THE PRESENT STATUS OF THE GERM-CELL PROBLEM IN VERTEBRATES

(i) Morphological studies relating to the origin and differentiation of the definitive germ cells in vertebrates have, as indicated, resulted in conflicting views. In many instances two or more competent investigators who have studied the same form have reached different conclusions. (2) Some contend that the germ cells are set aside from the soma during the early stages of embryonic development, and that these alone serve as the progenitors of the functional sex cells. (3) Others recognize an early differentiation of sex cells but hold that these are supplemented by others produced from the somatic epithelium of the gonad in late embryonic or post-embryonic stages. (4) Another group recognizes the early differentiated cells as germ cells but contend that these all degenerate and that the definitive ones are formed from the germinal epithelium. These degenerating germ cells are believed by certain authors to be a phylogenetic recapitulation of the condition in lower forms. (5) Finally, yet another group contends that the so-called primordial germ cells are not germ cells at all but are enlarged cells in some stage of mitosis or in some specific metabolic phase. This group believes that all germ cells are derived from the somatic cells of the germinal epithelium. (6) Experimental work supports the view that the primordial germ cells, which are recognized early, are the progenitors of the definitive sex cells. When these primordial germ cells are prevented from reaching the site of the developing gonad the individual fails to develop sex cells, although a sterile gonad and its associated structures may develop. (7) I suggest that the observed proliferation of germ cells from the germinal epithelium, reported by numerous investigators, can be interpreted in another way by a thorough study of the enlarged germ cells in relation to the epithelium. It seems probable that the cells of the epithelium, which form functional sex elements, are not and never were a part of the mesothelial covering, but are cells which were segregated early, and are merely stored in the epithelium.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74677/1/j.1469-185X.1945.tb00313.x.pd

Neonatal presentation of ventricular tachycardia and a Reye-like syndrome episode associated with disturbed mitochondrial energy metabolism

BACKGROUND: Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period. CASE PRESENTATION: We describe an atypical presentation of mitochondrial cytopathy in a 2 day-old neonate. She presented with a Reye-like syndrome episode, premature ventricular contractions and ventricular tachycardia. Initial laboratory evaluation exhibited a large amount of 3-methylglutaconic acid on urine organic acid analysis, mild orotic aciduria and a nonspecific abnormal acylcarnitine profile. The evaluation for carnitine-acylcarnitine translocase deficiency and other fatty acid oxidation disorders was negative. The patient later developed a hypertrophic cardiomyopathy and continued to be affected by recurrent Reye-like syndrome episodes triggered by infections. A muscle biopsy exhibited signs of a mitochondrial cytopathy. During the course of her disease, her Reye-like syndrome episodes have subsided; however, cardiomyopathy has persisted along with fatigue and exercise intolerance. CONCLUSIONS: This case illustrates that, in the neonatal period, hyperammonemia and ventricular tachycardia may be the presenting features of a lethal carnitine-acylcarnitine translocase deficiency or of a mitochondrial cytopathy, associated with a milder clinical course. This association broadens the spectrum of presenting phenotypes observed in patients with disturbed mitochondrial energy metabolism. Also, the presence of 3-methylglutaconic aciduria suggests mitochondrial dysfunction and mild orotic aciduria could potentially be used as a marker of mitochondrial disease

Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer

BACKGROUND The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

BACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy

Prospective Validation of a 21-Gene Expression Assay in Breast Cancer

Prior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker

Anomalous inferior Vena cava as the cause of multiple deep venous thrombosis.

An anomalous Inferior Vena Cava (IVC) is a possible independent risk factor for deep vein thrombosis (DVT). This case represents the rare complication of an anomalous IVC causing multiple DVTs, not only in the lower extremity, but also in the abdominal periaortic circulation. In young patients who develop a DVT without risk factors, an anomalous IVC should be in the differential diagnosis

Stretch reflexes of triceps surae in patients with upper motor neuron syndromes

Electromyographic responses of triceps surae to dorsiflexion stretch were studied in 47 patients with a variety of lesions producing an upper motor neuron syndrome. The short latency spinal reflexes, both when patient was at rest and when he was exerting a voluntary plantarflexion, were frequently enhanced in magnitude and the rate of increase with acceleration was also enhanced. Long-latency reflexes were uncommon at rest. With background force long-latency reflexes were present unless the short latency reflex was very large. Long latency reflexes often were normal, but in some patients they were either excessively large or even of abnormal shape with prolonged continuous activity. The clinical assessment of the ankle jerk correlated with the magnitude of the short latency reflex. The clinical assessment of tone correlated with the magnitude of the short latency reflex, the magnitude of the long latency reflex and the duration of the long latency reflex. There appear to be multiple physiological mechanisms underlying the clinical phenomenon of spasticity

Stretch reflexes of triceps surae in patients with upper motor neuron syndromes.

Electromyographic responses of triceps surae to dorsiflexion stretch were studied in 47 patients with a variety of lesions producing an upper motor neuron syndrome. The short latency spinal reflexes, both when the patient was at rest and when he was exerting a voluntary plantarflexion, were frequently enhanced in magnitude and the rate of increase with acceleration was also enhanced. Long-latency reflexes were uncommon at rest. With background force long-latency reflexes were present unless the short latency reflex was very large. Long latency reflexes often were normal, but in some patients they were either excessively larger or even of abnormal shape with prolonged continuous activity. The clinical assessment of the ankle jerk correlated with the magnitude of the short latency reflex. The clinical assessment of tone correlated with the magnitude of the short latency reflex, the magnitude of the long latency reflex and the duration of the long latency reflex. There appear to be multiple physiological mechanisms underlying the clinical phenomenon of spasticity