dilution. Instead, they indicate an absolute decrease in lytic potential. Additional experiments have precluded suppressor cell involvement and competitive inhibition of blasts with target cells as possible causes for depressed lysis.

Comparative effects of different strains of Corynebacterium parvum on natural cell-mediated cytotoxicity.

Because there are conflicting reports regarding the effects of Corynebacterium parvum (CP) on natural killer (NK) cell activity, several different strains of CP were compared. In replicate experiments, age- and sex-matched mice received 0.25-mg i.p. injections of one of four types of CP; formalin-killed strain 6134; heat-killed strain 6134; formalin-killed strain 5888 (actually Corynebacterium granulosum); or formalin-killed CP from the Pasteur Institute. At various days thereafter, two to three mice from each group were sacrificed to determine spleen weight, cellularity, and NK cell activity versus YAC-1 lymphoma cells. The CP from the Pasteur Institute augmented NK cell activity 3 days following injections; however, the activity returned to normal by Day 7 and remained at that level. On the other hand, strain 5888 did not cause as great an increase in lytic activity as did the Pasteur Institute CP at Day 3; but by Day 10 after injection, NK cell levels were above control, and they remained elevated through Day 21. Both the heat-killed and formalin-killed preparations of strain 6134 stimulated NK cell activity initially but resulted in a loss of activity at the later times tested. Experiments done with different doses and routes of injection yielded similar results. Thus, we were able to demonstrate that different types of CP have different effects on NK cell activity in mice and that the general kinetics of these effects were independent of dose or route of administration.

Suicide in subtypes of major affective disorder. A comparison with general population suicide mortality.

We investigated the risk of suicide among 705 patients with primary unipolar depression, 302 patients with secondary unipolar depression, and 586 patients with bipolar affective disorder (BAD). The suicide rates among the study subjects were compared with that of the general population of Iowa, the area from which the subjects were selected. An increased risk of suicide was found in all psychiatric groups, except the group of female patients with BAD, which was associated with a lower risk of suicide than unipolar disorders. Thirty suicides (73.2%) occurred during the first two years of follow-up; this trend was particularly pronounced in female patients with primary unipolar depression and male patients with BAD.

The prediction of suicide. Sensitivity, specificity, and predictive value of a multivariate model applied to suicide among 1906 patients with affective disorders.

Stepwise multiple logistic regression was utilized in an attempt to develop a statistical model that would predict suicide in a group of 1906 Iowans with affective disorders admitted to a tertiary care hospital. The risk factors identified by this approach included the number of prior suicide attempts, suicidal ideation on admission, bipolar affective disorder (manic or mixed type), gender, outcome at discharge, and unipolar depressive disorder in individuals with a family history of mania. However, the model failed to identify any of the patients who committed suicide. The results appear to support the contention that, based on present knowledge, it is not possible to predict suicide, even among a high-risk group of inpatients.

Complicated mania. Comorbidity and immediate outcome in the treatment of mania.

In a case-control study, 57 manics with antecedent or coexisting nonaffective psychiatric disorders (n = 38) or serious medical illnesses (n = 19) ("complicated mania") were compared with 114 age-, sex-, and year-of-admission-matched controls with no other disorder ("uncomplicated mania"). Significant differences emerged between the three groups in age, marital status, age at onset, number of prior hospitalizations and prior suicide attempts, organic features, and outcome measures (recovery and death rates). Patients were divided into four treatment groups based on primary mode of therapy during index admission; the groups included electroconvulsive therapy, adequate lithium carbonate, inadequate lithium carbonate, and neither treatment. Uncomplicated manics were significantly more likely to receive adequate lithium carbonate and less likely to receive inadequate lithium carbonate than were complicated manics. The latter patients had a significantly poorer immediate response to treatment overall, and to adequate lithium carbonate specifically. Seventy-eight (68.4%) uncomplicated manics had recovered ad discharge, compared with 26 (45.6%) complicated manics. Logistic regression suggested that the influence of comorbidity on outcome was more important for women than men. We conclude that complicated mania is a useful clinical construct.

Augmentation of natural killer cell activity in spleens of infant, aged, and low responder strain mice by Corynebacterium parvum.

Murine natural killer (NK) cell activity is both age- and strain-dependent. NK activity does not appear in murine spleen cells until three weeks after birth. Activity peaks at approximately 10 weeks, decreasing thereafter with mice over one year old showing significantly reduced levels. Mice showing low or no NK activity because of age (aged and infant mice, respectively) can be stimulated to show significant levels of NK lysis by i.p. injection of formalin killed Corynebacterium parvum (CP). In addition, CP treatment is also capable of increasing NK activity in mice from the normally low responding AKR strain. The NK activity induced or stimulated by CP appears to be like normal NK reactivity in that it is not decreased by removal of T-cells or adherent cells. Thus, in addition to increasing NK activity in normally responsive mice, CP is capable of augmenting NK activity in mice which normally show low or no levels of NK lysis.

DST nonsuppressor status: relationship to specific aspects of the depressive syndrome.

Using a conservative definition of suppressor status in hospitalized depressives, we found a relationship between abnormal endocrine function and certain kinds of depressive symptoms, i.e., melancholic symptoms, delusions, and memory deficit. Normal suppressor status is related to an early age of onset, absence of delusions, absence of memory deficit, absence of melancholia symptoms, and a presence of a diagnosis of secondary depression or a family history of alcoholism in depressives. The data suggest the distinction between neurotic-reactive depression and endogenous depression. It is equally important to note that these specific symptoms and characteristics possibly are associated with suppressor status independently of each other.

Predictors of immediate response in the treatment of mania: the importance of comorbidity.

Four hundred thirty-eight bipolar manics were admitted to an acute care psychiatric inpatient ward over a 12-year period. Eighty percent had good and 20% poor immediate outcome. Good outcome patients were characterized by short episode duration, older age of onset, a longer hospitalization, fewer suicide thoughts, and less psychiatric and medical comorbidity than the poor outcome group. Patients were divided into four treatment groups based on primary mode of therapy during index hospitalization: electroconvulsive therapy (ECT), adequate lithium, inadequate lithium, and neither treatment. Patients experiencing good outcome were more likely to be in the adequate lithium group and less likely to receive neither treatment. Regression analysis identified the absence of comorbidity, duration of lithium treatment more than 2 weeks, and duration of episode of less than 1 month as predictors of good outcome at hospital discharge.

Depressions secondary to other psychiatric disorders and medical illnesses.

The authors studied 401 patients with depressions secondary to psychiatric illnesses (substance abuse disorders or somatoform, anxiety, or personality disorders) or depressions secondary to medical illnesses. They found that the patients with depressions secondary to psychiatric illnesses had an earlier age at onset, were more likely to have suicidal thoughts or to have made suicide attempts, were less likely to have memory problems, were less improved with treatment and more likely to relapse on follow-up, and had more alcoholism in their families than patients with depressions secondary to medical illnesses. Depressions secondary to medical illnesses seem to fit the category of reactive depression, and depressions secondary to psychiatric illnesses fit the definition of neurotic depression.

Effect of psychosis on suicide risk in 1,593 patients with unipolar and bipolar affective disorders.

The authors report suicide risk among 1,593 patients with major depression or bipolar disorder, 443 (27.8%) of whom were psychotic (260 bipolar and 183 unipolar). The subjects were followed for 0-14 years, and their suicide experience was compared with that of the state population. Eight (19.5%) of the 41 suicide victims were from the psychotic group. The psychotic and nonpsychotic subjects in each diagnostic group had similar risks for suicide. A higher risk for suicide was not found in the bipolar subjects. The authors conclude that among patients with major affective disorder psychosis per se does not predispose to suicide.

Congenital and surgical atrioventricular block within the His bundle.

In three patients with congenital heart disease the site of atrioventricular (A-V) block was localized within the His bundle with the aid of His bundle electrograms. In one patient with first degree A-V block and normal QRS configuration, electrophysiologic studies revealed "split" His potentials. The other two patients had complete A-V block, and their His bundle electrograms revealed His spikes both proximal and distal to the site of block. One of the two patients, who had a pattern of left bundle branch block in the electrocardiogram, had surgically induced complete A-V block after repair of an ostium primum atrial septal defect. The other patient with congenital A-V block had a narrow QRS complex and, in addition to complete block within the His bundle, prolonged A-V nodal conduction time but no associated cardiac anomaly. Both patients with complete heart block required pacemaker insertion. The natural history of intra-H-is bundle block is not known, and it is difficult to recommend appropriate therapy. More electrophysiologic studies are needed in patients with A-V block to determine the prognostic significance of such block or conduction delay in the His bundle.

Concealed his bundle extrasystoles in congenital heart disease.

His bundle electrograms were recorded in two children with cardiac conduction disturbances. In the surface electrocardiograms of one patient His bundle extrasystoles mimicked atrial nonconducted bigeminal rhythms; in the other, they simulated second degree atrioventricular (A-V) block and conducted junctional extrasystoles. In both instances the conduction disturbance was a result of concealed conduction of the His bundle extrasystole into the A-V junction. We conclude that the surface electrocardiogram is suggestive but not definitive in diagnosing His bundle extrasystoles and that His bundle recordings are indispensable for correct diagnosis and treatment.

Surgical experience in patients with Marfan's syndrome, ascending aortic aneurysm and aortic regurgitation.

Surgical treatment of cardiovascular complications in patients with Marfan's syndrome is usually recommended with apprehension since the systemic nature of the disease predisposes to early and late complications. To define the incidence of these complications, 30 patients were evaluated after surgical treatment of aortic insufficiency and ascending aortic aneurysm at the Texas Heart Institute. To provide a minimal follow-up period of 5 years, only patients operated upon during of before 1968 were included in this series. There were 9 female and 21 male patients aged 4 to 80 years (mean 44 years). Aortic insufficiency was treated by valvuloplasty in 3 patients and by aortic valve replacement in 27. Graft replacement of the ascending aorta was required in 23 patients, and the aneurysm was excised and the aorta repaired by direct anastomosis in 7. Two patients were lost to follow-up study; 12 of the remaining 28 (42.8 percent) lived 5 years or more. The hospital mortality rate was 20 percent (6 of 30); the causes of death included dissection or rupture of the aorta in three patients, congestive heart failure in two and pulmonary embolism in one. The 24 survivors lived from 5 weeks to 9 years. Follow-up data were available on 22 of these patients. Ten of these (45.4 percent) died of late complications. Seven died suddenly, four of these had redissection, one patient had occlusion of the right coronary artery, and two had ventricular fibrillation of no apparent cause. The remaining three died of noncardiac causes. Although the risk of ascending aortic and aortic valve surgery in patients with Marfan's syndrome is high, 42.8 percent of the patients in our series survived 5 years or more. We believe that surgery should be recommended for patients with Marfan's disease who have dissection of the aorta or severe aortic regurgitation, or both.

Unilateral pulmonary vein atresia: Diagnosis and treatment.

The clinical, hemodynamic, angiographic and pathologic features of unilateral pulmonary vein atresia in a 16 month old boy are described. The relevant findings were symptoms and signs of influenza, roentgenographic evidence of unilateral diffuse interstitial edema, prominent interlobar fissures and pleural effusion, absence of abnormal cardiac structure and prominent unilateral bronchial circulation. Angiocardiography was necessary for a definitive diagnosis and revealed the lack of a site of entry for venous blood from the right lung into the circulation. The patient was treated successfully by a right pneumonectomy. The histologic hallmark in this case was extensive intimal fibrosis of the pulmonary veins.

Treatment of mania: a naturalistic study of electroconvulsive therapy versus lithium in 438 patients.

The efficacy of electroconvulsive therapy (ECT), adequate lithium therapy, inadequate lithium therapy, and neither ECT nor lithium therapy was compared by reviewing the charts of 438 patients hospitalized because of mania over a 12-year period. A significantly (p less than .05) greater percentage (78%) of patients who received ECT had "marked improvement" than did those who received either adequate or inadequate lithium treatment (62% and 56%, respectively) or neither treatment (37%). Of the patients with schizoaffective disorder, manic type, 87.5% who received ECT showed "marked improvement"; almost 70% of patients who failed to respond to adequate lithium had "marked improvement" with ECT. Unilateral and bilateral ECTs were equally effective. Psychosis was not useful in predicting treatment response. ECT was demonstrated to be an effective treatment for mania.

Treatment and outcome in secondary depression: a naturalistic study of 1087 patients.

In a naturalistic study, the treatment response and outcome of 1087 patients with nonbipolar primary (N = 763) and secondary (N = 324) depression were compared by a chart review. The patients were divided into four treatment groups, based on the primary mode of therapy received during the index hospitalization: ECT, adequate antidepressant, inadequate antidepressant, and neither treatment. Primary depressives were more likely to have received ECT, and secondary depressives were more likely to have received inadequate antidepressant or neither treatment. A total of 436 (57.1%) primary depressives received adequate therapy, but only 113 (34.9%) secondary depressives did (p less than .001). Overall, primary depressives responded better to treatment (both ECT and antidepressants) than did secondary depressives. A total of 470 (61.6%) primary depressives but only 140 (43.2%) secondary depressives were recovered at discharge (p less than .001). The conclusion is that secondary depressives are more likely to receive inadequate treatment and are less likely to respond to adequate treatment than are primary depressives.